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CA 02542835 2006-04-13
WO 2005/044981 PCT/US2004/027403
RNA INTERFERENCE MEDIATED INHIBITION OF GENE EXPRESSION
USING SHORT INTERFERING NUCLEIC ACID (siNA)
This application is a continuation-in-part of International Patent Application
No.
PCT/US04/16390, filed May 24, 2004, which is a continuation-in-part of U.S.
Patent
Application No. 10/826,966, filed April 16, 2004, which is continuation-in-
part of U.S.
Patent Application No. 10/757,803, filed January 14, 2004, which is a
continuation-in-
part of U.S. Patent Application No. 10/720,448, filed November 24, 2003, which
is a
continuation-in-part of U.S. Patent Application No. 10/693,059, filed October
23, 2003,
which is a continuation-in-part of U.S. Patent Application No. 10/444,853,
filed May 23,
2003, which is a continuation-in-part of International Patent Application No.
PCT/US03/05346, filed February 20, 2003, and a continuation-in-part of
International
Patent Application No. PCT/US03/05028, filed February 20, 2003, both of which
claim
the benefit of U.S. Provisional Application No. 60/358,580 filed February 20,
2002, U.S.
Provisional Application No. 60/363,124 filed March 11, 2002, U.S. Provisional
Application No. 601386,782 filed June 6, 2002, U.S. Provisional Application
No.
60/406,784 filed August 29, 2002, U.S. Provisional Application No. 60/408,378
'filed
September 5, 2002, U.S. Provisional Application No. 601409,293 filed September
9,
2002, and U.S. Provisional Application No. 60/440,129 filed January 15, 2003.
This
application is also a continuation-in-part of International Patent Application
No.
PCT/US04/13456, filed April 30, 2004, which is a continuation-in-part of U.S.
Patent
Application No. 10/780,447, filed February 13, 2004, which is a continuation-
in-part of
U.S. Patent Application No. 10/427,160, filed April 30, 2003, which is a
continuation-in-
part of International Patent Application No. PCT/US02/15876 filed May 17,
2002, which
claims the benefit of U.S. Provisional Application No. 60/292,217, filed May
18, 2001,
U.S. Provisional Application No. 60/362,016, filed March 6, 2002, U.S.
Provisional
Application No. 60/306,883, filed July 20, 2001, and U.S. Provisional
Application No.
60/311,865, filed August 13, 2001. This application is also a continuation-in-
part of U.S.
Patent Application No. 10/727,780 filed December 3, 2003. This application
also claims
the benefit of U.S. Provisional Application No. 60/543,480, filed February 10,
2004.
The instant application claims the benefit of all the listed applications,
which are hereby
incorporated by reference herein in their entireties, including the drawings.
CA 02542835 2006-04-13
WO 2005/044981 PCT/US2004/027403
Field Of The Invention
The present invention relates to compounds, compositions, and methods for the
study, diagnosis, and treatment of traits, diseases and conditions that
respond to the
modulation of tartget gene expression and/or activity. The present invention
is also
S directed to compounds, compositions, and methods relating to traits,
diseases and
conditions that respond to the modulation of expression and/or activity of
genes involved
in gene expression pathways or other cellular processes that mediate the
maintenance or
development of such traits, diseases and conditions. Specifically, the
invention relates to
small nucleic acid molecules, such as short interfering nucleic acid (siNA),
short
interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), and
short hairpin RNA (shRNA) molecules capable of mediating RNA interference
(RNAi)
against target gene expression. Such small nucleic acid molecules are usefixl,
for
example, in providing compositions for treatment of traits, diseases and
conditions that
can respond to modulation of gene expression in a subject or organism.
Background Of The Invention
The following is a discussion of relevant art pertaining to RNAi. The
discussion is
provided only for understanding of the invention that follows. The summary is
not an
admission that any of the work described below is prior art to the claimed
invention.
RNA interference refers to the process of sequence-specific post-
transcriptional
gene silencing in animals mediated by short interfering RNAs (siRNAs) (Zamore
et al.,
2000, Cell, 101, 25-33; Fire et al., 1998, Nature, 391, 806; Hamilton et al.,
1999,
Scief~ce, 286, 950-951; Lin et al., 1999, Nature, 402, 128-129; Sharp, 1999,
Genes &
Dev., 13:139-141; and Strauss, 1999, Scief~ce, 286, 886). The corresponding
process in
plants (Heifetz et al., International PCT Publication No. WO 99/61631) is
commonly
referred to as post-transcriptional gene silencing or RNA silencing and is
also referred to
as quelling in fungi. The process of post-transcriptional gene silencing is
thought to be
an evolutionarily-conserved cellular defense mechanism used to prevent the
expression
of foreign genes and is commonly shared by diverse flora and phyla (Fire et
al., 1999,
Trefads Genet., 15, 358). Such protection from foreign gene expression may
gave
evolved in response to the production of double-stranded RNAs (dsRNAs) derived
from
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WO 2005/044981 PCT/US2004/027403
viral infection or from the random integration of transposon elements mto a
host genome
via a cellular response that specifically destroys homologous single-stranded
RNA or
viral genomic RNA. The presence of dsRNA in cells triggers the RNAi response
through a mechanism that has yet to be fully characterized. 'This mechanism
appears to
be different from other known mechanisms involving double stranded RNA-
specific
ribonucleases, such as the interferon response that results from dsRNA-
mediated
activation of protein kinase PIER and 2',5'-oligoadenylate synthetase
resulting in non
specific cleavage of mRNA by ribonuclease L (see for example US Patent Nos.
6,107,094; 5,898,031; Clemens et al., 1997, J. Iraterferort & Cytokirz.e Res.,
17, 503-524;
Adah et al., 2001, Curt. Med. Claerra., 8, 1189).
The presence of long dsRNAs in cells stimulates the activity of a ribonuclease
III
enzyme referred to as dicer (Bass, 2000, Cell, 101, 235; Zamore et al., 2000,
Cell, 101,
25-33; Hammond et al., 2000, Nature, 404, 293). Dicer is involved in the
processing of
the dsRNA into short pieces of dsRNA known as short interfering RNAs (siRNAs)
(Zamore et al., 2000, Cell, 101, 25-33; Bass, 2000, Cell, 101, 235; Berstein
et al., 2001,
Nature, 409, 363). Short interfering RNAs derived from dicer activity are
typically
about 21 to about 23 nucleotides in length and comprise about 19 base pair
duplexes
(Zamore et al., 2000, Cell, 101, 25-33; Elbashir et al., 2001, Genes Dev., 15,
188). Dicer
has also been implicated in the excision of 21- and 22-nucleotide small
temporal RNAs
(stRNAs) from precursor RNA of conserved structure that are implicated in
translational
control (Hutvagner et al., 2001, Science, 293, 834). The RNAi response also
features an
endonuclease complex, commonly referred to as an RNA-induced silencing complex
(RISC), which mediates cleavage of single-stranded RNA having sequence
complementary to the antisense strand of the siRNA duplex. Cleavage of the
target RNA
takes place in the middle of the region complementary to the antisense strand
of the
siRNA duplex (Elbashir et al., 2001, Genes Dev., 15, 188).
RNAi has been studied in a variety of systems. Fire et al., 1998, Nature, 391,
806,
were the first to observe RNAi in C. elegaras. Bahramian and Zarbl, 1999,
Molecular
arad Cellular Biology, 19, 274-283 and Wianny and Goetz, 1999, Nature Cell
Biol., 2,
70, describe RNAi mediated by dsRNA in mammalian systems. Hammond et al.,
2000,
Nature, 404, 293, describe RNAi in Drosophila cells transfected with dsRNA.
Elbashir
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WO 2005/044981 PCT/US2004/027403
et. al., 2001, Nature, 411, 494 and Tuschl et al., International YC;'1'
Yublcat~on tvo. wu
01/75164, describe RNAi induced by introduction of duplexes of synthetic 21-
nucleotide
RNAs in cultured mammalian cells including human embryonic kidney and HeLa
cells.
Recent work in Drosophila embryonic lysates (Elbashir et al., 2001, EMBO J.,
20, 6877
and Tuschl et al., International PCT Publication No. WO 01/75164) has revealed
certain
requirements for siRNA length, structure, chemical composition, and sequence
that are
essential to mediate efficient RNAi activity. These studies have shown that 21-
nucleotide siRNA duplexes are most active when containing 3'-terminal
dinucleotide
overhangs. Furthermore, complete substitution of one or both siRNA strands
with 2'-
deoxy (2'-H) or 2'-O-methyl nucleotides abolishes RNAi activity, whereas
substitution of
the 3'-terminal siRNA overhang nucleotides with 2'-deoxy nucleotides (2'-H)
was shown
to be tolerated. Single mismatch sequences in the center of the siRNA duplex
were also
shown to abolish RNAi activity. In addition, these studies also indicate that
the position
of the cleavage site in the target RNA is defined by the 5'-end of the siRNA
guide
sequence rather than the 3'-end of the guide sequence (Elbashir et al., 2001,
EMBO J.,
20, 6877). Other studies have indicated that a 5'-phosphate on the target-
complementary
strand of a siRNA duplex is required for siRNA activity and that ATP is
utilized to
maintain the 5'-phosphate moiety on the siRNA (Nykanen et al., 2001, Cell,
107, 309).
Studies have shown that replacing the 3'-terminal nucleotide overhanging
segments
of a 21-mer siRNA duplex having two-nucleotide 3'-overhangs with
deoxyribonucleotides does not have an adverse effect on RNAi activity.
Replacing up to
four nucleotides on each end of the siRNA with deoxyribonucleotides has been
reported
to be well tolerated, whereas complete substitution with deoxyribonucleotides
results in
no RNAi activity (Elbashir et al., 2001, EMBO J., 20, 6877 and Tuschl et al.,
International PCT Publication No. WO 01/75164). In addition, Elbashir et al.,
supra,
also report that substitution of siRNA with 2'-O-methyl nucleotides completely
abolishes
RNAi activity. Li et al., International PCT Publication No. WO 00/44914, and
Beach et
al., International PCT Publication No. WO 01/68836 preliminarily suggest that
siRNA
may include modifications to either the phosphate-sugar backbone or the
nucleoside to
include at least one of a nitrogen or sulfur heteroatom, however, neither
application
postulates to what extent such modifications would be tolerated in siRNA
molecules, nor
provides any further guidance or examples of such modified siRNA. Kreutzer et
al.,
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CA 02542835 2006-04-13
WO 2005/044981 PCT/US2004/027403
Canadian Patent Application No. 2,359,180, also describe certain chexmcal
moditications
for use in dsRNA constructs in order to counteract activation of double-
stranded RNA-
dependent protein lcinase PKR, specifically 2'-amino or 2'-O-methyl
nucleotides, and
nucleotides containing a 2'-O or 4'-C methylene bridge. However, Kreutzer et
al.
similarly fails to provide examples or guidance as to what extent these
modifications
would be tolerated in dsRNA molecules.
Parnsh et al., 2000, Molecular Cell, 6, 1077-1087, tested certain chemical
modifications targeting the unc-22 gene in C. elegans using long (>25 nt)
siRNA
transcripts. The authors describe the introduction of thiophosphate residues
into these
siRNA transcripts by incorporating thiophosphate nucleotide analogs with T7
and T3
RNA polymerase and observed that RNAs with two phosphorothioate modified bases
also had substantial decreases in effectiveness as RNAi. Further, Parrish et
al. reported
that phosphorothioate modification of more than two residues greatly
destabilized the
RNAs ifa vitro such that interference activities could not be assayed. Id. at
1081. The
authors also tested certain modifications at the 2'-position of the nucleotide
sugar in the
long siRNA transcripts and found that substituting deoxynucleotides for
ribonucleotides
produced a substantial decrease in interference activity, especially in the
case of Uridine
to Thymidine and/or Cytidine to deoxy-Cytidine substitutions. Id. In addition,
the
authors tested certain base modifications, including substituting, in sense
and antisense
strands of the siRNA, 4-thiouracil, 5-bromouracil, 5-iodouracil, and 3-
(aminoallyl)uracil
for uracil, and inosine for guanosine. Whereas 4-thiouracil and 5-brornouracil
substitution appeared to be tolerated, Parrish reported that inosine produced
a substantial
decrease in interference activity when incorporated in either strand. Parrish
also reported
that incorporation of 5-iodouracil and 3-(aminoallyl)uracil in the antisense
strand
resulted in a substantial decrease in RNAi activity as well.
The use of longer dsRNA has been described. For example, Beach et al.,
International PCT Publication No. WO 01/68836, describes specific methods for
attenuating gene expression using endogenously-derived dsRNA. Tuschl et al.,
International PCT Publication No. WO 01/75164, describe a Drosoplaila in vitro
RNAi
system and the use of specific siRNA molecules for certain functional genomic
and
certain therapeutic applications; although Tuschl, 2001, Chern. Biochem., 2,
239-245,
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WO 2005/044981 PCT/US2004/027403
doubts that KNAi can be used to cure genetic diseases or coral mieciion aue to
the aanger
of activating interferon response. Li et al., International PCT Publication
No. WO
00/44914, describe the use of specific long (141 bp-488 bp) enzymatically
synthesized or
vector expressed dsRNAs for attenuating the expression of certain target
genes.
Zernicka-Goetz et al., International PCT Publication No. WO 01/36646, describe
certain
methods for inhibiting the expression of particular genes in mammalian cells
using
certain long (550 bp-714 bp), enzymatically synthesized or vector expressed
dsRNA
molecules. Fire et al., International PCT Publication No. WO 99/32619,
describe
particular methods for introducing certain long dsRNA molecules into cells for
use in
inhibiting gene expression in nematodes. Plaetinck et al., International PCT
Publication
No. WO 00/01846, describe certain methods for identifying specific genes
responsible
for conferring a particular phenotype in a cell using specific long dsRNA
molecules.
Mello et al., International PCT Publication No. WO 01/29058, describe the
identification
of specific genes involved in dsRNA-mediated RNAi. Pachuck et al.,
International PCT
Publication No. WO 00/63364, describe certain long (at least 200 nucleotide)
dsRNA
constructs. Deschamps Depaillette et al., International PCT Publication No. WO
99/07409, describe specific compositions consisting of particular dsRNA
molecules
combined with certain anti-viral agents. Waterhouse et al., International PCT
Publication No. 99/53050 and 1998, PNAS, 95, 13959-13964, describe certain
methods
for decreasing the phenotypic expression of a nucleic acid in plant cells
using certain
dsRNAs. Driscoll et al., International PCT Publication No. WO 01/49844,
describe
specific DNA expression constructs for use in facilitating gene silencing in
targeted
organisms.
Others have reported on various RNAi and gene-silencing systems. For example,
Parrish et al., 2000, Molecular Cell, 6, 1077-1087, describe specific
chemically-modified
dsRNA constructs targeting the unc-22 gene of C. elegahs. Grossniklaus,
International
PCT Publication No. WO 01/38551, describes certain methods for regulating
polycomb
gene expression in plants using certain dsRNAs. Churikov et al., International
PCT
Publication No. WO 01/42443, describe certain methods for modifying genetic
characteristics of an organism using certain dsRNAs. Cogoni et al"
International PCT
Publication No. WO 01/53475, describe certain methods for isolating a
Neurospora
silencing gene and uses thereof. Reed et al., International PCT Publication
No. WO
6
CA 02542835 2006-04-13
WO 2005/044981 PCT/US2004/027403
01/68836, describe certain methods for gene silencing in plants. Honer et at.,
International PCT Publication No. WO 01/70944, describe certain methods of
drug
screening using transgenic nematodes as Parkinson's Disease models using
certain
dsRNAs. Deak et al., International PCT Publication No. WO 01/72774, describe
certain
Drosoplaila-derived gene products that may be related to RNAi in Drosophila.
Arndt et
al., International PCT Publication No. WO 01/92513 describe certain methods
for
mediating gene suppression by using factors that enhance RNAi. Tuschl et al.,
International PCT Publication No. WO 02/44321, describe certain synthetic
siRNA
constructs. Pachuk et al., International PCT Publication No. WO 00/63364, and
Satishchandran et al., International PCT Publication No. WO 01/04313, describe
certain
methods and compositions for inhibiting the function of certain polynucleotide
sequences using certain long (over 250 bp), vector expressed dsRNAs. Echeverri
et al.,
International PCT Publication No. WO 02/38805, describe certain C. elegans
genes
identified via RNAi. Kreutzer et al., International PCT Publications Nos. WO
02/055692, WO 02/055693, and EP 1144623 Bl describes certain methods for
inhibiting
gene expression using dsRNA. Graham et al., International PCT Publications
Nos. WO
99/49029 and WO 01/70949, and AU 4037501 describe certain vector expressed
siRNA
molecules. Fire et al., US 6,506,559, describe certain methods for inhibiting
gene
expression in vitro using certain long dsRNA (299 bp-1033 bp) constructs that
mediate
RNAi. Martinez et al., 2002, Cell, 110, 563-574, describe certain single
stranded siRNA
constructs, including certain 5'-phosphorylated single stranded siRNAs that
mediate
RNA interference in Hela cells. Harborth et al., 2003, Antisense & Nucleic
Acid Drug
Development, 13, 83-105, describe certain chemically and structurally modified
siRNA
molecules. Chiu and Rana, 2003, RNA, 9, 1034-1048, describe certain chemically
and
structurally modified siRNA molecules. Woolf et al., International PCT
Publication
Nos. WO 03/064626 and WO 03/064625 describe certain chemically modified dsRNA
constructs.
SUMMARY OF THE INVENTION
This invention relates to compounds, compositions, and methods useful for
modulating gene expression using short interfering nucleic acid (siNA)
molecules. This
invention also relates to compounds, compositions, and methods useful for
modulating
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WO 2005/044981 PCT/US2004/027403
the expression and activity of other genes involved in pathways of gene
expression
and/or activity by RNA interference (RNAi) using small nucleic acid molecules.
In
particular, the instant invention features small nucleic acid molecules, such
as short
interfering nucleic acid (siNA), short interfering RNA (siRNA), double-
stranded RNA
(dsRNA), micro-RNA (miRNA), and short hairpin RNA (shRNA) molecules and
methods used to modulate the expression of genes, including gene targets
having RNA
transcripts referred to by Genbank Accession Numbers shown in Table I.
A siNA of the invention can be unmodified or chemically-modified. A siNA of
the
instant invention can be chemically synthesized, expressed from a vector or
enzymatically synthesized. The instant invention also features various
chemically-
modified synthetic short interfering nucleic acid (siNA) molecules capable of
modulating
target gene expression or activity in cells by RNA interference (RNAi). The
use of
chemically-modified siNA improves various properties of native siNA molecules
through increased resistance to nuclease degradation in vivo and/or through
improved
cellular uptake. Further, contrary to earlier published studies, siNA having
multiple
chemical modifications retains its RNAi activity. The siNA molecules of the
instant
invention provide useful reagents and methods for a variety of therapeutic,
veterinary,
diagnostic, target validation, genomic discovery, genetic engineering, and
pharmacogenomic applications.
In one embodiment, the invention features one or more siNA molecules and
methods that independently or in combination modulate the expression of target
genes
encoding proteins, such as proteins that are associated with the maintenance
and/or
development of diseases, traits, disorders, and/or conditions as described
herein or
otherwise known in the art, such as genes encoding sequences comprising those
sequences referred to by GenBank Accession Nos. shown in Table I, referred to
herein
generally as "target". The description below of the various aspects and
embodiments of
the invention is provided with reference to exemplary target genes referred to
herein as
gene targets. However, the various aspects and embodiments are also directed
to other
genes, such as gene homologs, transcript variants, and polyrnorphisms (e.g.,
single
nucleotide polymorphism, (SNPs)) associated with certain genes. As such, the
various
aspects and embodiments are also directed to other genes that are involved in
disease,
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WO 2005/044981 PCT/US2004/027403
trait, condition, or disorder related pathways of signal transduction or gene
expression
that are involved, for example, in the maintenence or development of diseases,
traits,
conditions, or disorders described herein. These additional genes can be
analyzed for
target sites using the methods described for exemplary genes herein. Thus, the
modulation of other genes and the effects of such modulation of the other
genes can be
performed, determined, and measured as described herein.
In one embodiment, the invention features a double-stranded short interfering
nucleic acid (siNA) molecule that down-regulates expression of a target gene
or that
directs cleavage of a target RNA, wherein said siNA molecule comprises about
15 to
about 28 base pairs.
In one embodiment, the invention features a double stranded short interfering
nucleic acid (siNA) molecule that directs cleavage of a target RNA via RNA
interference
(RNAi), wherein the double stranded siNA molecule comprises a first and a
second
strand, each strand of the siNA molecule is about 18 to about 28 nucleotides
in length,
the first strand of the siNA molecule comprises nucleotide sequence having
sufficient
complementarity to the target RNA for the siNA molecule to direct cleavage of
the target
RNA via RNA interference, and the second strand of said siNA molecule
comprises
nucleotide sequence that is complementary to the first strand.
In one embodiment, the invention features a double stranded short interfering
nucleic acid (siNA) molecule that directs cleavage of a target RNA via RNA
interference
(RNAi), wherein the double stranded siNA molecule comprises a first and a
second
strand, each strand of the siNA molecule is about 18 to about 23 nucleotides
in length,
the first strand of the siNA molecule comprises nucleotide sequence having
sufficient
complementarity to the target RNA for the siNA molecule to direct cleavage of
the target
RNA via RNA interference, and the second strand of said siNA molecule
comprises
nucleotide sequence that is complementary to the first strand.
In one embodiment, the invention features a chemically synthesized double
stranded short interfering nucleic acid (siNA) molecule that directs cleavage
of a target
RNA via RNA interference (RNAi), wherein each strand of the siNA molecule is
about
18 to about 28 nucleotides in length; and one strand of the siNA molecule
comprises
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nucleotide sequence having sufficient complementarity to the target RNA for
the siNA
molecule to direct cleavage of the target RNA via RNA interference.
In one embodiment, the invention features a chemically synthesized double
stranded short interfering nucleic acid (siNA) molecule that directs cleavage
of a target
RNA via RNA interference (RNAi), wherein each strand of the siNA molecule is
about
1 ~ to about 23 nucleotides in length; and one strand of the siNA molecule
comprises
nucleotide sequence having sufficient complementarity to the target RNA for
the siNA
molecule to direct cleavage of the target RNA via RNA interference.
In one embodiment, the invention features a siNA molecule that down-regulates
expression of a target gene or that directs cleavage of a target RNA, for
example,
wherein the gene comprises protein encoding sequence. In one embodiment, the
invention features a siNA molecule that down-regulates expression of a target
gene or
that directs cleavage of a target RNA, for example, wherein the gene comprises
non-
coding sequence or encodes sequence of regulatory elements involved in gene
expression
(e.g., non-coding RNA).
In one embodiment, a siNA of the invention is used to inhibit the expression
of
target genes or a target gene family, wherein the genes or gene family
sequences share
sequence homology. Such homologous sequences can be identified as is known in
the
art, for example using sequence alignments. siNA molecules can be designed to
target
such homologous sequences, for example using perfectly complementary sequences
or
by incorporating non-canonical base pairs, for example mismatches and/or
wobble base
pairs, that can provide additional target sequences. In instances where
mismatches are
identified, non-canonical base pairs (for example, mismatches and/or wobble
bases) can
be used to generate siNA molecules that target more than one gene sequence. In
a non-
limiting example, non-canonical base pairs such as W and CC base pairs are
used to
generate siNA molecules that are capable of targeting sequences for differing
targets that
share sequence homology. As such, one advantage of using siNAs of the
invention is
that a single siNA can be designed to include nucleic acid sequence that is
complementary to the nucleotide sequence that is conserved between the
homologous
genes. In this approach, a single siNA can be used to inhibit expression of
more than one
gene instead of using more than one siNA molecule to target the different
genes.
CA 02542835 2006-04-13
WO 2005/044981 PCT/US2004/027403
In one embodiment, a target RNA of the invention is an expressed pseudogene
(see
for example pseudogene sequences referred to by Genbank Accession Numbers in
Table
I). As used herein the term "disease related expressed pseudogene" refers to
any
expressed pseudogene that is associated with a disease, disorder, condition,
or trait.
In one embodiment, the invention features a siNA molecule having RNAi activity
against target RNA (e.g., coding or non-coding RNA), wherein the siNA molecule
comprises a sequence complementary to any RNA sequence, such as those
sequences
having GenBank Accession Nos. shown in Table I. In another embodiment, the
invention features a siNA molecule having RNAi activity against target RNA,
wherein
the siNA molecule comprises a sequence complementary to an RNA having variant
encoding sequence, for example other mutant genes not shown in Table I but
known in
the art to be associated with the maintenance and/or development of diseases,
traits,
disorders, and/or conditions described herein or otherwise known in the art.
Chemical
modifications as shown in Table II or otherwise described herein can be
applied to any
siNA construct of the invention. In another embodiment, a siNA molecule of the
invention includes a nucleotide sequence that can interact with nucleotide
sequence of a
target gene and thereby mediate silencing of gene expression, for example,
wherein the
siNA mediates regulation of gene expression by cellular processes that
modulate the
chromatin structure or methylation patterns of the gene and prevent
transcription of the
gene.
In one embodiment, siNA molecules of the invention are used to down regulate
or
inhibit the expression of proteins arising from haplotype polymorphisms that
are
associated with a disease or condition. Analysis of genes, or protein or RNA
levels can
be used to identify subjects with such polymorphisms or those subjects who are
at risk of
developing traits, conditions, or diseases described herein. These subjects
are amenable
to treatment, for example, treatment with siNA molecules of the invention and
any other
composition useful in treating diseases related to gene expression. As such,
analysis of
protein or RNA levels can be used to determine treatment type and the course
of therapy
in treating a subject. Monitoring of protein or RNA levels can be used to
predict
treatment outcome and to determine the efficacy of compounds and compositions
that
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modulate the level and/or activity of certain proteins associated with a
trait, disorder,
condition, or disease.
In one embodiment of the invention a siNA molecule comprises an antisense
strand comprising a nucleotide sequence that is complementary to a target
polynucleotide
sequence or a portion thereof. The siNA further comprises a sense strand,
wherein said
sense strand comprises a nucleotide sequence of a target polynucleotide
sequence or a
portion thereof, (e.g., about 15 to about 25 or more, or about 15, 16, 17, 18,
19, 20, 21,
22, 23, 24, or 25 or more contiguous nucleotides in a target polynucleotide
sequence). In
one embodiment, the target polynucleotide sequence is a target DNA. In one
embodiment, the target polynucleotide sequence is a target RNA.
In one embodiment, the invention features a siNA molecule comprising a first
sequence, for example, the antisense sequence of the siNA construct,
complementary to a
sequence or portion of sequence comprising sequence represented by GenBank
Accession Nos. shown in Table I, and a second sequence, for example a sense
sequence,
that is complementary to the antisense sequence. Chemical modifications in
Table II
and described herein can be applied to any siNA construct (e.g., sense or
antisenase
sequence) of the invention.
In one embodiment of the invention a siNA molecule comprises an antisense
strand having about 15 to about 30 (e.g., about 15, 16, 17, 18, 19, 20, 21,
22, 23, 24, 25,
26, 27, 28, 29, or 30) nucleotides, wherein the antisense strand is
complementary to a
target RNA sequence or a portion thereof, and wherein said siNA further
comprises a
sense strand having about 15 to about 30 (e.g., about 15, 16, 17, 18, 19, 20,
21, 22, 23,
24, 25, 26, 27, 28, 29, or 30) nucleotides, and wherein said sense strand and
said
antisense strand are distinct nucleotide sequences where at least about 15
nucleotides in
each strand are complementary to the other strand.
In another embodiment of the invention a siNA molecule of the invention
comprises an antisense region having about 15 to about 30 (e.g., about 15, 16,
17, 18, 19,
20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) nucleotides, wherein the
antisense region is
complementary to a target DNA sequence, and wherein said siNA further
comprises a
sense region having about 15 to about 30 (e.g., about 15, 16, 17, 18, 19, 20,
21, 22, 23,
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L.-t, LJ, GV, G l , GO, ~,7, yr w~ nucieot~aes, wherein said sense region and
said antisense
region are comprised in a linear molecule where the sense region comprises at
least about
15 nucleotides that are complementary to the antisense region.
In one embodiment, a siNA molecule of the invention has RNAi activity that
modulates expression of RNA encoded by one or more genes. Because various
genes
can share some degree of sequence homology with each other, siNA molecules can
be
designed to target a class of genes or alternately specific genes (e.g.,
polyrnorphic
variants) by selecting sequences that are either shared amongst different gene
targets or
alternatively that are unique for a specific gene target. °Therefore,
in one embodiment,
the siNA molecule can be designed to target conserved regions of target RNA
sequences
having homology among several gene variants so as to target a class of genes
with one
siNA molecule. Accordingly, in one embodiment, the siNA molecule of the
invention
modulates the expression of one or both gene alleles in a subject. In another
embodiment, the siNA molecule can be designed to target a sequence that is
unique to a
specific target RNA sequence (e.g., a single allele or single nucleotide
polymorphism
(SNP)) due to the high degree of specificity that the siNA molecule requires
to mediate
RNAi activity.
In one embodiment, nucleic acid molecules of the invention that act as
mediators
of the RNA interference gene silencing response are double-stranded nucleic
acid
molecules. In another embodiment, the siNA molecules of the invention consist
of
duplex nucleic acid molecules containing about 15 to about 30 base pairs
between
oligonucleotides comprising about 15 to about 30 (e.g., about 15, 16, 17, 18,
19, 20, 21,
22, 23, 24, 25, 26, 27, 28, 29, or 30) nucleotides. In yet another embodiment,
siNA
molecules of the invention comprise duplex nucleic acid molecules with
overhanging
ends of about 1 to about 3 (e.g., about l, 2, or 3) nucleotides, for example,
about 21-
nucleotide duplexes with about 19 base pairs and 3'-terminal mononucleotide,
dinucleotide, or trinucleotide overhangs. In yet another embodiment, siNA
molecules of
the invention comprise duplex nucleic acid molecules with blunt ends, where
both ends
are blunt, or alternatively, where one of the ends is blunt.
In one embodiment, the invention features one or more chemically-modified siNA
constructs having specificity for a target polynucleotide (e.g., RNA or DNA),
such as
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-~~n ~il~~mll~ ~~r~ sequences referred to herein by (ienbank Accession number
or
such RNA sequences referred to herein by Genbank Accession number. In one
embodiment, the invention features a RNA based siNA molecule (e.g., a siNA
comprising 2'-OH nucleotides) having specificity for target polynucleotides
(e.g., RNA
or DNA) that includes one or more chemical modifications described herein. Non-
limiting examples of such chemical modifications include without limitation
phosphorothioate internucleotide linkages, 2'-deoxyribonucleotides, 2'-O-
methyl
ribonucleotides, 2'-deoxy-2'-fluoro ribonucleotides, "universal base"
nucleotides,
"acyclic" nucleotides, 5-C-methyl nucleotides, and terminal glyceryl and/or
inverted
deoxy abasic residue incorporation. These chemical modifications, when used in
various
siNA constructs, (e.g., RNA based siNA constructs), are shown to preserve RNAi
activity in cells while at the same time, dramatically increasing the serum
stability of
these compounds. Furthermore, contrary to the data published by Parrish et
al., supra,
applicant demonstrates that multiple (greater than one) phosphorothioate
substitutions
are well-tolerated and confer substantial increases in serum stability for
modified siNA
constructs.
In one embodiment, a siNA molecule of the invention comprises modified
nucleotides while maintaining the ability to mediate RNAi. The modified
nucleotides
can be used to improve izz vitro or izz vivo characteristics such as
stability, activity, and/or
bioavailability. For example, a siNA molecule of the invention can comprise
modified
nucleotides as a percentage of the total number of nucleotides present in the
siNA
molecule. As such, a siNA. molecule of the invention can generally comprise
about S%
to about 100% modified nucleotides (e.g., about 5%, 10%, 15%, 20%, 25%, 30%,
35%,
40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% modified
nucleotides). The actual percentage of modified nucleotides present in a given
siNA
molecule will depend on the total number of nucleotides present in the siNA.
If the siNA
molecule is single stranded, the percent modification can be based upon the
total number
of nucleotides present in the single stranded siNA molecules. Likewise, if the
siNA
molecule is double stranded, the percent modification can be based upon the
total
number of nucleotides present in the sense strand, antisense strand, or both
the sense and
antisense strands.
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One aspect of the invention features a double-stranded short interfering
nucleic
acid (siNA) molecule that down-regulates expression of a target gene or that
directs
cleavage of a target RNA. In one embodiment, the double stranded siNA molecule
comprises one or more chemical modifications and each strand of the double-
stranded
siNA is about 21 nucleotides long. In one embodiment, the double-stranded siNA
molecule does not contain any ribonucleotides. In another embodiment, the
double-
stranded siNA molecule comprises one or more ribonucleotides. In one
embodiment,
each strand of the double-stranded siNA molecule independently comprises about
15 to
about 30 (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,
29, or 30)
nucleotides, wherein each strand comprises about 15 to about 30 (e.g., about
15, 16, 17,
18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) nucleotides that are
complementary
to the nucleotides of the other strand. In one embodiment, one of the strands
of the
double-stranded siNA molecule comprises a nucleotide sequence that is
complementary
to a nucleotide sequence or a portion thereof of the gene, and the second
strand of the
double-stranded siNA molecule comprises a nucleotide sequence substantially
similar to
the nucleotide sequence of the gene or a portion thereof.
In another embodiment, the invention features a double-stranded short
interfering
nucleic acid (siNA) molecule that down-regulates expression of a target gene
or that
directs cleavage of a target RNA, comprising an antisense region, wherein the
antisense
region comprises a nucleotide sequence that is complementary to a nucleotide
sequence
of the gene or a portion thereof, and a sense region, wherein the sense region
comprises a
nucleotide sequence substantially similar to the nucleotide sequence of the
gene or a
portion thereof. In one embodiment, the antisense region and the sense region
independently comprise about 15 to about 30 (e.g. about 15, 16, 17, 18, 19,
20, 21, 22,
23, 24, 25, 26, 27, 28, 29, or 30) nucleotides, wherein the antisense region
comprises
about 15 to about 30 (e.g. about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,
26, 27, 28, 29,
or 30) nucleotides that are complementary to nucleotides of the sense region.
In another embodiment, the invention features a double-stranded short
interfering
nucleic acid (siNA) molecule that down-regulates expression of a target gene
or that
directs cleavage of a target RNA, comprising a sense region and an antisense
region,
wherein the antisense region comprises a nucleotide sequence that is
complementary to a
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nucleotide sequence of RNA encoded by the gene or a portion thereof and the
sense
region comprises a nucleotide sequence that is complementary to the antisense
region.
In one embodiment, a siNA molecule of the invention comprises blunt ends,
i.e.,
ends that do not include any overhanging nucleotides. For example, a siNA
molecule
comprising modifications described herein (e.g., comprising nucleotides having
Formulae I-VII or siNA constructs comprising "Stab 00"-"Stab 32" (Table II) or
any
combination thereof (see Table II)) and/or any length described herein can
comprise
blunt ends or ends with no overhanging nucleotides.
In one embodiment, any siNA molecule of the invention can comprise one or more
blunt ends, i.e. where a blunt end does not have any overhanging nucleotides.
In one
embodiment, the blunt ended siNA molecule has a number of base pairs equal to
the
number of nucleotides present in each strand of the siNA molecule. In another
embodiment, the siNA molecule comprises one blunt end, for example wherein the
5'-
end of the antisense strand and the 3'-end of the sense strand do not have any
overhanging nucleotides. In another example, the siNA molecule comprises one
blunt
end, for example wherein the 3'-end of the antisense strand and the 5'-end of
the sense
strand do not have any overhanging nucleotides. In another example, a siNA
molecule
comprises two blunt ends, for example wherein the 3'-end of the antisense
strand and the
5'-end of the sense strand as well as the 5'-end of the antisense strand and
3'-end of the
sense strand do not have any overhanging nucleotides. A blunt ended siNA
molecule
can comprise, for example, from about 15 to about 30 nucleotides (e.g., about
15, 16, 17,
18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides). Other
nucleotides
present in a blunt ended siNA molecule can comprise, for example, mismatches,
bulges,
loops, or wobble base pairs to modulate the activity of the siNA molecule to
mediate
RNA interference.
By "blunt ends" is meant symmetric termini or termini of a double stranded
siNA
molecule having no overhanging nucleotides. The two strands of a double
stranded
siNA molecule align with each other without over-hanging nucleotides at the
termini.
For example, a blunt ended siNA construct comprises terminal nucleotides that
are
complementary between the sense and antisense regions of the siNA molecule.
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In one embodiment, the invention features a double-stranded short interfering
nucleic acid (siNA) molecule that down-regulates expression of a target gene
or that
directs cleavage of a target RNA, wherein the siNA molecule is assembled from
two
separate oligonucleotide fragments wherein one fragment comprises the sense
region and
the second fragment comprises the antisense region of the siNA molecule. The
sense
region can be connected to the antisense region via a linker molecule, such as
a
polynucleotide linker or a non-nucleotide linker.
In one embodiment, the invention features double-stranded short interfering
nucleic acid (siNA) molecule that down-regulates expression of a target gene
or that
directs cleavage of a target RNA, wherein the siNA molecule comprises about 15
to
about 30 (e.g. about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,
29, or 30) base
pairs, and wherein each strand of the siNA molecule comprises one or more
chemical
modifications. In another embodiment, one of the strands of the double-
stranded siNA
molecule comprises a nucleotide sequence that is complementary to a nucleotide
sequence of a gene or a portion thereof, and the second strand of the double-
stranded
siNA molecule comprises a nucleotide sequence substantially similar to the
nucleotide
sequence or a portion thereof of the gene. In another embodiment, one of the
strands of
the double-stranded siNA molecule comprises a nucleotide sequence that is
complementary to a nucleotide sequence of a gene or portion thereof, and the
second
strand of the double-stranded siNA molecule comprises a nucleotide sequence
substantially similar to the nucleotide sequence or portion thereof of the
gene. In another
embodiment, each strand of the siNA molecule comprises about 15 to about 30
(e.g.
about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30)
nucleotides, and
each strand comprises at least about 15 to about 30 (e.g. about 15, 16, 17,
18, 19, 20, 21,
22, 23, 24, 25, 26, 27, 28, 29, or 30) nucleotides that are complementary to
the
nucleotides of the other strand. The gene can comprise, for example, a gene
that encodes
sequences referred to in Table I.
In one embodiment, a siNA molecule of the invention comprises no
ribonucleotides. In another embodiment, a siNA molecule of the invention
comprises
ribonucleotides.
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In one embodiment, a siNA molecule of the invention comprises an antisense
region comprising a nucleotide sequence that is complementary to a nucleotide
sequence
of a target gene or a portion thereof, and the siNA further comprises a sense
region
comprising a nucleotide sequence substantially similar to the nucleotide
sequence of the
target gene or a portion thereof. In another embodiment, the antisense region
and the
sense region each comprise about 15 to about 30 (e.g. about 15, 16, 17, 18,
19, 20, 21,
22, 23, 24, 25, 26, 27, 28, 29, or 30) nucleotides and the antisense region
comprises at
least about 15 to about 30 (e.g. about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,
25, 26, 27, 28,
29, or 30) nucleotides that are complementary to nucleotides of the sense
region. The
target gene can comprise, for example, sequence encoding sequences referred to
in Table
I. In another embodiment, the siNA is a double stranded nucleic acid molecule,
where
each of the two strands of the siNA molecule independently comprise about 15
to about
40 (e.g. about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,
31, 23, 33, 34,
35, 36, 37, 38, 39, or 40) nucleotides, and where one of the strands of the
siNA molecule
comprises at least about 15 (e.g. about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24
or 25 or
more) nucleotides that are complementary to the nucleic acid sequence of the
gene or a
portion thereof.
In one embodiment, a siNA molecule of the invention comprises a sense region
and an antisense region, wherein the antisense region comprises a nucleotide
sequence
that is complementary to a nucleotide sequence of RNA encoded by a target
gene, or a
portion thereof, and the sense region comprises a nucleotide sequence that is
complementary to the antisense region. In one embodiment, the siNA molecule is
assembled from two separate oligonucleotide fragments, wherein one fragment
comprises the sense region and the second fragment comprises the antisense
region of
the siNA molecule. In another embodiment, the sense region is connected to the
antisense region via a linker molecule. In another embodiment, the sense
region is
connected to the antisense region via a linker molecule, such as a nucleotide
or non-
nucleotide linker. The target gene can comprise, for example, sequence
encoding
sequences referred in to Table I.
In one embodiment, the invention features a double-stranded short interfering
nucleic acid (siNA) molecule that down-regulates expression of a target gene
or that
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directs cleavage of a target RNA comprising a sense region and an antisense
region,
wherein the antisense region comprises a nucleotide sequence that is
complementary to a
nucleotide sequence of RNA encoded by the target gene or a portion thereof and
the
sense region comprises a nucleotide sequence that is complementary to the
antisense
region, and wherein the siNA molecule has one or more modified pyrimidine
and/or
purine nucleotides. In one embodiment, the pyrimidine nucleotides in the sense
region
are 2'-O-methyl pyrimidine nucleotides or 2'-deoxy-2'-fluoro pyrirnidine
nucleotides and
the purine nucleotides present in the sense region are 2'-deoxy purine
nucleotides. In
another embodiment, the pyrimidine nucleotides in the sense region are 2'-
deoxy-2'-
fluoro pyrimidine nucleotides and the purine nucleotides present in the sense
region are
2'-O-methyl purine nucleotides. In another embodiment, the pyrimidine
nucleotides in
the sense region are 2'-deoxy-2'-fluoro pyrimidine nucleotides and the purine
nucleotides
present in the sense region are 2'-deoxy purine nucleotides. In one
embodiment, the
pyrimidine nucleotides in the antisense region are 2'-deoxy-2'-fluoro
pyrimidine
nucleotides and the purine nucleotides present in the antisense region are 2'-
O-methyl or
2'-deoxy purine nucleotides. In another embodiment of any of the above-
described siNA
molecules, any nucleotides present in a non-complementary region of the sense
strand
(e.g. overhang region) are 2'-deoxy nucleotides.
In one embodiment, the invention features a double-stranded short interfering
nucleic acid (siNA) molecule that down-regulates expression of a target gene
or that
directs cleavage of a target RNA, wherein the siNA molecule is assembled from
two
separate oligonucleotide fragments wherein one fragment comprises the sense
region and
the second fragment comprises the antisense region of the siNA molecule, and
wherein
the fragment comprising the sense region includes a terminal cap moiety at the
5'-end,
the 3'-end, or both of the 5' and 3' ends of the fragment. In one embodiment,
the terminal
cap moiety is an inverted deoxy abasic moiety or glyceryl moiety. In one
embodiment,
each of the two fragments of the siNA molecule independently comprise about 15
to
about 30 (e.g. about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,
29, or 30)
nucleotides. In another embodiment, each of the two fragments of the siNA
molecule
independently comprise about 15 to about 40 (e.g. about 15, 16, 17, 18, 19,
20, 21, 22,
23, 24, 25, 26, 27, 28, 29, 30, 31, 23, 33, 34, 35, 36, 37, 38, 39, or 40)
nucleotides. In a
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non-limiting example, each of the two fragments of the siNA molecule comprise
about
21 nucleotides.
In one embodiment, the invention features a siNA molecule comprising at least
one
modified nucleotide, wherein the modified nucleotide is a 2'-deoxy-2'-fluoro
nucleotide.
The siNA can be, for example, about 15 to about 40 nucleotides in length. In
one
embodiment, all pyrimidine nucleotides present in the siNA are 2'-deoxy-2'-
fluoro
pyrirnidine nucleotides. In one embodiment, the modified nucleotides in the
siNA
include at least one 2'-deoxy-2'-fluoro cytidine or 2'-deoxy-2'-fluoro uridine
nucleotide.
In another embodiment, the modified nucleotides in the siNA include at least
one 2'-
fluoro cytidine and at least one 2'-deoxy-2'-fluoro uridine nucleotides. In
one
embodiment, all uridine nucleotides present in the siNA are 2'-deoxy-2'-fluoro
uridine
nucleotides. In one embodiment, all cytidine nucleotides present in the siNA
are 2'-
deoxy-2'-fluoro cytidine nucleotides. In one embodiment, all adenosine
nucleotides
present in the siNA are 2'-deoxy-2'-fluoro adenosine nucleotides. In one
embodiment,
all guanosine nucleotides present in the siNA are 2'-deoxy-2'-fluoro guanosine
nucleotides. The siNA can further comprise at least one modified
internucleotidic
linkage, such as phosphorothioate linkage. In one embodiment, the 2'-deoxy-2'-
fluoronucleotides are present at specifically selected locations in the siNA
that are
sensitive to cleavage by ribonucleases, such as locations having pyrimidine
nucleotides.
In one embodiment, the invention features a method of increasing the stability
of a
siNA molecule against cleavage by ribonucleases comprising introducing at
least one
modified nucleotide into the siNA molecule, wherein the modified nucleotide is
a 2'-
deoxy-2'-fluoro nucleotide. In one embodiment, all pyrimidine nucleotides
present in
the siNA are 2'-deoxy-2'-fluoro pyrimidine nucleotides. In one embodiment, the
modified nucleotides in the siNA include at least one 2'-deoxy-2'-fluoro
cytidine or 2'-
deoxy-2'-fluoro uridine nucleotide. In another embodiment, the modified
nucleotides in
the siNA include at least one 2'-fluoro cytidine and at least one 2'-deoxy-2'-
fluoro
uridine nucleotides. In one embodiment, all uridine nucleotides present in the
siNA are
2'-deoxy-2'-fluoro uridine nucleotides. In one embodiment, all cytidine
nucleotides
present in the siNA are 2'-deoxy-2'-fluoro cytidine nucleotides. In one
embodiment, all
adenosine nucleotides present in the siNA are 2'-deoxy-2'-fluoro adenosine
nucleotides.
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In one embodiment, all guanosine nucleotides present in the siNA are 2'-deoxy-
2'-fluoro
guanosine nucleotides. The siNA can further comprise at least one modified
internucleotidic linkage, such as phosphorothioate linkage. In one embodiment,
the 2'-
deoxy-2'-fluoronucleotides are present at specifically selected locations in
the siNA that
are sensitive to cleavage by ribonucleases, such as locations having
pyrimidine
nucleotides.
In one embodiment, the invention features a double-stranded short interfering
nucleic acid (siNA) molecule that down-regulates expression of a target gene
or that
directs cleavage of a target RNA comprising a sense region and an antisense
region,
wherein the antisense region comprises a nucleotide sequence that is
complementary to a
nucleotide sequence of RNA encoded by the gene or a portion thereof and the
sense
region comprises a nucleotide sequence that is complementary to the antisense
region,
and wherein the purine nucleotides present in the antisense region comprise 2'-
deoxy-
purine nucleotides. In an alternative embodiment, the purine nucleotides
present in the
antisense region comprise 2'-O-methyl purine nucleotides. In either of the
above
embodiments, the antisense region can comprise a phosphorothioate
internucleotide
linkage at the 3' end of the antisense region. Alternatively, in either of the
above
embodiments, the antisense region can comprise a glyceryl modification at the
3' end of
the antisense region. In another embodiment of any of the above-described siNA
molecules, any nucleotides present in a non-complementary region of the
antisense
strand (e.g. overhang region) are 2'-deoxy nucleotides.
In one embodiment, the antisense region of a siNA molecule of the invention
comprises sequence complementary to a portion of a target polynucleotide
sequence
having sequence unique to a particular disease related allele, such as
sequence
comprising a single nucleotide polymorphism (SNP) associated with the disease
specific
allele. As such, the antisense region of a siNA molecule of the invention can
comprise
sequence complementary to sequences that are unique to a particular allele to
provide
specif city in mediating selective RNAi against the disease, condition, or
trait related
allele.
In one embodiment, the invention features a double-stranded short interfering
nucleic acid (siNA) molecule that down-regulates expression of a target gene
or that
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directs cleavage of a target RNA, wherein the siNA molecule is assembled from
two
separate oligonucleotide fragments wherein one fragment comprises the sense
region and
the second fragment comprises the antisense region of the siNA molecule. In
another
embodiment, the siNA molecule is a double stranded nucleic acid molecule,
where each
strand is about 21 nucleotides long and where about 19 nucleotides of each
fragment of
the siNA molecule are base-paired to the complementary nucleotides of the
other
fragment of the siNA molecule, wherein at least two 3' terminal nucleotides of
each
fragment of the siNA molecule are not base-paired to the nucleotides of the
other
fragment of the siNA molecule. In another embodiment, the siNA molecule is a
double
stranded nucleic acid molecule, where each strand is about 19 nucleotide long
and where
the nucleotides of each fragment of the siNA molecule are base-paired to the
complementary nucleotides of the other fragment of the siNA molecule to form
at least
about 15 (e.g., 15, 16, 17, 18, or 19) base pairs, wherein one or both ends of
the siNA
molecule are blunt ends. In one embodiment, each of the two 3' terminal
nucleotides of
each fragment of the siNA molecule is a 2'-deoxy-pyrimidine nucleotide, such
as a 2'-
deoxy-thymidine. In another embodiment, all nucleotides of each fragment of
the siNA
molecule are base-paired to the complementary nucleotides of the other
fragment of the
siNA molecule. In another embodiment, the siNA molecule is a double stranded
nucleic
acid molecule of about 19 to about 25 base pairs having a sense region and an
antisense
region, where about 19 nucleotides of the antisense region are base-paired to
the
nucleotide sequence or a portion thereof of the RNA encoded by the target
gene. In
another embodiment, about 21 nucleotides of the antisense region are base-
paired to the
nucleotide sequence or a portion thereof of the RNA encoded by the target
gene. In any
of the above embodiments, the 5'-end of the fragment comprising said antisense
region
can optionally include a phosphate group.
In one embodiment, the invention features a double-stranded short interfering
nucleic acid (siNA) molecule that inhibits the expression of a target RNA
sequence (e.g.,
wherein said target RNA sequence is encoded by a gene involved in a pathway of
gene
expression), wherein the siNA molecule does not contain any ribonucleotides
and
wherein each strand of the double-stranded siNA molecule is about 15 to about
30
nucleotides. In one embodiment, the siNA molecule is 21 nucleotides in length.
Examples of non-ribonucleotide containing siNA constructs are combinations of
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stabilization chemistries shown in Table II in any combination of
Sense/Antisense
chemistries, such as Stab 718, Stab 7/11, Stab 8/8, Stab 18/8, Stab 18/11,
Stab 12/13,
Stab 7/13, Stab 18/13, Stab 7/19, Stab 8/19, Stab 18/19, Stab 7/20, Stab 8/20,
Stab 18/20,
Stab 7/32, Stab 8/32, or Stab 18/32 (e.g., any siNA having Stab 7, 8, 11, 12,
13, 14, 15,
17, 18, 19, 20, or 32 sense or antisense strands or any combination thereof).
In one embodiment, the invention features a chemically synthesized double
stranded RNA molecule that directs cleavage of a target RNA via RNA
interference,
wherein each strand of said RNA molecule is about 15 to about 30 nucleotides
in length;
one strand of the RNA molecule comprises nucleotide sequence having sufficient
complementarity to the target RNA for the RNA molecule to direct cleavage of
the target
RNA via RNA interference; and wherein at least one strand of the RNA molecule
optionally comprises one or more chemically modified nucleotides described
herein,
such as without limitation deoxynucleotides, 2'-O-methyl nucleotides, 2'-deoxy-
2'-
fluoro nucleotides, 2'-O-methoxyethyl nucleotides etc.
In one embodiment, a target RNA of the invention comprises sequence encoding a
protein.
In one embodiment, target RNA of the invention comprises non-coding RNA
sequence (e.g., miRNA, snRNA siRNA etc.).
In one embodiment, the invention features a medicament comprising a siNA
molecule of the invention.
In one embodiment, the invention features an active ingredient comprising a
siNA
molecule of the invention.
In one embodiment, the invention features the use of a double-stranded short
interfering nucleic acid (siNA) molecule to inhibit, down-regulate, or reduce
expression
of a gene or that directs cleavage of a target RNA, wherein the siNA molecule
comprises
one or more chemical modifications and each strand of the double-stranded siNA
is
independently about 15 to about 30 or more (e.g., about 15, 16, 17, 18, 19,
20, 21, 22, 23,
24, 25, 26, 27, 28, 29 or 30 or more) nucleotides long. In one embodiment, the
siNA
molecule of the invention is a double stranded nucleic acid molecule
comprising one or
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more chemical modifications, where each of the two fragments of the siNA
molecule
independently comprise about 15 to about 40 (e.g. about 15, 16, 17, 18, 19,
20, 21, 22,
23, 24, 25, 26, 27, 28, 29, 30, 31, 23, 33, 34, 35, 36, 37, 38, 39, or 40)
nucleotides and
where one of the strands comprises at least 15 nucleotides that are
complementary to
nucleotide sequence of target RNA or a portion thereof. In a non-limiting
example, each
of the two fragments of the siNA molecule comprise about 21 nucleotides. In
another
embodiment, the siNA molecule is a double stranded nucleic acid molecule
comprising
one or more chemical modifications, where each strand is about 21 nucleotide
long and
where about 19 nucleotides of each fragment of the siNA molecule are base-
paired to the
complementary nucleotides of the other fragment of the siNA molecule, wherein
at least
two 3' terminal nucleotides of each fragment of the siNA molecule are not base-
paired to
the nucleotides of the other fragment of the siNA molecule. In another
embodiment, the
siNA molecule is a double stranded nucleic acid molecule comprising one or
more
chemical modifications, where each strand is about 19 nucleotide long and
where the
nucleotides of each fragment of the siNA molecule are base-paired to the
complementary
nucleotides of the other fragment of the siNA molecule to form at least about
15 (e.g.,
15, 16, 17, 18, or 19) base pairs, wherein one or both ends of the siNA
molecule are
blunt ends. In one embodiment, each of the two 3' terminal nucleotides of each
fragment
of the siNA molecule is a 2'-deoxy-pyrimidine nucleotide, such as a 2'-deoxy-
thymidine.
In another embodiment, all nucleotides of each fragment of the siNA molecule
are base-
paired to the complementary nucleotides of the other fragment of the siNA
molecule. In
another embodiment, the siNA molecule is a double stranded nucleic acid
molecule of
about 19 to about 25 base pairs having a sense region and an antisense region
and
comprising one or more chemical modifications, where about 19 nucleotides of
the
antisense region are base-paired to the nucleotide sequence or a portion
thereof of the
RNA encoded by the target gene. In another embodiment, about 21 nucleotides of
the
antisense region are base-paired to the nucleotide sequence or a portion
thereof of the
RNA encoded by the target gene. In any of the above embodiments, the 5'-end of
the
fragment comprising said antisense region can optionally include a phosphate
group.
In one embodiment, the invention features the use of a double-stranded short
interfering nucleic acid (siNA) molecule that inhibits, down-regulates, or
reduces
expression of a target gene or that directs cleavage of a target RNA, wherein
one of the
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strands of the double-stranded siNA molecule is an antisense strand which
comprises
nucleotide sequence that is complementary to nucleotide sequence of target RNA
or a
portion thereof, the other strand is a sense strand which comprises nucleotide
sequence
that is complementary to a nucleotide sequence of the antisense strand and
wherein a
majority of the pyrimidine nucleotides present in the double-stranded siNA
molecule
comprises a sugar modification (e.g., 2'-deoxy-2'-fluoro, 2'-O-methyl, or 2'-
deoxy
modifications).
In one embodiment, the invention features a double-stranded short interfering
nucleic acid (siNA) molecule that inhibits, down-regulates, or reduces
expression of a
target gene or that directs cleavage of a target RNA, wherein one of the
strands of the
double-stranded siNA molecule is an antisense strand which comprises
nucleotide
sequence that is complementary to nucleotide sequence of target RNA or a
portion
thereof, wherein the other strand is a sense strand which comprises nucleotide
sequence
that is complementary to a nucleotide sequence of the antisense strand and
wherein a
majority of the pyrirnidine nucleotides present in the double-stranded siNA
molecule
comprises a sugar modification (e.g., 2'-deoxy-2'-fluoro, 2'-O-methyl, or 2'-
deoxy
modif catins).
In one embodiment, the invention features a double-stranded short interfering
nucleic acid (siNA) molecule that inhibits, down-regulates, or reduces
expression of a
gene or that directs cleavage of a target RNA, wherein one of the strands of
the double-
stranded siNA molecule is an antisense strand which comprises nucleotide
sequence that
is complementary to nucleotide sequence of target RNA that encodes a protein
or portion
thereof, the other strand is a sense strand which comprises nucleotide
sequence that is
complementary to a nucleotide sequence of the antisense strand and wherein a
majority
of the pyrimidine nucleotides present in the double-stranded siNA molecule
comprises a
sugar modification. In one embodiment, each strand of the siNA molecule
comprises
about 15 to about 30 or more (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23,
24, 25, 26,
27, 28, 29, or 30 or more) nucleotides, wherein each strand comprises at least
about 15
nucleotides that are complementary to the nucleotides of the other strand. In
one
embodiment, the siNA molecule is assembled from two oligonucleotide fragments,
wherein one fragment comprises the nucleotide sequence of the antisense strand
of the
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siNA molecule and a second fragment comprises nucleotide sequence of the sense
region
of the siNA molecule. In one embodiment, the sense strand is connected to the
antisense
strand via a linker molecule, such as a polynucleotide linker or a non-
nucleotide linker.
In a further embodiment, the pyrimidine nucleotides present in the sense
strand are 2'-
deoxy-2'fluoro pyrimidine nucleotides and the purine nucleotides present in
the sense
region are 2'-deoxy purine nucleotides. In another embodiment, the pyrimidine
nucleotides present in the sense strand are 2'-deoxy-2'fluoro pyrimidine
nucleotides and
the purine nucleotides present in the sense region are 2'-O-methyl purine
nucleotides. In
still another embodiment, the pyrimidine nucleotides present in the antisense
strand are
2'-deoxy-2'-fluoro pyrimidine nucleotides and any purine nucleotides present
in the
antisense strand are 2'-deoxy purine nucleotides. In another embodiment, the
antisense
strand comprises one or more 2'-deoxy-2'-fluoro pyrimidine nucleotides and one
or
more 2'-O-methyl purine nucleotides. In another embodiment, the pyrimidine
nucleotides present in the antisense strand are 2'-deoxy-2'-fluoro pyrimidine
nucleotides
and any purine nucleotides present in the antisense strand are 2'-O-methyl
purine
nucleotides. In a further embodiment the sense strand comprises a 3'-end and a
5'-end,
wherein a terminal cap moiety (e.g., an inverted deoxy abasic moiety or
inverted deoxy
nucleotide moiety such as inverted thymidine) is present at the 5'-end, the 3'-
end, or both
of the 5' and 3' ends of the sense strand. In another embodiment, the
antisense strand
comprises a phosphorothioate internucleotide linkage at the 3' end of the
antisense
strand. In another embodiment, the antisense strand comprises a glyceryl
modification at
the 3' end. In another embodiment, the 5'-end of the antisense strand
optionally includes
a phosphate group.
In any of the above-described embodiments of a double-stranded short
interfering
nucleic acid (siNA) molecule that inhibits expression of a target gene or that
directs
cleavage of a target RNA, wherein a majority of the pyrimidine nucleotides
present in
the double-stranded siNA molecule comprises a sugar modification, each of the
two
strands of the siNA molecule can comprise about 15 to about 30 or more (e.g.,
about 15,
16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or more)
nucleotides. In one
embodiment, about 15 to about 30 or more (e.g., about 15, 16, 17, 18, 19, 20,
21, 22, 23,
24, 25, 26, 27, 28, 29, or 30 or more) nucleotides of each strand of the siNA
molecule are
base-paired to the complementary nucleotides of the other strand of the siNA
molecule.
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In another embodiment, about 15 to about 30 or more (e.g., about 15, 16, 17,
18, 19, 20,
21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or more) nucleotides of each strand
of the siNA
molecule are base-paired to the complementary nucleotides of the other strand
of the
siNA molecule, wherein at least two 3' terminal nucleotides of each strand of
the siNA
molecule are not base-paired to the nucleotides of the other strand of the
siNA molecule.
In another embodiment, each of the two 3' terminal nucleotides of each
fragment of the
siNA molecule is a 2'-deoxy-pyrimidine, such as 2'-deoxy-thymidine. In one
embodiment, each strand of the siNA molecule is base-paired to the
complementary
nucleotides of the other strand of the siNA molecule. In one embodiment, about
15 to
about 30 (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,
29, or 30)
nucleotides of the antisense strand are base-paired to the nucleotide sequence
of the
target RNA or a portion thereof. In one embodiment, about 18 to about 25
(e.g., about
18, 19, 20, 21, 22, 23, 24, or 25) nucleotides of the antisense strand are
base-paired to the
nucleotide sequence of the target RNA or a portion thereof.
In one embodiment, the invention features a double-stranded short interfering
nucleic acid (siNA) molecule that inhibits expression of a target gene or that
directs
cleavage of a target RNA, wherein one of the strands of the double-stranded
siNA
molecule is an antisense strand which comprises nucleotide sequence that is
complementary to nucleotide sequence of target RNA or a portion thereof, the
other
strand is a sense strand which comprises nucleotide sequence that is
complementary to a
nucleotide sequence of the antisense strand and wherein a majority of the
pyrimidine
nucleotides present in the double-stranded siNA molecule comprises a sugar
modification, and wherein the 5'-end of the antisense strand optionally
includes a
phosphate group.
In one embodiment, the invention features a double-stranded short interfering
nucleic acid (siNA) molecule that inhibits expression of a target gene or that
directs
cleavage of a target RNA, wherein one of the strands of the double-stranded
siNA
molecule is an antisense strand which comprises nucleotide sequence that is
complementary to nucleotide sequence of target RNA or a portion thereof, the
other
strand is a sense strand which comprises nucleotide sequence that is
complementary to a
nucleotide sequence of the antisense strand and wherein a majority of the
pyrimidine
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nucleotides present in the double-stranded siNA molecule comprises a sugar
modification, and wherein the nucleotide sequence or a portion thereof of the
antisense
strand is complementary to a nucleotide sequence of the untranslated region or
a portion
thereof of the target RNA.
In one embodiment, the invention features a double-stranded short interfering
nucleic acid (siNA) molecule that inhibits expression of a target gene or that
directs
cleavage of a target RNA, wherein one of the strands of the double-stranded
siNA
molecule is an antisense strand which comprises nucleotide sequence that is
complementary to nucleotide sequence of target RNA or a portion thereof,
wherein the
other strand is a sense strand which comprises nucleotide sequence that is
complementary to a nucleotide sequence of the antisense strand, wherein a
majority of
the pyrimidine nucleotides present in the double-stranded siNA molecule
comprises a
sugar modification, and wherein the nucleotide sequence of the antisense
strand is
complementary to a nucleotide sequence of the target RNA or a portion thereof
that is
present in the target RNA.
In one embodiment, the invention features a composition comprising a siNA
molecule of the invention in a pharmaceutically acceptable Garner or diluent.
In a non-limiting example, the introduction of chemically-modified nucleotides
into nucleic acid molecules provides a powerful tool in overcoming potential
limitations
of ir1 vivo stability and bioavailability inherent to native RNA molecules
that are
delivered exogenously. For example, the use of chemically-modified nucleic
acid
molecules can enable a lower dose of a particular nucleic acid molecule for a
given
therapeutic effect since chemically-modified nucleic acid molecules tend to
have a
longer half life in serum. Furthermore, certain chemical modifications can
improve the
bioavailability of nucleic acid molecules by targeting particular cells or
tissues and/or
improving cellular uptake of the nucleic acid molecule. Therefore, even if the
activity of
a chemically-modified nucleic acid molecule is reduced as compared to a native
nucleic
acid molecule, for example, when compared to an all-RNA nucleic acid molecule,
the
overall activity of the modified nucleic acid molecule can be greater than
that of the
native molecule due to improved stability and/or delivery of the molecule.
Unlike native
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unmodified siNA, chemically-modified siNA can also minimize the possibility of
activating interferon activity in humans.
In any of the embodiments of siNA molecules described herein, the antisense
region of a siNA molecule of the invention can comprise a phosphorothioate
internucleotide linkage at the 3'-end of said antisense region. In any of the
embodiments
of siNA molecules described herein, the antisense region can comprise about
one to
about five phosphorothioate internucleotide linkages at the 5'-end of said
antisense
region. In any of the embodiments of siNA molecules described herein, the 3'-
terminal
nucleotide overhangs of a siNA molecule of the invention can comprise
ribonucleotides
or deoxyribonucleotides that are chemically-modified at a nucleic acid sugar,
base, or
backbone. In any of the embodiments of siNA molecules described herein, the 3'-
terminal nucleotide overhangs can comprise one or more universal base
ribonucleotides.
In any of the embodiments of siNA molecules described herein, the 3'-terminal
nucleotide overhangs can comprise one or more acyclic nucleotides.
One embodiment of the invention provides an expression vector comprising a
nucleic acid sequence encoding at least one siNA molecule of the invention in
a manner
that allows expression of the nucleic acid molecule. Another embodiment of the
invention provides a mammalian cell comprising such an expression vector. The
mammalian cell can be a human cell. The siNA molecule of the expression vector
can
comprise a sense region and an antisense region. The antisense region can
comprise
sequence complementary to a RNA or DNA sequence encoding the target and the
sense
region can comprise sequence complementary to the antisense region. The siNA
molecule can comprise two distinct strands having complementary sense and
antisense
regions. The siNA molecule can comprise a single strand having complementary
sense
and antisense regions.
In one embodiment, the invention features a chemically-modified short
interfering
nucleic acid (siNA) molecule capable of mediating RNA interference (RNAi)
against a
target polynucleotide (e.g., DNA or RNA) inside a cell or reconstituted iya
vitro system,
wherein the chemical modification comprises one or more (e.g., about l, 2, 3,
4, 5, 6, 7,
8, 9, 10, or more) nucleotides comprising a backbone modified internucleotide
linkage
having Formula I:
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Z
R~ X ~ Y R2
W
wherein each Rl and R2 is independently any nucleotide, non-nucleotide, or
polynucleotide which can be naturally-occurring or chemically-modified, each X
and Y
is independently O, S, N, alkyl, or substituted alkyl, each Z and W is
independently O, S,
N, alkyl, substituted alkyl, O-alkyl, S-alkyl, alkaryl, aralkyl, or acetyl and
wherein W, X,
Y, and Z are optionally not all O. In another embodiment, a backbone
modification of
the invention comprises a phosphonoacetate and/or thiophosphonoacetate
internucleotide
linkage (see for example Sheehan et al., 2003, Nucleic Acids Research, 31,
4109-4118).
The chemically-modified internucleotide linkages having Formula I, for
example,
wherein any Z, W, X, and/or Y independently comprises a sulphur atom, can be
present
in one or both oligonucleotide strands of the siNA duplex, for example, in the
sense
strand, the antisense strand, or both strands. The siNA molecules of the
invention can
comprise one or more (e.g., about l, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more)
chemically-
modified internucleotide linkages having Formula I at the 3'-end, the 5'-end,
or both of
the 3' and 5'-ends of the sense strand, the antisense strand, or both strands.
For example,
an exemplary siNA molecule of the invention can comprise about 1 to about 5 or
more
(e.g., about 1, 2, 3, 4, 5, or morel chemically-modified internucleotide
linkages having
Formula I at the 5'-end of the sense strand, the antisense strand, or both
strands. In
another non-limiting example, an exemplary siNA molecule of the invention can
comprise one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more)
pyrimidine
nucleotides with chemically-modified internucleotide linkages having Formula I
in the
sense strand, the antisense strand, or both strands. In yet another non-
limiting example,
an exemplary siNA molecule of the invention can comprise one or more (e.g.,
about 1, 2,
3, 4, 5, 6, 7, 8, 9, 10, or more) purine nucleotides with chemically-modified
internucleotide linkages having Formula I in the sense strand, the antisense
strand, or
both strands. In another embodiment, a siNA molecule of the invention having
internucleotide linkages) of Formula I also comprises a chemically-modified
nucleotide
or non-nucleotide having any of Formulae I-VII.
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In one embodiment, the invention features a chemically-modified short
interfering
nucleic acid (siNA) molecule capable of mediating RNA interference (RNAi)
against a
target polynucleotide (e.g., DNA or RNA) inside a cell or reconstituted in
vitro system,
wherein the chemical modification comprises one or more (e.g., about l, 2, 3,
4, 5, 6, 7,
8, 9, 10, or more) nucleotides or non-nucleotides having Formula II:
B
0
wherein each R3, R4, R5, R6, R7, R8, R10, Rl 1 and R12 is independently H, OH,
alkyl,
substituted alkyl, alkaryl or aralkyl, F, Cl, Br, CN, CF3, OCF3, OCN, O-alkyl,
S-alkyl,
N-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, SO-alkyl, alkyl-OSH, alkyl-OH, O-
alkyl-OH,
O-alkyl-SH, S-alkyl-OH, S-alkyl-SH, alkyl-S-alkyl, alkyl-O-alkyl, ON02, N02,
N3,
NH2, aminoalkyl, aminoacid, aminoacyl, ONH2, O-aminoalkyl, O-aminoacid, O-
aminoacyl, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino,
polyalklylamino,
substituted silyl, or group having Formula I or II; R9 is O, S, CH2, S=O, CHF,
or CF2,
and B is a nucleosidic base such as adenine, guanine, uracil, cytosine,
thymine, 2-
aminoadenosine, 5-methylcytosine, 2,6-diaminopurine, or any other non-
naturally
occurnng base that can be complementary or non-complementary to target RNA or
a
non-nucleosidic base such as phenyl, naphthyl, 3-nitropyrrole, 5-nitroindole,
nebularine,
pyridone, pyridinone, or any other non-naturally occurring universal base that
can be
complementary or non-complementary to target RNA.
The chemically-modified nucleotide or non-nucleotide of Formula II can be
present in one or both oligonucleotide strands of the siNA duplex, for example
in the
sense strand, the antisense strand, or both strands. The siNA molecules of the
invention
can comprise one or more chemically-modified nucleotides or non-nucleotides of
Formula II at the 3'-end, the 5'-end, or both of the 3' and 5'-ends of the
sense strand, the
antisense strand, or both strands. For example, an exemplary siNA molecule of
the
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invention can comprise about 1 to about S or more (e.g., about 1, 2, 3, 4, 5,
or more)
chemically-modified nucleotides or non-nucleotides of Formula II at the 5'-end
of the
sense strand, the antisense strand, or both strands. In anther non-limiting
example, an
exemplary siNA molecule of the invention can comprise about 1 to about 5 or
more (e.g.,
about 1, 2, 3, 4, 5, or more) chemically-modified nucleotides or non-
nucleotides of
Formula II at the 3'-end of the sense strand, the antisense strand, or both
strands.
In one embodiment, the invention features a chemically-modified short
interfering
nucleic acid (siNA) molecule capable of mediating RNA interference (RNAi)
against a
target polynucleotide (e.g., DNA or RNA) inside a cell or reconstituted ih
vitro system,
wherein the chemical modification comprises one or more (e.g., about 1, 2, 3,
4, 5, 6, 7,
8, 9, 10, or more) nucleotides or non-nucleotides having Formula III:
R~ n
wherein each R3, R4, R5, R6, R7, R8, R10, Rl 1 and R12 is independently H, OH,
alkyl,
substituted alkyl, alkaryl or aralkyl, F, Cl, Br, CN, CF3, OCF3, OCN, O-alkyl,
S-alkyl,
N-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, SO-alkyl, alkyl-OSH, alkyl-OH, O-
alkyl-OH,
O-alkyl-SH, S-alkyl-OH, S-alkyl-SH, alkyl-S-alkyl, alkyl-O-alkyl, ON02, N02,
N3,
NH2, aminoalkyl, aminoacid, aminoacyl, ONH2, O-aminoalkyl, O-aminoacid, O-
aminoacyl, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino,
polyalklylamino,
substituted silyl, or group having Formula I or II; R9 is O, S, CH2, S=O, CHF,
or CF2,
and B is a nucleosidic base such as adenine, guanine, uracil, cytosine,
thymine, 2-
aminoadenosine, 5-methylcytosine, 2,6-diaminopurine, or any other non-
naturally
occurring base that can be employed to be complementary or non-complementary
to
target RNA or a non-nucleosidic base such as phenyl, naphthyl, 3-nitropyrrole,
5
nitroindole, nebularine, pyridone, pyridinone, or any other non-naturally
occurring
universal base that can be complementary or non-complementary to target RNA.
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The chemically-modified nucleotide or non-nucleotide of Formula III can be
present in one or both oligonucleotide strands of the siNA duplex, for
example, in the
sense strand, the antisense strand, or both strands. The siNA molecules of the
invention
can comprise one or more chemically-modified nucleotides or non-nucleotides of
S Formula III at the 3'-end, the 5'-end, or both of the 3' and 5'-ends of the
sense strand, the
antisense strand, or both strands. For example, an exemplary siNA molecule of
the
invention can comprise about 1 to about 5 or more (e.g., about l, 2, 3, 4, 5,
or more)
chemically-modified nucleotides) or non-nucleotides) of Formula III at the 5'-
end of
the sense strand, the antisense strand, or both strands. In anther non-
limiting example, an
exemplary siNA molecule of the invention can comprise about 1 to about 5 or
more (e.g.,
about 1, 2, 3, 4, 5, or more) chemically-modified nucleotide or non-nucleotide
of
Formula III at the 3'-end of the sense strand, the antisense strand, or both
strands.
In another embodiment, a siNA molecule of the invention comprises a nucleotide
having Formula II or III, wherein the nucleotide having Formula II or III is
in an inverted
configuration. For example, the nucleotide having Formula II or III is
connected to the
siNA construct in a 3'-3', 3'-2', 2'-3', or 5'-S' configuration, such as at
the 3'-end, the 5'-
end, or both of the 3' and 5'-ends of one or both siNA strands.
In one embodiment, the invention features a chemically-modified short
interfering
nucleic acid (siNA) molecule capable of mediating RNA interference (RNAi)
against a
target polynucleotide (e.g., DNA or RNA) W side a cell or reconstituted ira
vitro system,
wherein the chemical modification comprises a 5'-terminal phosphate group
having
Formula IV:
Z
X P Y
W
wherein each X and Y is independently O, S, N, alkyl, substituted alkyl, or
alkylhalo;
wherein each Z and W is independently O, S, N, alkyl, substituted alkyl, O-
alkyl, S-
alkyl, alkaryl, aralkyl, alkylhalo, or acetyl; and wherein W, X, Y and Z are
not all O.
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In one embodiment, the invention features a siNA molecule having a 5'-terminal
phosphate group having Formula IV on the target-complementary strand, for
example, a
strand complementary to a target RNA, wherein the siNA molecule comprises an
all
RNA siNA molecule. In another embodiment, the invention features a siNA
molecule
having a 5'-terminal phosphate group having Formula IV on the target-
complementary
strand wherein the siNA molecule also comprises about 1 to about 3 (e.g.,
about l, 2, or
3) nucleotide 3'-terminal nucleotide overhangs having about 1 to about 4
(e.g., about 1, 2,
3, or 4) deoxyribonucleotides on the 3'-end of one or both strands. In another
embodiment, a 5'-terminal phosphate group having Formula IV is present on the
target-
complementary strand of a siNA molecule of the invention, for example a siNA
molecule having chemical modifications having any of Formulae I-VII.
In one embodiment, the invention features a chemically-modified short
interfering
nucleic acid (siNA) molecule capable of mediating RNA interference (RNAi)
against a
target polynucleotide (e.g., DNA or RNA) inside a cell or reconstituted in
vitro system,
wherein the chemical modification comprises one or more phosphorothioate
internucleotide linkages. For example, in a non-limiting example, the
invention features
a chemically-modified short interfering nucleic acid (siNA) having about 1, 2,
3, 4, 5, 6,
7, 8 or more phosphorothioate internucleotide linkages in one siNA strand. In
yet
another embodiment, the invention features a chemically-modified short
interfering
nucleic acid (siNA) individually having about 1, 2, 3, 4, 5, 6, 7, 8 or more
phosphorothioate internucleotide linkages in both siNA strands. The
phosphorothioate
internucleotide linkages can be present in one or both oligonucleotide strands
of the
siNA duplex, for example in the sense strand, the antisense strand, or both
strands. The
siNA molecules of the invention can comprise one or more phosphorothioate
internucleotide linkages at the 3'-end, the 5'-end, or both of the 3'- and 5'-
ends of the
sense strand, the antisense strand, or both strands. For example, an exemplary
siNA
molecule of the invention can comprise about 1 to about 5 or more (e.g., about
1, 2, 3; 4,
5, or more) consecutive phosphorothioate internucleotide linkages at the 5'-
end of the
sense strand, the antisense strand, or both strands. In another non-limiting
example, an
exemplary siNA molecule of the invention can comprise one or more (e.g., about
1, 2, 3,
4, 5, 6, 7, 8, 9, 10, or more) pyrimidine phosphorothioate internucleotide
linkages in the
sense strand, the antisense strand, or both strands. In yet another non-
limiting example,
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an exemplary siNA molecule of the invention can comprise one or more (e.g.,
about 1, 2,
3, 4, 5, 6, 7, 8, 9, 10, or more) purine phosphorothioate internucleotide
linkages in the
sense strand, the antisense strand, or both strands.
In one embodiment, a siNA molecule of the invention is featured, wherein the
sense strand comprises one or more, for example, about l, 2, 3, 4, 5, 6, 7, 8,
9, 10, or
more phosphorothioate internucleotide linkages, andlor one or more (e.g.,
about 1, 2, 3,
4, 5, 6, 7, 8, 9, 10 or more) 2'-deoxy, 2'-O-methyl, 2'-deoxy-2'-fluoro,
and/or about one
or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) universal base
modified
nucleotides, and optionally a terminal cap molecule at the 3'-end, the 5'-end,
or both of
the 3'- and 5'-ends of the sense strand; and wherein the antisense strand
comprises about
1 to about 10 or more, specifically about l, 2, 3, 4, 5, 6, 7, 8, 9, 10, or
more
phosphorothioate internucleotide linkages, and/or one or more (e.g., about l,
2, 3, 4, 5, 6,
7, 8, 9, 10 or more) 2'-deoxy, 2'-O-methyl, 2'-deoxy-2'-fluoro, and/or one or
more (e.g.,
about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) universal base modified
nucleotides, and
optionally a terminal cap molecule at the 3'-end, the 5'-end, or both of the
3'- and 5'-ends
of the antisense strand. In another embodiment, one or more, for example about
l, 2, 3,
4, 5, 6, 7, 8, 9, 10, or more, pyrimidine nucleotides of the sense and/or
antisense siNA
strand are chemically-modified with 2'-deoxy, 2'-O-methyl and/or 2'-deoxy-2'-
fluoro
nucleotides, with or without one or more, for example about l, 2, 3, 4, 5, 6,
7, 8, 9, 10, or
more, phosphorothioate internucleotide linkages andlor a terminal cap molecule
at the 3'-
end, the 5'-end, or both of the 3'- and 5'-ends, being present in the same or
different
strand.
In another embodiment, a siNA molecule of the invention is featured, wherein
the
sense strand comprises about 1 to about 5, specifically about 1, 2, 3, 4, or 5
phosphorothioate internucleotide linkages, and/or one or more (e.g., about 1,
2, 3, 4, 5, or
more) 2'-deoxy, 2'-O-methyl, 2'-deoxy-2'-fluoro, and/or one or more (e.g.,
about l, 2, 3,
4, 5, or more) universal base modified nucleotides, and optionally a terminal
cap
molecule at the 3-end, the 5'-end, or both of the 3'- and 5'-ends of the sense
strand; and
wherein the antisense strand comprises about 1 to about 5 or more,
specifically about l,
2, 3, 4, 5, or more phosphorothioate internucleotide linkages, and/or one or
more (e.g.,
about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) 2'-deoxy, 2'-O-methyl, 2'-deoxy-
2'-fluoro,
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and/or one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more)
universal base
modified nucleotides, and optionally a terminal cap molecule at the 3'-end,
the 5'-end, or
both of the 3'- and 5'-ends of the antisense strand. In another embodiment,
one or more,
for example about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, pyrimidine
nucleotides of the
sense and/or antisense siNA strand are chemically-modified with 2'-deoxy, 2'-O-
methyl
and/or 2'-deoxy-2'-fluoro nucleotides, with or without about 1 to about 5 or
more, for
example about 1, 2, 3, 4, 5, or more phosphorothioate internucleotide linkages
and/or a
terminal cap molecule at the 3'-end, the 5'-end, or both of the 3'- and 5'-
ends, being
present in the same or different strand.
In one embodiment, a siNA molecule of the invention is featured, wherein the
antisense strand comprises one or more, for example, about l, 2, 3, 4, 5, 6,
7, 8, 9, 10, or
more phosphorothioate internucleotide linkages, and/or about one or more
(e.g., about 1,
2, 3, 4, 5, 6, 7, 8, 9, 10 or more) 2'-deoxy, 2'-O-methyl, 2'-deoxy-2'-fluoro,
and/or one or
more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) universal base
modified nucleotides,
and optionally a terminal cap molecule at the 3'-end, the 5'-end, or both of
the 3'- and 5'-
ends of the sense strand; and wherein the antisense strand comprises about 1
to about 10
or more, specifically about l, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more
phosphorothioate
internucleotide linkages, and/or one or more (e.g., about 1, 2, 3, 4, 5, 6, 7,
8, 9, 10 or
more) 2'-deoxy, 2'-O-methyl, 2'-deoxy-2'-fluoro, and/or one or more (e.g.,
about l, 2, 3,
4, 5, 6, 7, 8, 9, 10 or more) universal base modified nucleotides, and
optionally a
terminal cap molecule at the 3'-end, the 5'-end, or both of the 3'- and 5'-
ends of the
antisense strand. In another embodiment, one or more, for example about l, 2,
3, 4, 5, 6,
7, 8, 9, 10 or more pyrimidine nucleotides of the sense and/or antisense siNA
strand are
chemically-modified with 2'-deoxy, 2'-O-methyl and/or 2'-deoxy-2'-fluoro
nucleotides,
with or without one or more, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10
or more
phosphorothioate internucleotide linkages and/or a terminal cap molecule at
the 3'-end,
the 5'-end, or both of the 3' and 5'-ends, being present in the same or
different strand.
In another embodiment, a siNA molecule of the invention is featured, wherein
the
antisense strand comprises about 1 to about 5 or more, specifically about 1,
2, 3, 4, 5 or
more phosphorothioate internucleotide linkages, and/or one or more (e.g.,
about 1, 2, 3,
4, 5, 6, 7, 8, 9, 10 or more) 2'-deoxy, 2'-O-methyl, 2'-deoxy-2'-fluoro,
and/or one or more
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(e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) universal base modified
nucleotides, and
optionally a terminal cap molecule at the 3'-end, the 5'-end, or both of the
3'- and 5'-ends
of the sense strand; and wherein the antisense strand comprises about 1 to
about 5 or
more, specifically about 1, 2, 3, 4, 5 or more phosphorothioate
internucleotide linkages,
and/or one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) 2'-
deoxy, 2'-O-methyl,
2'-deoxy-2'-fluoro, and/or one or more (e.g., about l, 2, 3, 4, 5, 6, 7, 8, 9,
10 or more)
universal base modified nucleotides, and optionally a terminal cap molecule at
the 3'-
end, the 5'-end, or both of the 3'- and 5'-ends of the antisense strand. In
another
embodiment, one or more, for example about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or
more
pyrimidine nucleotides of the sense and/or antisense siNA strand are
chemically-
modified with 2'-deoxy, 2'-O-methyl and/or 2'-deoxy-2'-fluoro nucleotides,
with or
without about 1 to about 5, for example about 1, 2, 3, 4, 5 or more
phosphorothioate
internucleotide linkages and/or a terminal cap molecule at the 3'-end, the 5'-
end, or both
of the 3'- and 5'-ends, being present in the same or different strand.
In one embodiment, a chemically-modified short interfering nucleic acid (siNA)
molecule of the invention comprises about 1 to about 5 or more (specifically
about 1, 2,
3, 4, 5 or more) phosphorothioate internucleotide linkages in each strand of
the siNA
molecule.
In another embodiment, a siNA molecule of the invention comprises 2'-5'
internucleotide linkages. The 2'-5' internucleotide linkages) can be at the 3'-
end, the 5'-
end, or both of the 3'- and 5'-ends of one or both siNA sequence strands. In
addition, the
2'-5' internucleotide linkages) can be present at various other positions
within one or
both siNA sequence strands, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
or more
including every internucleotide linkage of a pyrimidine nucleotide in one or
both strands
of the siNA molecule can comprise a 2'-5' internucleotide linkage, or about 1,
2, 3, 4, 5,
6, 7, 8, 9, 10, or more including every internucleotide linleage of a purine
nucleotide in
one or both strands of the siNA molecule can comprise a 2'-5' internucleotide
linkage.
In another embodiment, a chemically-modified siNA molecule of the invention
comprises a duplex having two strands, one or both of which can be chemically-
modified, wherein each strand is independently about 15 to about 30 (e.g.,
about 15, 16,
17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) nucleotides in
length, wherein the
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duplex has about 15 to about 30 (e.g., about 15, 16, 17, 18, 19, 20, 21, 22,
23, 24, 25, 26,
27, 28, 29, or 30) base pairs, and wherein the chemical modification comprises
a
structure having any of Formulae I-VII. For example, an exemplary chemically-
modified siNA molecule of the invention comprises a duplex having two strands,
one or
both of which can be chemically-modified with a chemical modification having
any of
Formulae I-VII or any combination thereof, wherein each strand consists of
about 21
nucleotides, each having a 2-nucleotide 3'-terminal nucleotide overhang, and
wherein the
duplex has about 19 base pairs. In another embodiment, a siNA molecule of the
invention comprises a single stranded hairpin structure, wherein the siNA is
about 36 to
about 70 (e.g., about 36, 40, 45, 50, 55, 60, 65, or 70) nucleotides in length
having about
to about 30 (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,
28, 29, or 30)
base pairs, and wherein the siNA can include a chemical modification
comprising a
structure having any of Formulae I-VII or any combination thereof. For
example, an
exemplary chemically-modified siNA molecule of the invention comprises a
linear
15 oligonucleotide having about 42 to about 50 (e.g., about 42, 43, 44, 45,
46, 47, 48, 49, or
50) nucleotides that is chemically-modified with a chemical modification
having any of
Formulae I-VII or any combination thereof, wherein the linear oligonucleotide
forms a
hairpin structure having about 19 to about.21 (e.g., 19, 20, or 21) base pairs
and a 2-
nucleotide 3'-terminal nucleotide overhang. In another embodiment, a linear
hairpin
siNA molecule of the invention contains a stem loop motif, wherein the loop
portion of
the siNA molecule is biodegradable. For example, a linear hairpin siNA
molecule of the
invention is designed such that degradation of the loop portion of the siNA
molecule ira
vivo can generate a double-stranded siNA molecule with 3'-terminal overhangs,
such as
3'-terminal nucleotide overhangs comprising about 2 nucleotides.
In another embodiment, a siNA molecule of the invention comprises a hairpin
structure, wherein the siNA is about 25 to about 50 (e.g., about 25, 26, 27,
28, 29, 30, 31,
32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50)
nucleotides in
length having about 3 to about 25 (e.g., about 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16,
17, 18, 19, 20, 21, 22, 23, 24, or 25) base pairs, and wherein the siNA can
include one or
more chemical modifications comprising a structure having any of Formulae I-
VII or any
combination thereof. For example, an exemplary chemically-modified siNA
molecule of
the invention comprises a linear oligonucleotide having about 25 to about 35
(e.g., about
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25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) nucleotides that is chemically-
modified with
one or more chemical modifications having any of Formulae I-VII or any
combination
thereof, wherein the linear oligonucleotide forms a hairpin structure having
about 3 to
about 25 (e.g., about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,
19, 20, 21, 22,
23, 24, or 25) base pairs and a 5'-terminal phosphate group that can be
chemically
modified as described herein (for example a 5'-terminal phosphate group having
Formula
IV). In another embodiment, a linear hairpin siNA molecule of the invention
contains a
stem loop motif, wherein the loop portion of the siNA molecule is
biodegradable. In one
embodiment, a linear hairpin siNA molecule of the invention comprises a loop
portion
comprising a non-nucleotide linker.
In another embodiment, a siNA molecule of the invention comprises an
asymmetric hairpin structure, wherein the siNA is about 25 to about 50 (e.g.,
about 25,
26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,
45, 46, 47, 48, 49,
or 50) nucleotides in length having about 3 to about 25 (e.g., about 3, 4, 5,
6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25) base pairs, and
wherein the
siNA can include one or more chemical modifications comprising a structure
having any
of Formulae I-VII or any combination thereof. For example, an exemplary
chemically-
modified siNA molecule of the invention comprises a linear oligonucleotide
having
about 25 to about 35 (e.g., about 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or
35) nucleotides
that is chemically-modified with one or more chemical modifications having any
of
Formulae I-VII or any combination thereof, wherein the linear oligonucleotide
forms an
asymmetric hairpin structure having about 3 to about 25 (e.g., about 3, 4, 5,
6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25) base pairs and
a 5'-terminal
phosphate group that can be chemically modified as described herein (for
example a 5'-
terminal phosphate group having Formula IV). In one embodiment, an asymmetric
hairpin siNA molecule of the invention contains a stem loop motif, wherein the
loop
portion of the siNA molecule is biodegradable. In another embodiment, an
asymmetric
hairpin siNA molecule of the invention comprises a loop portion comprising a
non-
nucleotide linker.
In another embodiment, a siNA molecule of the invention comprises an
asymmetric double stranded structure having separate polynucleotide strands
comprising
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sense and antisense regions, wherein the antisense region is about 1 S to
about 30 (e.g.,
about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30)
nucleotides in
length, wherein the sense region is about 3 to about 25 (e.g., about 3, 4, 5,
6, 7, 8, 9, 10,
1 l, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25) nucleotides in
length, wherein
the sense region and the antisense region have at least 3 complementary
nucleotides, and
wherein the siNA can include one or more chemical modifications comprising a
structure
having any of Formulae I-VII or any combination thereof. For example, an
exemplary
chemically-modified siNA molecule of the invention comprises an asymmetric
double
stranded structure having separate polynucleotide strands comprising sense and
antisense
regions, wherein the antisense region is about 18 to about 23 (e.g., about 18,
19, 20, 21,
22, or 23) nucleotides in length and wherein the sense region is about 3 to
about 15 (e.g.,
about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) nucleotides in length,
wherein the sense
region the antisense region have at least 3 complementary nucleotides, and
wherein the
siNA can include one or more chemical modifications comprising a structure
having any
of Formulae I-VII or any combination thereof. In another embodiment, the
asymmetric
double stranded siNA molecule can also have a 5'-terminal phosphate group that
can be
chemically modified as described herein (for example a 5'-terminal phosphate
group
having Formula IV).
In another embodiment, a siNA molecule of the invention comprises a circular
nucleic acid molecule, wherein the siNA is about 38 to about 70 (e.g., about
38, 40, 45,
50, 55, 60, 65, or 70) nucleotides in length having about 15 to about 30
(e.g., about 15,
16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) base pairs, and
wherein the
siNA can include a chemical modification, which comprises a structure having
any of
Formulae I-VII or any combination thereof. For example, an exemplary
chemically-
modified siNA molecule of the invention comprises a circular oligonucleotide
having
about 42 to about 50 (e.g., about 42, 43, 44, 45, 46, 47, 48, 49, or 50~
nucleotides that is
chemically-modified with a chemical modification having any of Formulae I-VII
or any
combination thereof, wherein the circular oligonucleotide forms a dumbbell
shaped
structure having about 19 base pairs and 2 loops.
In another embodiment, a circular siNA molecule of the invention contains two
loop motifs, wherein one or both loop portions of the siNA molecule is
biodegradable.
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ror example, a cmcular siNA molecule of the invention is designed such that
degradation
of the loop portions of the siNA molecule in vivo can generate a double-
stranded siNA
molecule with 3'-terminal overhangs, such as 3'-terminal nucleotide overhangs
comprising about 2 nucleotides.
In one embodiment, a siNA molecule of the invention comprises at least one
(e.g.,
about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) abasic moiety, for example a
compound having
Formula V:
0
3
wherein each R3, R4, R5, R6, R7, R8, R10, Rl l, R12, and R13 is independently
H, OH,
alkyl, substituted alkyl, alkaryl or aralkyl, F, Cl, Br, CN, CF3, OCF3, OCN, O-
alkyl, S-
alkyl, N-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, SO-alkyl, alkyl-OSH, alkyl-
OH, O-
alkyl-OH, O-alkyl-SH, S-alkyl-OH, S-alkyl-SH, alkyl-S-alkyl, alkyl-O-alkyl,
ON02,
N02, N3, NH2, aminoalkyl, aminoacid, aminoacyl, ONH2, O-arninoalkyl, O-
aminoacid,
O-aminoacyl, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino,
polyalklylamino,
substituted silyl, or group having Formula I or II; R9 is O, S, CH2, S=O, CHF,
or CF2.
In one embodiment, a siNA molecule of the invention comprises at least one
(e.g.,
about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) inverted abasic moiety, for
example a
compound having Formula VI:
Z12
R~
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wherein each R3, R4, R5, R6, R7, R8, R10, Rl l, R12, and R13 is independently
H, OH,
alkyl, substituted alkyl, alkaryl or aralkyl, F, Cl, Br, CN, CF3, OCF3, OCN, O-
alkyl, S-
alkyl, N-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, SO-alkyl, alkyl-OSH, alkyl-
OH, O-
alkyl-OH, O-alkyl-SH, S-alkyl-OH, S-alkyl-SH, alkyl-S-alkyl, alkyl-O-alkyl,
ON02,
N02, N3, NH2, aininoalkyl, aminoacid, aminoacyl, ONH2, O-aminoalkyl, 0-
aminoacid,
O-aminoacyl, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino,
polyalklylamino,
substituted silyl, or group having Formula I or II; R9 is O, S, CH2, S=O, CHF~
or CF2,
and either R2, R3, R8 or R13 serve as points of attachment to the siNA
molecule of the
invention.
In another embodiment, a siNA molecule of the invention comprises at least one
(e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) substituted polyalkyl
moieties, for
example a compound having Formula VII:
R~ n ~ n - R3
R2
wherein each n is independently an integer from 1 to 12, each Rl, R2 arid R3
is
independently H, OH, alkyl, substituted alkyl, alkaryl or aralkyl, F, Cl, Br,
CN, CF3,
OCF3, OCN, O-alkyl, S-alkyl, N-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, SO-
alkyl,
alkyl-OSH, alkyl-OH, 0-alkyl-OH, O-alkyl-SH, S-alkyl-OH, S-alkyl-SH, alkyl-S-
alkyl,
alkyl-O-alkyl, ON02, N02, N3, NH2, aminoalkyl, aminoacid, aminoacyl, ONH2, O-
aminoalkyl, O-aminoacid, O-aminoacyl, heterocycloalkyl, heterocycloalkaryl,
aminoalkylamino, polyalklylamino, substituted silyl, or a group having Formula
I, and
Rl, R2 or R3 serves as points of attachment to the siNA molecule of the
invention.
In another embodiment, a siNA molecule of the invention comprises a compound
having Formula VII, wherein Rl and R2 are hydroxyl (OH) groups, n = 1, and R3
comprises O and is the point of attachment to the 3'-end, the 5'-end, or both
of the 3' and
5'-ends of one or both strands of a double-stranded siNA molecule of the
invention or to
a single-stranded siNA molecule of the invention. This modification is
referred to herein
as "glyceryl" (for example modification 6 in Figure 10).
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In another embodiment, a chemically modified nucleoside or non-nucleoside
(e.g.
a moiety having any of Formula V, VI or VII) of the invention is at the 3'-
end, the 5'-end,
or both of the 3' and 5'-ends of a siNA molecule of the invention. For
example,
chemically modified nucleoside or non-nucleoside (e.g., a moiety having
Formula V, VI
or VII) can be present at the 3'-end, the 5'-end, or both of the 3' and 5'-
ends of the
antisense strand, the sense strand, or both antisense and sense strands of the
siNA
molecule. In one embodiment, the chemically modified nucleoside or non-
nucleoside
(e.g., a moiety having Formula V, VI or VII) is present at the 5'-end and 3'-
end of the
sense strand and the 3'-end of the antisense strand of a double stranded siNA
molecule of
the invention. In one embodiment, the chemically modified nucleoside or non-
nucleoside (e.g., a moiety having Formula V, VI or VII) is present at the
terminal
position of the 5'-end and 3'-end of the sense strand and the 3'-end of the
antisense
strand of a double stranded siNA molecule of the invention. In one embodiment,
the
chemically modified nucleoside or non-nucleoside (e.g., a moiety having
Formula v, VI
or VII) is present at the two terminal positions of the 5'-end and 3'-end of
the sense
strand and the 3'-end of the antisense strand of a double stranded siNA
molecule of the
invention. In one embodiment, the chemically modified nucleoside or non-
nucleoside
(e.g., a moiety having Formula V, VI or VII) is present at the penultimate
position of the
5'-end and 3'-end of the sense strand and the 3'-end of the antisense strand
of a double
stranded siNA molecule of the invention. In addition, a moiety having Formula
VII can
be present at the 3'-end or the 5'-end of a hairpin siNA molecule as described
herein_
In another embodiment, a siNA molecule of the invention comprises an abasic
residue having Formula V or VI, wherein the abasic residue having Formula VI
or VI is
connected to the siNA construct in a 3'-3', 3'-2', 2'-3', or 5'-5'
configuration, such as at the
3'-end, the 5'-end, or both of the 3' and 5'-ends of one or both siNA strands.
In one embodiment, a siNA molecule of the invention comprises one or more
(e.g.,
about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) locked nucleic acid (LNA)
nucleotides, for
example, at the 5'-end, the 3'-end, both of the 5' and 3'-ends, or any
combination thereof,
of the siNA molecule.
In another embodiment, a siNA molecule of the invention comprises one or more
(e.g., 'about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) acyclic nucleotides, for
example, at the
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S'-end, the 3'-end, both of the 5' and 3'-ends, or any combination thereof, of
the siNA
molecule.
In one embodiment, the invention features a chemically-modified short
interfering
nucleic acid (siNA) molecule of the invention comprising a sense region,
wherein any
(e.g., one or more or all) pyrimidine nucleotides present in the sense region
are 2'-deoxy-
2'-fluoro pyrimidine nucleotides (e.g., wherein all pyrimidine nucleotides are
2'-deoxy-
2'-fluoro pyrimidine nucleotides or alternately a plurality of pyrimidine
nucleotides are
2'-deoxy-2'-fluoro pyrimidine nucleotides), and wherein any (e.g., one or more
or all)
purine nucleotides present in the sense region are 2'-deoxy purine nucleotides
(e.g.,
wherein all purine nucleotides are 2'-deoxy purine nucleotides or alternately
a plurality
of purine nucleotides are 2'-deoxy purine nucleotides).
In one embodiment, the invention features a chemically-modified short
interfering
nucleic acid (siNA) molecule of the invention comprising a sense region,
wherein any
(e.g., one or more or all) pyrimidine nucleotides present in the sense region
are 2'-deoxy-
2'-fluoro pyrimidine nucleotides (e.g., wherein all pyrimidine nucleotides are
2'-deoxy-
2'-fluoro pyrimidine nucleotides or alternately a plurality of pyrimidine
nucleotides are
2'-deoxy-2'-fluoro pyrimidine nucleotides), and wherein any (e.g., one or more
or all)
purine nucleotides present in the sense region are 2'-deoxy purine nucleotides
(e.g.,
wherein all purine nucleotides are 2'-deoxy purine nucleotides or alternately
a plurality
of purine nucleotides are 2'-deoxy purine nucleotides), wherein any
nucleotides
comprising a 3'-terminal nucleotide overhang that are present in said sense
region are 2'-
deoxy nucleotides.
In one embodiment, the invention features a chemically-modified short
interfering
nucleic acid (siNA) molecule of the invention comprising a sense region,
wherein any
(e.g., one or more or all) pyrimidine nucleotides present in the sense region
are 2'-deoxy-
2'-fluoro pyrimidine nucleotides (e.g., wherein all pyrimidine nucleotides are
2'-deoxy-
2'-fluoro pyrimidine nucleotides or alternately a plurality of pyrimidine
nucleotides are
2'-deoxy-2'-fluoro pyrimidine nucleotides), and wherein any (e.g., one or more
or all)
purine nucleotides present in the sense region are 2'-O-methyl purine
nucleotides (e.g.,
wherein all purine nucleotides are 2'-O-methyl purine nucleotides or
alternately a
plurality of purine nucleotides are 2'-O-methyl purine nucleotides).
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In one embodiment, the invention features a chemically-modified short
interfering
nucleic acid (siNA) molecule of the invention comprising a sense region,
wherein any
(e.g., one or more or all) pyrimidine nucleotides present in the sense region
are 2'-deoxy-
2'-fluoro pyrimidine nucleotides (e.g., wherein all pyrimidine nucleotides are
2'-deoxy-
2'-fluoro pyrimidine nucleotides or alternately a plurality of pyrimidine
nucleotides are
2'-deoxy-2'-fluoro pyrimidine nucleotides), wherein any (e.g., one or more or
all) purine
nucleotides present in the sense region are 2'-O-methyl purine nucleotides
(e.g., wherein
all purine nucleotides are 2'-O-methyl purine nucleotides or alternately a
plurality of
purine nucleotides are 2'-O-methyl purine nucleotides), and wherein any
nucleotides
comprising a 3'-terminal nucleotide overhang that are present in said sense
region are 2'-
deoxy nucleotides.
In one embodiment, the invention features a chemically-modified short
interfering
nucleic acid (siNA) molecule of the invention comprising an antisense region,
wherein
any (e.g., one or more or all) pyrimidine nucleotides present in the antisense
region are
2'-deoxy-2,'-fluoro pyrimidine nucleotides (e.g., wherein all pyrimidine
nucleotides are
2'-deoxy-2'-fluoro pyrimidine nucleotides or alternately a plurality of
pyrimidine
nucleotides are 2'-deoxy-2'-fluoro pyrimidine nucleotides), and wherein any
(e.g., one or
more or all) purine nucleotides present in the antisense region are 2,'-O-
methyl purine
nucleotides (e.g., wherein all purine nucleotides are 2'-O-methyl purine
nucleotides or
alternately a plurality of purine nucleotides are 2'-O-methyl purine
nucleotides).
In one embodiment, the invention features a chemically-modified short
interfering
nucleic acid (siNA) molecule of the invention comprising an antisense region,
wherein
any (e.g., one or more or all) pyrimidine nucleotides present in the antisense
region are
2'-deoxy-2'-fluoro pyrimidine nucleotides (e.g., wherein all pyrimidine
nucleotides are
2'-deoxy-2'-fluoro pyrimidine nucleotides or alternately a plurality of
pyrimidine
nucleotides are 2'-deoxy-2'-fluoro pyrimidine nucleotides), wherein any (e.g.,
one or
more or all) purine nucleotides present in the antisense region are 2'-O-
methyl purine
nucleotides (e.g., wherein all purine nucleotides are 2'-O-methyl purine
nucleotides or
alternately a plurality of purine nucleotides are 2'-O-methyl purine
nucleotides), and
wherein any nucleotides comprising a 3'-terminal nucleotide overhang that are
present in
said antisense region are 2'-deoxy nucleotides.
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In one embodiment, the invention features a chemically-modified short
interfering
nucleic acid (siNA) molecule of the invention comprising an antisense region,
wherein
any (e.g., one or more or all) pyrimidine nucleotides present in the antisense
region are
2'-deoxy-2'-fluoro pyrimidine nucleotides (e.g., wherein all pyrimidine
nucleotides are
2'-deoxy-2'-fluoro pyrimidine nucleotides or alternately a plurality of
pyrimidine
nucleotides are 2'-deoxy-2'-fluoro pyrimidine nucleotides), and wherein any
(e.g., one or
more or all) purine nucleotides present in the antisense region are 2'-deoxy
purine
nucleotides (e.g., wherein all purine nucleotides are 2'-deoxy purine
nucleotides or
alternately a plurality of purine nucleotides are 2'-deoxy purine
nucleotides).
In one embodiment, the invention features a chemically-modified short
interfering
nucleic acid (siNA) molecule of the invention comprising an antisense region,
wherein
any (e.g., one or more or all) pyrimidine nucleotides present in the antisense
region are
2'-deoxy-2'-fluoro pyrimidine nucleotides (e.g., wherein all pyrimidine
nucleotides are
2'-deoxy-2'-fluoro pyrimidine nucleotides or alternately a plurality of
pyrimidine
nucleotides are 2'-deoxy-2'-fluoro pyrimidine nucleotides), and wherein any
(e.g., one or
more or all) purine nucleotides present in the antisense region are 2'-O-
methyl purine
nucleotides (e.g., wherein all purine nucleotides are 2'-O-methyl purine
nucleotides or
alternately a plurality of purine nucleotides are 2'-O-methyl purine
nucleotides).
In one embodiment, the invention features a chemically-modified short
interfering
nucleic acid (siNA) molecule of the invention capable of mediating RNA
interference
(RNAi) against a target polynucleotide (e.g., DNA or RNA) inside a cell or
reconstituted
in vitro system comprising a sense region, wherein one or more pyrimidine
nucleotides
present in the sense region are 2'-deoxy-2'-fluoro pyrimidine nucleotides
(e.g., wherein
all pyrimidine nucleotides are 2'-deoxy-2'-fluoro pyrimidine nucleotides or
alternately a
plurality of pyrimidine nucleotides are 2'-deoxy-2'-fluoro pyrimidine
nucleotides), arid
one or more purine nucleotides present in the sense region are 2'-deoxy purine
nucleotides (e.g., wherein all purine nucleotides are 2'-deoxy purine
nucleotides or
alternately a plurality of purine nucleotides are 2'-deoxy purine
nucleotides), and an
antisense region, wherein one or more pyrimidine nucleotides present in the
antisense
region are 2'-deoxy-2'-fluoro pyrimidine nucleotides (e.g., wherein all
pyrimidine
nucleotides are 2'-deoxy-2'-fluoro pyrimidine nucleotides or alternately a
plurality of
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pyrimidine nucleotides are 2'-deoxy-2'-fluoro pyrimidine nucleotides), and one
or more
purine nucleotides present in the antisense region are 2'-O-methyl purine
nucleotides
(e.g., wherein all purine nucleotides are 2,'-O-methyl purine nucleotides or
alternately a
plurality of purine nucleotides are 2'-O-methyl purine nucleotides). The sense
region
and/or the antisense region can have a terminal cap modification, such as any
modification described herein or shown in Figure 10, that is optionally
present at the 3'-
end, the 5'-end, or both of the 3' and 5'-ends of the sense and/or antisense
sequence. The
sense and/or antisense region can optionally further comprise a 3'-terminal
nucleotide
overhang having about 1 to about 4 (e.g., about 1, 2, 3, or 4) 2'-
deoxynucleotides. The
overhang nucleotides can further comprise one or more (e.g., about 1, 2, 3, 4
or more)
phosphorothioate, phosphonoacetate, and/or thiophosphonoacetate
internucleotide
linkages. Non-limiting examples of these chemically-modified siNAs are shown
in
Figures 4 and 5 and Table II herein. In any of these described embodiments,
the purine
nucleotides present in the sense region are alternatively 2'-O-methyl purine
nucleotides
(e.g., wherein all purine nucleotides are 2'-O-methyl purine nucleotides or
alternately a
plurality of purine nucleotides are 2'-O-methyl purine nucleotides) and one or
more
purine nucleotides present in the antisense region are 2'-O-methyl purine
nucleotides
(e.g., wherein all purine nucleotides are 2'-O-methyl purine nucleotides or
alternately a
plurality of purine nucleotides are 2'-O-methyl purine nucleotides). Also, in
any of these
embodiments, one or more purine nucleotides present in the sense region are
alternatively purine ribonucleotides (e.g., wherein all purine nucleotides are
purine
ribonucleotides or alternately a plurality of purine nucleotides are purine
ribonucleotides)
and any purine nucleotides present in the antisense region are 2'-O-methyl
purine
nucleotides (e.g., wherein all purine nucleotides are 2'-O-methyl purine
nucleotides or
alternately a plurality of purine nucleotides are 2'-O-methyl purine
nucleotides).
Additionally, in any of these embodiments, one or more purine nucleotides
present in the
sense region and/or present in the antisense region are alternatively selected
from the
group consisting of 2'-deoxy nucleotides, locked nucleic acid (LNA)
nucleotides, 2'-
methoxyethyl nucleotides, 4'-thionucleotides, and 2'-O-methyl nucleotides
(e.g.,
wherein all purine nucleotides are selected from the group consisting of 2'-
deoxy
nucleotides, locked nucleic acid (LNA) nucleotides, 2'-methoxyethyl
nucleotides, 4'-
thionucleotides, and 2'-O-methyl nucleotides or alternately a plurality of
purine
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nucleotides are selected from the group consisting of 2'-deoxy nucleotides,
locked
nucleic acid (LNA) nucleotides, 2'-methoxyethyl nucleotides, 4'-
thionucleotides, and 2'-
O-methyl nucleotides).
In another embodiment, any modified nucleotides present in the siNA molecules
of
the invention, preferably in the antisense strand of the siNA molecules of the
invention,
but also optionally in the sense and/or both antisense and sense strands,
comprise
modified nucleotides having properties or characteristics similar to naturally
occurring
ribonucleotides. For example, the invention features siNA molecules including
modified
nucleotides having a Northern conformation (e.g., Northern pseudorotation
cycle, see for
example Saenger, P~irzciples of Nucleic Acid Structuf°e, Springer-
Verlag ed., 1984). As
such, chemically modified nucleotides present in the siNA molecules of the
invention,
preferably in the antisense strand of the siNA molecules of the invention, but
also
optionally in the sense and/or both antisense and sense strands, are resistant
to nuclease
degradation while at the same time maintaining the capacity to mediate RNAi.
Non-
limiting examples of nucleotides having a northern configuration include
locked nucleic
acid (LNA) nucleotides (e.g., 2'-O, 4'-C-methylene-(D-ribofuranosyl~
nucleotides); 2'-
methoxyethoxy (MOE) nucleotides; 2'-methyl-thio-ethyl, 2'-deoxy-2'-fluoro
nucleotides, 2'-deoxy-2'-chloro nucleotides, 2'-azido nucleotides, and 2'-O-
methyl
nucleotides.
In one embodiment, the sense strand of a double stranded siNA molecule of the
invention comprises a terminal cap moiety, (see for example Figure 10) such as
an
inverted deoxyabaisc moiety, at the 3'-end, 5'-end, or both 3' and 5'-ends of
the sense
strand.
In one embodiment, the invention features a chemically-modified short
interfering
nucleic acid molecule (siNA) capable of mediating RNA interference (RNAi)
against a
target polynucleotide (e.g., DNA or RNA) inside a cell or reconstituted in
vitf~o system,
wherein the chemical modification comprises a conjugate covalently attached to
the
chemically-modified siNA molecule. Non-limiting examples of conjugates
contemplated by the invention include conjugates and ligands described in
Vargeese et
al., USSN 10/427,160, filed April 30, 2003, incorporated by reference herein
in its
entirety, including the drawings. In another embodiment, the conjugate is
covalently
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WO 2005/044981 PCT/US2004/027403
attached to the chemically-modified siNA molecule via a biodegradable linker.
In one
embodiment, the conjugate molecule is attached at the 3'-end of either the
sense strand,
the antisense strand, or both strands of the chemically-modified siNA
molecule. In
another embodiment, the conjugate molecule is attached at the 5'-end of either
the sense
strand, the antisense strand, or both strands of the chemically-modified siNA
molecule.
In yet another embodiment, the conjugate molecule is attached both the 3'-end
and 5'-end
of either the sense strand, the antisense strand, or both strands of the
chemically-
modified siNA molecule, or any combination thereof. In one embodiment, a
conjugate
molecule of the invention comprises a molecule that facilitates delivery of a
chemically-
modified siNA molecule into a biological system, such as a cell. In another
embodiment,
the conjugate molecule attached to the chemically-modified siNA molecule is a
polyethylene glycol, human serum albumin, or a ligand for a cellular receptor
that can
mediate cellular uptake. Examples of specific conjugate molecules contemplated
by the
instant invention that can be attached to chemically-modified siNA molecules
are
described in Vargeese et al., U.S. Serial No. 10/201,394, filed July 22, 2002
incorporated
by reference herein. The type of conjugates used and the extent of conjugation
of siNA
molecules of the invention can be evaluated for improved pharmacokinetic
profiles,
bioavailability, and/or stability of siNA constructs while at the same time
maintaining the
ability of the siNA to mediate RNAi activity. As such, one skilled in the art
can screen
siNA constructs that are modified with various conjugates to determine whether
the
siNA conjugate complex possesses improved properties while maintaining the
ability to
mediate RNAi, for example in animal models as are generally known in the art.
In one embodiment, the invention features a short interfering nucleic acid
(siNA)
molecule of the invention, wherein the siNA further comprises a nucleotide,
non-
nucleotide, or mixed nucleotide/non-nucleotide linker that joins the sense
region of the
siNA to the antisense region of the siNA. In one embodiment, a nucleotide
linker of the
invention can be a linker of >_ 2 nucleotides in length, for example about 3,
4, 5, 6, 7, 8,
9, or 10 nucleotides in length. In another embodiment, the nucleotide linker
can be a
nucleic acid aptamer. By "aptamer" or "nucleic acid aptamer" as used herein is
meant a
nucleic acid molecule that binds specifically to a target molecule wherein the
nucleic
acid molecule has sequence that comprises a sequence recognized by the target
molecule
in its natural setting. Alternately, an aptamer can be a nucleic acid molecule
that binds to
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a target molecule where the target molecule does not naturally bind to a
nucleic acid.
The target molecule can be any molecule of interest. For example, the aptamer
can be
used to bind to a ligand-binding domain of a protein, thereby preventing
interaction of
the naturally occurnng ligand with the protein. This is a non-limiting example
and those
in the art will recognize that other embodiments can be readily generated
using
techniques generally known in the art. (See, for example, Gold et al., 1995,
Azznu. Rev.
Biochenz., 64, 763; Brody and Gold, 2000, J. BiotecJznol., 74, 5; Sun, 2000,
Curr. Opiya.
Mol. Tlzer., 2, 100; Kusser, 2000, J. Bioteclzzzol., 74, 27; Hermann and
Patel, 2000,
Science, 287, 820; and Jayasena, 1999, Clizzical Chenzistzy, 45, 1628.)
In yet another embodiment, a non-nucleotide linker of the invention comprises
abasic nucleotide, polyether, polyamine, polyamide, peptide, carbohydrate,
lipid,
polyhydrocarbon, or other polymeric compounds (e.g. polyethylene glycols such
as those
having between 2 and 100 ethylene glycol units). Specific examples include
those
described by Seela and Kaiser, Nucleic Acids Res. 1990, 18:6353 and Nucleic
Acids Res.
1987, 15:3113; Cload and Schepartz, J. Am. Chem. Soc. 1991, 113:6324;
Richardson and
Schepartz, J. Azn. Clzenz. Soc. 1991, 113:5109; Ma et al., Nucleic Acids Res.
1993,
21:2585 and Biochenzistzy 1993, 32:1751; Durand et al., Nucleic Acids Res.
1990,
18:6353; McCurdy et al., Nucleosides & Nucleotides 1991, 10:287; Jschke et
aZ.,
Tetrahedron Lett. 1993, 34:301; Ono et al., Bioclzemistzy 1991, 30:9914;
Arnold et al.,
International Publication No. WO 89/02439; Usman et al., International
Publication No.
WO 95/06731; Dudycz et al., International Publication No. WO 95/11910 and
Ferentz
and Verdine, J. Anz. Chem. Soc. 1991, 113:4000, all hereby incorporated by
reference
herein. A "non-nucleotide" further means any group or compound that can be
incorporated into a nucleic acid chain in the place of one or more nucleotide
units,
including either sugar and/or phosphate substitutions, and allows the
remaining bases to
exhibit their enzymatic activity. The group or compound can be abasic in that
it does not
contain a commonly recognized nucleotide base, such as adenosine, guanine,
cytosine,
uracil or thymine, for example at the C 1 position of the sugar.
In one embodiment, the invention features a short interfering nucleic acid
(siNA)
molecule capable of mediating RNA interference (RNAi) inside a cell or
reconstituted in
vitro system, wherein one or both strands of the siNA molecule that are
assembled from
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two separate oligonucleotides do not comprise any ribonucleotides. For
example, a siNA
molecule can be assembled from a single oligonculeotide where the sense and
antisense
regions of the siNA comprise separate oligonucleotides that do not have any
ribonucleotides (e.g., nucleotides having a 2'-OH group) present in the
oligonucleotides.
In another example, a siNA molecule can be assembled from a single
oligonculeotide
where the sense and antisense regions of the siNA are linked or circularized
by a
nucleotide or non-nucleotide linker as described herein, wherein the
oligonucleotide does
not have any ribonucleotides (e.g., nucleotides having a 2'-OH group) present
in the
oligonucleotide. Applicant has surprisingly found that the presense of
ribonucleotides
(e.g., nucleotides having a 2'-hydroxyl group) within the siNA molecule is not
required
or essential to support RNAi activity. As such, in one embodiment, all
positions within
the siNA can include chemically modified nucleotides andlor non-nucleotides
such as
nucleotides and or non-nucleotides having Formula I, II, III, IV, V, VI, or
VII or any
combination thereof to the extent that the ability of the siNA molecule to
support RNAi
activity in a cell is maintained.
In one embodiment, a siNA molecule of the invention is a single stranded siNA
molecule that mediates RNAi activity in a cell or reconstituted in vitro
system
comprising a single stranded polynucleotide having complementarity to a target
nucleic
acid sequence. In another embodiment, the single stranded siNA molecule of the
invention comprises a 5'-terminal phosphate group. In another embodiment, the
single
stranded siNA molecule of the invention comprises a 5'-terminal phosphate
group and a
3'-terminal phosphate group (e.g., a 2',3'-cyclic phosphate). In another
embodiment, the
single stranded siNA molecule of the invention comprises about 15 to about 30
(e.g.,
about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30)
nucleotides. In yet
another embodiment, the single stranded siNA molecule of the invention
comprises one
or more chemically modified nucleotides or non-nucleotides described herein.
For
example, all the positions within the siNA molecule can include chemically-
modified
nucleotides such as nucleotides having any of Formulae I-VII, or any
combination
thereof to the extent that the ability of the siNA molecule to support RNAi
activity in a
cell is maintained.
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In one embodiment, a siNA molecule of the invention is a single stranded siNA
molecule that mediates RNAi activity in a cell or reconstituted in vitro
system
comprising a single stranded polynucleotide having complementarity to a target
nucleic
acid sequence, wherein one or more pyrimidine nucleotides present in the siNA
are 2'-
deoxy-2'-fluoro pyrimidine nucleotides (e.g., wherein all pyrimidine
nucleotides are 2'-
deoxy-2'-fluoro pyrimidine nucleotides or alternately a plurality of
pyrimidine
nucleotides are 2'-deoxy-2'-fluoro pyrimidine nucleotides), and wherein any
purine
nucleotides present in the antisense region are 2'-O-methyl purine nucleotides
(e.g.,
wherein all purine nucleotides are 2'-O-methyl purine nucleotides or
alternately a
plurality of purine nucleotides are 2'-O-methyl purine nucleotides), and a
terminal cap
modification, such as any modification described herein or shown in Figure 10,
that is
optionally present at the 3'-end, the 5'-end, or both of the 3' and 5'-ends of
the antisense
sequence. The siNA optionally further comprises about 1 to about 4 or more
(e.g., about
1, 2, 3, 4 or more) terminal 2'-deoxynucleotides at the 3'-end of the siNA
molecule,
wherein the terminal nucleotides can further comprise one or more (e.g., 1, 2,
3, 4 or
more) phosphorothioate, phosphonoacetate, and/or thiophosphonoacetate
internucleotide
linkages, and wherein the siNA optionally further comprises a terminal
phosphate group,
such as a 5'-terminal phosphate group. In any of these embodiments, any purine
nucleotides present in the antisense region are alternatively 2'-deoxy purine
nucleotides
(e.g., wherein all purine nucleotides are 2'-deoxy purine nucleotides or
alternately a
plurality of purine nucleotides are 2'-deoxy purine nucleotides). Also, in any
of these
embodiments, any purine nucleotides present in the siNA (i.e., purine
nucleotides present
in the sense and/or antisense region) can alternatively be locked nucleic acid
(LNA)
nucleotides (e.g., wherein all purine nucleotides are LNA nucleotides or
alternately a
plurality of purine nucleotides are LNA nucleotides). Also, in any of these
embodiments, any purine nucleotides present in the siNA are alternatively 2'-
methoxyethyl purine nucleotides (e.g., wherein all purine nucleotides are 2'-
methoxyethyl purine nucleotides or alternately a plurality of purine
nucleotides are 2'-
methoxyethyl purine nucleotides). In another embodiment, any modified
nucleotides
present in the single stranded siNA molecules of the invention comprise
modified
nucleotides having properties or characteristics similar to naturally occurnng
ribonucleotides. For example, the invention features siNA molecules including
modified
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nucleotides having a Northern conformation (e.g., Northern pseudorotation
cycle, see for
example Saenger, Principles of Nucleic Acid St~uctuf~e, Springer-Verlag ed.,
1984). As
such, chemically modified nucleotides present in the single stranded siNA
molecules of
the invention are preferably resistant to nuclease degradation while at the
same tune
maintaining the capacity to mediate RNAi.
In one embodiment, a siNA molecule of the invention comprises chemically
modified nucleotides or non-nucleotides (e.g., having any of Formulae I-VII,
such as 2'-
deoxy, 2'-deoxy-2'-fluoro, or 2'-O-methyl nucleotides) at alternating
positions within
one or more strands or regions of the siNA molecule. For example, such
chemical
modifications can be introduced at every other position of a RNA based siNA
molecule,
starting at either the first or second nucleotide from the 3'-end or 5'-end of
the siNA. In
a non-limiting example, a double stranded siNA molecule of the invention in
which each
strand of the siNA is 21 nucleotides in length is featured wherein positions
1, 3, 5, 7, 9,
11, 13, 15, 17, 19 and 21 of each strand are chemically modified (e.g., with
compounds
having any of Formulae 1-VII, such as such as 2'-deoxy, 2'-deoxy-2'-fluoro, or
2'-O-
methyl nucleotides). In another non-limiting example, a double stranded siNA
molecule
of the invention in which each strand of the siNA is 21 nucleotides in length
is featured
wherein positions 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 of each strand are
chemically
modified (e.g., with compounds having any of Formulae 1-VII, such as such as
2'-deoxy,
2'-deoxy-2'-fluoro, or 2'-O-methyl nucleotides). Such siNA molecules can
further
comprise terminal cap moieties and/or backbone modifications as described
herein.
In one embodiment, the invention features a method for modulating the
expression
of a target gene within a cell comprising: (a) synthesizing a siNA molecule of
the
invention, which can be chemically-modified, wherein one of the siNA strands
comprises a sequence complementary to RNA of the target gene; and (b)
introducing the
siNA molecule into a cell under conditions suitable to modulate the expression
of the
target gene in the cell.
In one embodiment, the invention features a method for modulating the
expression
of a target gene within a cell comprising: (a) synthesizing a siNA molecule of
the
invention, which can be chemically-modified, wherein one of the siNA strands
comprises a sequence complementary to RNA of the target gene and wherein the
sense
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~~l~~~u ~G~uGmcC m rne smr~ comprises a sequence identical or substantially
similar to the
sequence of the target RNA; and (b) introducing the siNA molecule into a cell
under
conditions suitable to modulate the expression of the target gene in the cell.
In another embodiment, the invention features a method for modulating the
S expression of more than one target gene within a cell comprising: (a)
synthesizing siNA
molecules of the invention, which can be chemically-modibed, wherein one of
the siNA
strands comprises a sequence complementary to RNA of the target genes; and (b)
introducing the siNA molecules into a cell under conditions suitable to
modulate the
expression of the target genes in the cell.
In another embodiment, the invention features a method for modulating the
expression of two or more target genes within a cell comprising: (a)
synthesizing one or
more siNA molecules of the invention, which can be chemically-modified,
wherein the
siNA strands comprise sequences complementary to RNA of the target genes and
wherein the sense strand sequences of the siNAs comprise sequences identical
or
substantially similar to the sequences of the target RNAs; and (b) introducing
the siNA
molecules into a cell under conditions suitable to modulate the expression of
the target
genes in the cell.
In another embodiment, the invention features a method for modulating the
expression of more than one target gene within a cell comprising: (a)
synthesizing a
siNA molecule of the invention, which can be chemically-modified, wherein one
of the
siNA strands comprises a sequence complementary to RNA of the target gene and
wherein the sense strand sequence of the siNA comprises a sequence identical
or
substantially similar to the sequences of the target RNAs; and (b) introducing
the siNA
molecule into a cell under conditions suitable to modulate the expression of
the target
genes in the cell.
In one embodiment, siNA molecules of the invention are used as reagents in ex
vivo applications. For example, siNA reagents are introduced into tissue or
cells that are
transplanted into a subject for therapeutic effect. The cells and/or tissue
can be derived
from an organism or subject that later receives the explant, or can be derived
from
another organism or subject prior to transplantation. The siNA molecules can
be used to
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modulate the expression of one or more target genes in the cells or tissue,
such that the
cells or tissue obtain a desired phenotype or are able to perform a function
when
transplanted in vivo. In one embodiment, certain target cells from a patient
are extracted.
These extracted cells are contacted with siNAs targeting a specific nucleotide
sequence
within the cells under conditions suitable for uptake of the siNAs by these
cells (e.g.
using delivery reagents such as cationic lipids, liposomes and the like or
using
techniques such as electroporation to facilitate the delivery of siNAs into
cells). The cells
are then reintroduced back into the same patient or other patients. In one
embodiment,
the invention features a method of modulating the expression of a target gene
in a tissue
explant comprising: (a) synthesizing a siNA molecule of the invention, which
can be
chemically-modified, wherein one of the siNA strands comprises a sequence
complementary to RNA of the target gene; and (b) introducing the siNA molecule
into a
cell of the tissue explant derived from a particular organism under conditions
suitable to
modulate the expression of the target gene in the tissue explant. In another
embodiment,
the method further comprises introducing the tissue explant back into the
organism the
tissue was derived from or into another organism under conditions suitable to
modulate
the expression of the target gene in that organism.
In one embodiment, the invention features a method of modulating the
expression
of a target gene in a tissue explant comprising: (a) synthesizing a siN.A
molecule of the
invention, which can be chemically-modified, wherein one of the siNA strands
comprises a sequence complementary to RNA of the target gene and wherein the
sense
strand sequence of the siNA comprises a sequence identical or substantially
similar to the
sequence of the target RNA; and (b) introducing the siNA molecule into a cell
of the
tissue explant derived from a particular organism under conditions suitable to
modulate
the expression of the gene in the tissue explant. In another embodiment, the
method
further comprises introducing the tissue explant back into the organism the
tissue was
derived from or into another organism under conditions suitable to modulate
the
expression of the target gene in that organism.
In another embodiment, the invention features a method of modulating the
expression of more than one target gene in a tissue explant comprising: (a)
synthesizing
siNA molecules of the invention, which can be chemically-modified, wherein one
of the
CA 02542835 2006-04-13
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siNA strands comprises a sequence complementary to RNA of the target genes;
and (b)
introducing the siNA molecules into a cell of the tissue explant derived from
a particular
organism under conditions suitable to modulate the expression of the target
genes in the
tissue explant. In another embodiment, the method further comprises
introducing the
tissue explant back into the organism the tissue was derived from or into
another
organism under conditions suitable to modulate the expression of the target
genes in that
organism.
In one embodiment, the invention features a method of modulating the
expression
of a target gene in a subject or organism comprising: (a) synthesizing a siNA
molecule
of the invention, which can be chemically-modified, wherein one of the siNA
strands
comprises a sequence complementary to RNA of the target gene; and (b)
introducing the
siNA molecule into the subject or organism under conditions suitable to
modulate the
expression of the target gene in the subject or organism. The level of protein
or RNA
can be determined using various methods well-known in the art.
In another embodiment, the invention features a method of modulating the
expression of more than one target gene in a subject or organism comprising:
(a)
synthesizing siNA molecules of the invention, which can be chemically-
modified,
wherein one of the siNA strands comprises a sequence complementary to RNA of
the
target genes; and (b) introducing the siNA molecules into the subject or
organism under
conditions suitable to modulate the expression of the target genes in the
subject or
organism. The level of protein or RNA can be determined as is known in the
art.
In one embodiment, the invention features a method for modulating the
expression
of a target gene within a cell comprising: (a) synthesizing a siNA molecule of
the
invention, which can be chemically-modified, wherein the siNA comprises a
single
stranded sequence having complementarity to RNA of the target gene; and (b)
introducing the siNA molecule into a cell under conditions suitable to
modulate the
expression of the target gene in the cell.
In another embodiment, the invention features a method for modulating the
expression of more than one target gene within a cell comprising: (a)
synthesizing siNA
molecules of the invention, which can be chemically-modified, wherein the siNA
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comprises a single stranded sequence having complementarity to RNA of the
target
gene; and (b) contacting the cell ih vitYO or iri. vivo with the siNA molecule
under
conditions suitable to modulate the expression of the target genes in the
cell.
In one embodiment, the invention features a method of modulating the
expression
of a target gene in a tissue explant comprising: (a) synthesizing a siNA
molecule of the
invention, which can be chemically-modified, wherein the siNA comprises a
single
stranded sequence having complementarity to RNA of the gene; and (b)
contacting a cell
of the tissue explant derived from a particular subject or organism with the
siNA
molecule under conditions suitable to modulate the expression of the target
gene in the
tissue explant. In another embodiment, the method further comprises
introducing the
tissue explant back into the subject or organism the tissue was derived from
or into
another subject or organism under conditions suitable to modulate the
expression of the
target gene in that subject or organism.
In another embodiment, the invention features a method of modulating the
expression of more than one target gene in a tissue explant comprising: (a)
synthesizing
siNA molecules of the invention, which can be chemically-modified, wherein the
siNA
comprises a single stranded sequence having complementarity to RNA of the
target
gene; and (b) introducing the siNA molecules into a cell of the tissue explant
derived
from a particular subject or organism under conditions suitable to modulate
the
expression of the target genes in the tissue explant. In another embodiment,
the method
further comprises introducing the tissue explant back into the subject or
organism the
tissue was derived from or into another subject or organism under conditions
suitable to
modulate the expression of the target genes in that subject or organism.
In one embodiment, the invention features a method of modulating the
expression
of a target gene in a subject or organism comprising: (a) synthesizing a siNA
molecule
of the invention, which can be chemically-modified, wherein the siNA comprises
a
single stranded sequence having complementarity to RNA of the target gene; and
(b)
introducing the siNA molecule into the subject or organism under conditions
suitable to
modulate the expression of the target gene in the subject or organism.
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In another embodiment, the invention features a method of modulating the
expression of more than one target gene in a subject or organism comprising:
(a)
synthesizing siNA molecules of the invention, which can be chemically-
modified,
wherein the siNA comprises a single stranded sequence having complementarity
to RNA
of the target gene; and (b) introducing the siNA molecules into the subject or
organism
under conditions suitable to modulate the expression of the target genes in
the subject or
organism.
In one embodiment, the invention features a method of modulating the
expression
of a target gene in a subject or organism comprising contacting the subject or
organism
with a siNA molecule of the invention under conditions suitable to modulate
the
expression of the target gene in the subject or organism.
In one embodiment, the invention features a method for treating or preventing
a
disease, disorder, trait or condition related to gene expression in a subject
or organism
comprising contacting the subject or organism with a siNA molecule of the
invention
under conditions suitable to modulate the expression of the target gene in the
subject or
organism. The reduction of gene expression and thus reduction in the level of
the
respective protein/RNA relieves, to some extent, the symptoms of the disease,
disorder,
trait or condition.
In one embodiment, the invention features a method for treating or preventing
cancer in a subject or organism comprising contacting the subject or organism
with a
siNA molecule of the invention under conditions suitable to modulate the
expression of a
target gene associated with the maintenance or development of cancer in the
subject or
organism.
In one embodiment, the invention features a method for treating or preventing
a
proliferative disease, disorder, trait or condition in a subject or organism
comprising
contacting the subject or organism with a siNA molecule of the invention under
conditions suitable to modulate the expression of a target gene associated
with the
maintenance or development of the proliferative disease, disorder, trait or
condition in
the subject or organism.
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In one embodiment, the invention features a method for treating or preventing
transplant and/or tissue rejection (allograft rejection) in a subject or
organism comprising
contacting the subject or organism with a siNA molecule of the invention under
conditions suitable to modulate the expression of a target gene associated
with transplant
and/or tissue rejection (allograft rejection) in the subject or organism.
In one embodiment, the invention features a method for treating or preventing
an
autoimmune disease, disorder, trait or condition in a subject or organism
comprising
contacting the subject or organism with a siNA molecule of the invention under
conditions suitable to modulate the expression of a target gene associated
with the
maintenance or development of the autoimmune disease, disorder, trait or
condition in
the subject or organism.
In one embodiment, the invention features a method for treating or preventing
an
infectious disease, disorder, trait or condition in a subject or organism
comprising
contacting the subject or organism with a siNA molecule of the invention under
conditions suitable to modulate the expression of a target gene associated
with the
maintenance or development of the infectious disease, disorder, trait or
condition in the
subject or organism.
In one embodiment, the invention features a method for treating or preventing
an
age-related disease, disorder, trait or condition in a subject or organism
comprising
contacting the subject or organism with a siNA molecule of the invention under
conditions suitable to modulate the expression of a target gene associated
with the
maintenance or development of the age-related disease, disorder, trait or
condition in the
subject or organism.
In one embodiment, the invention features a method for treating or preventing
a
neurologic or neurodegenerative disease, disorder, trait or condition in a
subject or
organism comprising contacting the subject or organism with a siNA molecule of
the
invention under conditions suitable to modulate the expression of a target
gene
associated with the maintenance or development of the neurologic or
neurodegenerative
disease, disorder, trait or condition in the subject or organism.
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In one embodiment, the invention features a method for treating or preventing
a
metabolic disease, disorder, trait or condition in a subject or organism
comprising
contacting the subject or organism with a siNA molecule of the invention under
conditions suitable to modulate the expression of a target gene associated
with the
maintenance or development of the metabolic disease, disorder, trait or
condition in the
subject or organism.
In one embodiment, the invention features a method for treating or preventing
an
cardiovascular disease, disorder, trait or condition in a subject or organism
comprising
contacting the subject or organism with a siNA molecule of the invention under
conditions suitable to modulate the expression of a target gene associated
with the
maintenance or development of the cardiovascular disease, disorder, trait or
condition in
the subject or organism.
In one embodiment, the invention features a method for treating or preventing
a
respiratory disease, disorder, trait or condition in a subject or organism
comprising
contacting the subject or organism with a siNA molecule of the invention under
conditions suitable to modulate the expression of a target gene associated
with the
maintenance or development of the respiratory disease, disorder, trait or
condition in the
subject or organism.
In one embodiment, the invention features a method for treating or preventing
an
ocular disease, disorder, trait or condition in a subject or organism
comprising contacting
the subject or organism with a siNA molecule of the invention under conditions
suitable
to modulate the expression of a target gene associated with the maintenance or
development of the ocular disease, disorder, trait or condition in the subject
or organism.
In one embodiment, the invention features a method for treating or preventing
a
dermatological disease, disorder, trait or condition in a subject or organism
comprising
contacting the subject or organism with a siNA molecule of the invention under
conditions suitable to modulate the expression of a target gene associated
with the
maintenance or development of the dermatological disease, disorder, trait or
condition in
the subject or organism.
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In one embodiment, the invention features a method for treating or preventing
a
disease, disorder, trait or condition in a subject or organism comprising
contacting the
subject or organism with a siNA molecule of the invention under conditions
suitable to
modulate the expression of a target gene associated with the maintenance or
development
of the disease, disorder, trait or condition in the subject or organism.
In one embodiment, the invention features a method for treating or preventing
a
liver disease, disorder, trait or condition in a subject or organism
comprising contacting
the subject or organism with a siNA molecule of the invention under conditions
suitable
to modulate the expression of a target gene associated with the maintenance or
development of the liver disease, disorder, trait or condition in the subject
or organism.
In one embodiment, the invention features a method for treating or preventing
a
kidney disease, disorder, trait or condition in a subject or organism
comprising
contacting the subject or organism with a siNA molecule of the invention under
conditions suitable to modulate the expression of a target gene associated
with the
maintenance or development of the kidney disease, disorder, trait or condition
in the
subj ect or organism.
In one embodiment, the invention features a method for treating or preventing
a
bladder disease, disorder, trait or condition in a subject or organism
comprising
contacting the subject or organism with a siNA molecule of the invention under
conditions suitable to modulate the expression of a target gene associated
with the
maintenance or development of the bladder disease, disorder, trait or
condition in the
subject or organism.
In another embodiment, the invention features a method of modulating the
expression of more than one target gene in a subject or organism comprising
contacting
the subject or organism with one or more siNA molecules of the invention under
conditions suitable to modulate the expression of the genes in the subject or
organism.
The siNA molecules of the invention can be designed to down regulate or
inhibit
target gene expression through RNAi targeting of a variety of RNA molecules.
In one
embodiment, the siNA molecules of the invention are used to target various
RNAs
corresponding to a target gene. Non-limiting examples of such RNAs include
messenger
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KNA (mRIVA), alternate RNA splice variants of target gene(s), post-
transcnptionally
modified RNA of target gene(s), pre-mRNA of target gene(s), and/or RNA
templates. If
alternate splicing produces a family of transcripts that are distinguished by
usage of
appropriate exons, the instant invention can be used to inhibit gene
expression through
the appropriate exons to specifically inhibit or to distinguish among the
functions of gene
family members. For example, a protein that contains an alternatively spliced
transmembrane domain can be expressed in both membrane bound and secreted
forms.
Use of the invention to target the exon containing the transmembrane domain
can be
used to determine the functional consequences of pharmaceutical targeting of
mermbrane
bound as opposed to the secreted form of the protein. Non-limiting examples of
applications of the invention relating to targeting these RNA molecules
include
therapeutic pharmaceutical applications, pharmaceutical discovery
applications,
molecular diagnostic and gene function applications, and gene mapping, for
example
using single nucleotide polymorphism mapping with siNA molecules of the
invention.
Such applications can be implemented using known gene sequences or from
partial
sequences available from an expressed sequence tag (EST).
In another embodiment, the siNA molecules of the invention are used to target
conserved sequences corresponding to a target gene family or target gene
families . As
such, siNA molecules targeting multiple gene targets can provide increased
therapeutic
effect. In addition, siNA can be used to characterize pathways of gene
function in a
variety of applications. For example, the present invention can be used to
inhibit the
activity of target genes) in a pathway to determine the function of
uncharacterized
genes) in gene function analysis, mRNA function analysis, or translational
analysis.
The invention can be used to determine potential target gene pathways involved
in
various diseases and conditions toward pharmaceutical development. The
invention can
be used to understand pathways of gene expression involved in diseases,
traits, disorders,
and/or conditions described herein or otherwise known in the art.
In one embodiment, siNA molecules) and/or methods of the invention are used to
down regulate the expression of genes) that encode RNA referred to by Genbank
Accession, for example, target genes encoding RNA sequences) referred to
herein by
Genbank Accession number, for example, Genbank Accession Nos. shown in Table
I.
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In one embodiment, the invention features a method comprising: (a) generating
a
library of siNA constructs having a predetermined complexity; and (b) assaying
the siNA
constructs of (a) above, under conditions suitable to determine RNAi target
sites within
the target RNA sequence. In one embodiment, the siNA molecules of (a) have
strands of
a fixed length, for example, about 23 nucleotides in length. In another
embodiment, the
siNA molecules of (a) are of differing length, for example having strands of
about 15 to
about 30 (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,
29, or 30)
nucleotides in length. In one embodiment, the assay can comprise a
reconstituted in
vitro siNA assay as described herein. In another embodiment, the assay can
comprise a
cell culture system in which target RNA is expressed. In another embodiment,
fragments
of target RNA are analyzed for detectable levels of cleavage, for example by
gel
electrophoresis, northern blot analysis, or RNAse protection assays, to
determine the
most suitable target sites) within the target RNA sequence. The target RNA
sequence
can be obtained as is known in the art, for example, by cloning and/or
transcription for ifa
vitro systems, and by cellular expression in ih vivo systems.
In one embodiment, the invention features a method comprising: (a) generating
a
randomized library of siNA constructs having a predetermined complexity, such
as of 4N,
where N represents the number of base paired nucleotides in each of the siNA
construct
strands (eg. for a siNA construct having 21 nucleotide sense and antisense
strands with
19 base pairs, the complexity would be 419); and (b) assaying the siNA
constructs of (a)
above, under conditions suitable to determine RNAi target sites within the
target RNA
sequence. In another embodiment, the siNA molecules of (a) have strands of a
fixed
length, for example about 23 nucleotides in length. In yet another embodiment,
the siNA
molecules of (a) are of differing length, for example having strands of about
15 to about
30 (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or
30) nucleotides
in length. In one embodiment, the assay can comprise a reconstituted in vitro
siNA assay
as described in Example 6 herein. In another embodiment, the assay can
comprise a cell
culture system in which target RNA is expressed. In another embodiment,
fragments of
target RNA are analyzed for detectable levels of cleavage, for example, by gel
electrophoresis, northern blot analysis, or RNAse protection assays, to
determine the
most suitable target sites) within the target target RNA sequence. The target
target
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RNA sequence can be obtained as is known in the art, for example, by cloning
and/or
transcription for in vitro systems, and by cellular expression in i>2 vivo
systems.
In another embodiment, the invention features a method comprising: (a)
analyzing
the sequence of a RNA target encoded by a target gene; (b) synthesizing one or
more sets
of siNA molecules having sequence complementary to one or more regions of the
RNA
of (a); and (c) assaying the siNA molecules of (b) under conditions suitable
to determine
RNAi targets within the target RNA sequence. In one embodiment, the siNA
molecules
of (b) have strands of a fixed length, for example about 23 nucleotides in
length. In
another embodiment, the siNA molecules of (b) are of differing length, for
example
having strands of about 15 to about 30 (e.g., about 15, 16, 17, 18, 19, 20,
21, 22, 23, 24,
25, 26, 27, 28, 29, or 30) nucleotides in length. In one embodiment, the assay
can
comprise a reconstituted ifz vitro siNA assay as described herein. In another
embodiment, the assay can comprise a cell culture system in which target RNA
is
expressed. Fragments of target RNA are analyzed for detectable levels of
cleavage, for
example by gel electrophoresis, northern blot analysis, or RNAse protection
assays, to
determine the most suitable target sites) within the target RNA sequence. The
target
RNA sequence can be obtained as is known in the art, for example, by cloning
andlor
transcription for iTZ vitro systems, and by expression in in vivo systems.
By "target site" is meant a sequence within a target RNA that is "targeted"
for
cleavage mediated by a siNA construct which contains sequences within its
antisense
region that are complementary to the target sequence.
By "detectable level of cleavage" is meant cleavage of target RNA (and
formation
of cleaved product RNAs) to an extent sufficient to discern cleavage products
above the
background of RNAs produced by random degradation of the target RNA.
Production of
cleavage products from 1-5% of the target RNA is sufficient to detect above
the
background for most methods of detection.
In one embodiment, the invention features a composition comprising a siNA
molecule of the invention, which can be chemically-modified, in a
pharmaceutically
acceptable Garner or diluent. In another embodiment, the invention features a
pharmaceutical composition comprising siNA molecules of the invention, which
can be
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chemically-modified, targeting one or more genes in a pharmaceutically
acceptable
carrier or diluent. In another embodiment, the invention features a method for
diagnosing a disease or condition in a subject comprising administering to the
subject a
composition of the invention under conditions suitable for the diagnosis of
the disease or
condition in the subject. In another embodiment, the invention features a
method for
treating or preventing a disease or condition in a subject, comprising
administering to the
subject a composition of the invention under conditions suitable for the
treatment or
prevention of the disease or condition in the subject, alone or in conjunction
with one or
more other therapeutic compounds. In yet another embodiment, the invention
features a
method for treating or preventing diseases, traits, disorders, and/or
conditions in a subject
or organism comprising administering to the subject a composition of the
invention
under conditions suitable for the treatment or prevention of the disease,
trait, disorder,
andlor condition in the subject or organism.
In another embodiment, the invention features a method for validating a gene
target, comprising: (a) synthesizing a siNA molecule of the invention, which
can be
chemically-modified, wherein one of the siNA strands includes a sequence
complementary to RNA of a target gene; (b) introducing the siNA molecule into
a cell,
tissue, subject, or organism under conditions suitable for modulating
expression of the
target gene in the cell, tissue, subject, or organism; and (c) determining the
function of
the target gene by assaying for any phenotypic change in the cell, tissue,
subject, or
organism.
In another embodiment, the invention features a method for validating a gene
target comprising: (a) synthesizing a siNA molecule of the invention, which
can be
chemically-modified, wherein one of the siNA strands includes a sequence
complementary to RNA of a target gene; (b) introducing the siNA molecule into
a
biological system under conditions suitable for modulating expression of the
target gene
in the biological system; and (c) determining the function of the gene by
assaying for any
phenotypic change in the biological system.
By "biological system" is meant, material, in a purified or unpurified form,
from
biological sources, including but not limited to human or animal, wherein the
system
comprises the components required for RNAi activity. The term "biological
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includes, for example, a cell, tissue, subject, or organism, or extract
thereof. The term
biological system also includes reconstituted RNAi systems that can be used in
an in
vitf°o setting.
By "phenotypic change" is meant any detectable change to a cell that occurs in
response to contact or treatment with a nucleic acid molecule of the invention
(e.g.,
siNA). Such detectable changes include, but are not limited to, changes in
shape, size,
proliferation, motility, protein expression or RNA expression or other
physical or
chemical changes as can be assayed by methods known in the art. The detectable
change
can also include expression of reporter genes/molecules such as Green
Florescent Protein
(GFP) or various tags that are used to identify an expressed protein or any
other cellular
component that can be assayed.
In one embodiment, the invention features a kit containing a siNA molecule of
the
invention, which can be chemically-modified, that can be used to modulate the
expression of a target gene in a biological system, including, for example, in
a cell,
tissue, subject, or organism. In another embodiment, the invention features a
kit
containing more than one siNA molecule of the invention, which can be
chemically-
modified, that can be used to modulate the expression of more than one target
gene in a
biological system, including, for example, in a cell, tissue, subject, or
organism.
In one embodiment, the invention features a cell containing one or more siNA
molecules of the invention, which can be chemically-modified. In another
embodiment,
the cell containing a siNA molecule of the invention is a mammalian cell. In
yet another
embodiment, the cell containing a siNA molecule of the invention is a human
cell.
In one embodiment, the synthesis of a siNA molecule of the invention, which
can
be chemically-modified, comprises: (a) synthesis of two complementary strands
of the
siNA molecule; (b) annealing the two complementary strands together under
conditions
suitable to obtain a double-stranded siNA molecule. In another embodiment,
synthesis
of the two complementary strands of the siNA molecule is by solid phase
oligonucleotide
synthesis. In yet another embodiment, synthesis of the two complementary
strands of the
siNA molecule is by solid phase tandem oligonucleotide synthesis.
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In one embodiment, the invention features a method for synthesizing a siNA
duplex molecule comprising: (a) synthesizing a first oligonucleotide sequence
strand of
the siNA molecule, wherein the first oligonucleotide sequence strand comprises
a
cleavable linker molecule that can be used as a scaffold for the synthesis of
the second
oligonucleotide sequence strand of the siNA; (b) synthesizing the second
oligonucleotide
sequence strand of siNA on the scaffold of the first oligonucleotide sequence
strand,
wherein the second oligonucleotide sequence strand further comprises a
chemical moiety
than can be used to purify the siNA duplex; (c) cleaving the linker molecule
of (a) under
conditions suitable for the two siNA oligonucleotide strands to hybridize and
form a
stable duplex; and (d) purifying the siNA duplex utilizing the chemical moiety
of the
second oligonucleotide sequence strand. In one embodiment, cleavage of the
linker
molecule in (c) above takes place during deprotection of the oligonucleotide,
for
example, under hydrolysis conditions using an alkylamine base such as
methylamine. Ire
one embodiment, the method of synthesis comprises solid phase synthesis on a
solid
support such as controlled pore glass (CPG) or polystyrene, wherein the first
sequence of
(a) is synthesized on a cleavable linker, such as a succinyl linker, using the
solid support
as a scaffold. The cleavable linker in (a) used as a scaffold for synthesizing
the second
strand can comprise similar reactivity as the solid support derivatized
linker, such that
cleavage of the solid support derivatized linker and the cleavable linker of
(a) takes place
concomitantly. In another embodiment, the chemical moiety of (b) that can be
used to
isolate the attached oligonucleotide sequence comprises a trityl group, for
example a_
dimethoxytrityl group, which can be employed in a trityl-on synthesis strategy
as
described herein. In yet another embodiment, the chemical moiety, such as a.
dimethoxytrityl group, is removed during purification, for example, using
acidic
conditions.
In a further embodiment, the method for siNA synthesis is a solution phase
synthesis or hybrid phase synthesis wherein both strands of the siNA duplex
are
synthesized in tandem using a cleavable linker attached to the first sequence
which acts a.
scaffold for synthesis of the second sequence. Cleavage of the linker under
conditions
suitable for hybridization of the separate siNA sequence strands results in
formation of
the double-stranded siNA molecule.
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In another embodiment, the invention features a method for syntriesizmg a sm~
duplex molecule comprising: (a) synthesizing one oligonucleotide sequence
strand of
the siNA molecule, wherein the sequence comprises a cleavable linker molecule
that can
be used as a scaffold for the synthesis of another oligonucleotide sequence;
(b)
synthesizing a second oligonucleotide sequence having complementarity to the
first
sequence strand on the scaffold of (a), wherein the second sequence comprises
the other
strand of the double-stranded siNA molecule and wherein the second sequence
further
comprises a chemical moiety than can be used to isolate the attached
oligonucleotide
sequence; (c) purifying the product of (b) utilizing the chemical moiety of
the second
oligonucleotide sequence strand under conditions suitable for isolating the
full-length
sequence comprising both siNA oligonucleotide strands connected by the
cleavable
linker and under conditions suitable for the two siNA oligonucleotide strands
to
hybridize and form a stable duplex. In one embodiment, cleavage of the linker
molecule
in (c) above takes place during deprotection of the oligonucleotide, for
example, under
hydrolysis conditions. In another embodiment, cleavage of the linker molecule
in (c)
above takes place after deprotection of the oligonucleotide. In another
embodiment, the
method of synthesis comprises solid phase synthesis on a solid support such as
controlled
pore glass (CPG) or polystyrene, wherein the first sequence of (a) is
synthesized on a
cleavable linker, such as a succinyl linker, using the solid support as a
scaffold. The
cleavable linker in (a) used as a scaffold for synthesizing the second strand
can comprise
similar reactivity or differing reactivity as the solid support derivatized
linker, such that
cleavage of the solid support derivatized linker and the cleavable linker of
(a) takes place
either concomitantly or sequentially. In one embodiment, the chemical moiety
of (b) that
can be used to isolate the attached oligonucleotide sequence comprises a
trityl group, for
example a dimethoxytrityl group.
In another embodiment, the invention features a method for making a double-
stranded siNA molecule in a single synthetic process comprising: (a)
synthesizing an
oligonucleotide having a first and a second sequence, wherein the first
sequence is
complementary to the second sequence, and the ftrst oligonucleotide sequence
is linked
to the second sequence via a cleavable linker, and wherein a terminal 5'-
protecting group,
for example, a 5'-O-dimethoxytrityl group (5'-O-DMT) remains on the
oligonucleotide
having the second sequence; (b) deprotecting the oligonucleotide whereby the
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deprotection results in the cleavage of the linker joining the two
oligonucleotide
sequences; and (c) purifying the product of (b) under conditions suitable for
isolating the
double-stranded siNA molecule, for example using a trityl-on synthesis
strategy as
described herein.
In another embodiment, the method of synthesis of siNA molecules of the
invention comprises the teachings of Scaringe et al., US Patent Nos.
5,889,136;
6,008,400; and 6,111,086, incorporated by reference herein in their entirety.
In one embodiment, the invention features siNA constructs that mediate RNAi
against a target polynucleotide (e.g., DNA or RNA), wherein the siNA construct
comprises one or more chemical modifications, for example, one or more
chemical
modifications having any of Formulae I-VII or any combination thereof that
increases
the nuclease resistance of the siNA construct.
In another embodiment, the invention features a method for generating siNA
molecules with increased nuclease resistance comprising (a) introducing
nucleotides
having any of Formula I-VII or any combination thereof into a siNA molecule,
and (b)
assaying the siNA molecule of step (a) under conditions suitable for isolating
siNA
molecules having increased nuclease resistance.
In another embodiment, the invention features a method for generating siNA
molecules with improved toxicologic profiles (e.g., have attenuated or no
immunstimulatory properties) comprising (a) introducing nucleotides having any
of
Formula I-VII (e.g., siNA motifs referred to in Table II) or any combination
thereof into
a siNA molecule, and (b) assaying the siNA molecule of step (a) under
conditions
suitable for isolating siNA molecules having improved toxicologic profiles.
In another embodiment, the invention features a method for generating siNA
molecules that do not stimulate an interferon response (e.g., no interferon
response or
attenuated interferon response) in a cell, subject, or organism, comprising
(a) introducing
nucleotides having any of Formula I-VIT (e.g., siNA motifs referred to in
Table II) or
any combination thereof into a siNA molecule, and (b) assaying the siNA
molecule of
step (a) under conditions suitable for isolating siNA molecules that do not
stimulate an
interferon response.
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By "improved toxicologic profile", is meant that the chemically modified siNA
construct exhibits decreased toxicity in a cell, subject, or organism compared
to an
unmodified siNA or siNA molecule having fewer modifications or modifications
that are
less effective in imparting improved toxicology. In a non-limiting example,
siNA
molecules with improved toxicologic profiles are associated with a decreased
or
attenuated immunostimulatory response in a cell, subject, or organism compared
to an
unmodified siNA or siNA molecule having fewer modifications or modifications
that are
less effective in imparting improved toxicology. In one embodiment, a siNA
molecule
with an improved toxicological profile comprises no ribonucleotides. In one
embodiment, a siNA molecule with an improved toxicological profile comprises
less
than 5 ribonucleotides (e.g., 1, 2, 3, or 4 ribonucleotides). In one
embodiment, a siNA
molecule with an improved toxicological profile comprises Stab 7, Stab 8, Stab
11, Stab
12, Stab 13, Stab 16, Stab 17, Stab 18, Stab 19, Stab 20, Stab 23, Stab 24,
Stab 25, Stab
26, Stab 27, Stab 28, Stab 29, Stab 30, Stab 31, Stab 32 or any combination
thereof (see
Table II). In one embodiment, the level of immunostimulatory response
associated with
a given siNA molecule can be measured as is known in the art, for example by
determining the level of PKR/interferon response, proliferation, B-cell
activation, andlor
cytokine production in assays to quantitate the immunostimulatory response of
particular
siNA molecules (see, for example, Leifer et. al., 2003, Jlnamunotlzer. 26, 313-
9; and U.S.
Patent No. 5968909, incorporated in its entirety by reference).
In one embodiment, the invention features siNA constructs that mediate RNAi
against a target polynucleotide (e.g., DNA or RNA), wherein the siNA construct
comprises one or more chemical modifications described herein that modulates
the
binding affinity between the sense and antisense strands of the siNA
construct.
In another embodiment, the invention features a method for generating siNA
molecules with increased binding affinity between the sense and antisense
strands of the
siNA molecule comprising (a) introducing nucleotides having any of Formula I-
VII or
any combination thereof into a siNA molecule, and (b) assaying the siNA
molecule of
step (a) under conditions suitable for isolating siNA molecules having
increased binding
affinity between the sense and antisense strands of the siNA molecule.
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In one embodiment, the invention features siNA constructs that mediate RNAi
against a target polynucleotide (e.g., DNA or RNA), wherein the siNA construct
comprises one or more chemical modifications described herein that modulates
the
binding affinity between the antisense strand of the siNA construct and a
complementary
target RNA sequence within a cell.
In one embodiment, the invention features siNA constructs that mediate RNAi
against a target polynucleotide (e.g., DNA or RNA), wherein the siNA construct
comprises one or more chemical modifications described herein that modulates
the
binding affinity between the antisense strand of the siNA construct and a
complementary
target DNA sequence within a cell.
In another embodiment, the invention features a method for generating siNA
molecules with increased binding affinity between the antisense strand of the
siNA
molecule and a complementary target RNA sequence comprising (a) introducing
nucleotides having any of Formula I-VII or any combination thereof into a siNA
molecule, and (b) assaying the siNA molecule of step (a) under conditions
suitable for
isolating siNA molecules having increased binding affinity between the
antisense strand
of the siNA molecule and a complementary target RNA sequence.
In another embodiment, the invention features a method for generating siNA
molecules with increased binding affinity between the antisense strand of the
siNA
molecule and a complementary target DNA sequence comprising (a) introducing
nucleotides having any of Formula I-VII or any combination thereof into a siNA
molecule, and (b) assaying the siNA molecule of step (a) under conditions
suitable for
isolating siNA molecules having increased binding affinity between the
antisense strand
of the siNA molecule and a complementary target DNA sequence.
In one embodiment, the invention features siNA constructs that mediate RNAi
against a target polynucleotide (e.g., DNA or RNA), wherein the siNA construct
comprises one or more chemical modifications described herein that modulate
the
polymerase activity of a cellular polymerase capable of generating additional
endogenous siNA molecules having sequence homology to the chemically-modified
siNA construct.
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In another embodiment, the invention features a method for generating siNA
molecules capable of mediating increased polymerise activity of a cellular
polymerise
capable of generating additional endogenous siNA molecules having sequence
homology
to a chemically-modified siNA molecule comprising (a) introducing nucleotides
having
any of Formula I-VII or any combination thereof into a siNA molecule, and (b)
assaying
the siNA molecule of step (a) under conditions suitable for isolating siNA
molecules
capable of mediating increased polymerise activity of a cellular polymerise
capable of
generating additional endogenous siNA molecules having sequence homology to
the
chemically-modified siNA molecule.
In one embodiment, the invention features chemically-modified siNA constructs
that mediate RNAi against a target polynucleotide (e.g., DNA or RNA) in a
cell, wherein
the chemical modifications do not significantly effect the interaction of siNA
with a
target RNA molecule, DNA molecule and/or proteins or other factors that are
essential
for RNAi in a manner that would decrease the efficacy of RNAi mediated by such
siNA
constructs.
In another embodiment, the invention features a method for generating siNA
molecules with improved RNAi activity against a target polynucleotide (e.g.,
DNA or
RNA) comprising (a) introducing nucleotides having any of Formula I-VII or any
combination thereof into a siNA molecule, and (b) assaying the siNA molecule
of step
(a) under conditions suitable for isolating siNA molecules having improved
RNAi
activity.
In yet another embodiment, the invention features a method for generating siNA
molecules with improved RNAi activity against a target RNA comprising (a)
introducing
nucleotides having any of Formula I-VII or any combination thereof into a siNA
molecule, and (b) assaying the siNA molecule of step (a) under conditions
suitable for
isolating siNA molecules having improved RNAi activity against the target RNA.
In yet another embodiment, the invention features a method for generating siNA
molecules with improved RNAi activity against a target DNA comprising (a)
introducing
nucleotides having any of Formula I-VII or any combination thereof into a siNA
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molecule, and (b) assaying the siNA molecule of step (a) under conditions
suitable for
isolating siNA molecules having improved RNAi activity against the target DNA.
In one embodiment, the invention features siNA constructs that mediate RNAi
against a target polynucleotide (e.g., DNA or RNA), wherein the siNA construct
comprises one or more chemical modifications described herein that modulates
the
cellular uptake of the siNA construct.
In another embodiment, the invention features a method for generating siNA
molecules against a target polynucleotide (e.g., DNA or RNA) with improved
cellular
uptake comprising (a) introducing nucleotides having any of Formula I-VII or
any
combination thereof into a siNA molecule, and (b) assaying the siNA molecule
of step
(a) under conditions suitable for isolating siNA molecules having improved
cellular
uptake.
In one embodiment, the invention features siNA constructs that mediate RNAi
against a target polynucleotide (e.g., DNA or RNA), wherein the siNA construct
comprises one or more chemical modifications described herein that increases
the
bioavailability of the siNA construct, for example, by attaching polymeric
conjugates
such as polyethyleneglycol or equivalent conjugates that improve the
pharmacokinetics
of the siNA construct, or by attaching conjugates that target speciEc tissue
types or cell
types ira vivo. Non-limiting examples of such conjugates are described in
Vargeese et al.,
U.S. Serial No. 10/201,394 incorporated by reference herein.
In one embodiment, the invention features a method for generating siNA
molecules of the invention with improved bioavailability comprising (a)
introducing a
conjugate into the structure of a siNA molecule, and (b) assaying the siNA
molecule of
step (a) under conditions suitable for isolating siNA molecules having
improved
bioavailability. Such conjugates can include ligands for cellular receptors,
such as
peptides derived from naturally occurring protein ligands; protein
localization sequences,
including cellular ZIP code sequences; antibodies; nucleic acid aptamers;
vitamins and
other co-factors, such as folate and N-acetylgalactosamine; polymers, such as
polyethyleneglycol (PEG); phospholipids; cholesterol; polyamines, such as
spermine or
spermidine; and others.
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In one embodiment, the invention features a double stranded short interfering
nucleic acid (siNA) molecule that comprises a first nucleotide sequence
complementary
to a target RNA sequence or a portion thereof, and a second sequence having
complementarity to said first sequence, wherein said second sequence is
chemically
S modified in a manner that it can no longer act as a guide sequence for
efficiently
mediating RNA interference and/or be recognized by cellular proteins that
facilitate
RNAi.
In one embodiment, the invention features a double stranded short interfering
nucleic acid (siNA) molecule that comprises a first nucleotide sequence
complementary
to a target RNA sequence or a portion thereof, and a second sequence having
complementarity to said first sequence, wherein the second sequence is
designed or
modified in a manner that prevents its entry into the RNAi pathway as a guide
sequence
or as a sequence that is complementary to a target nucleic acid (e.g., RNA)
sequence.
Such design or modifications are expected to enhance the activity of siNA
and/or
improve the specificity of siNA molecules of the invention. These
modifications are also
expected to minimize any off target effects and/or associated toxicity.
In one embodiment, the invention features a double stranded short interfering
nucleic acid (siNA) molecule that comprises a first nucleotide sequence
complementary
to a target RNA sequence or a portion thereof, and a second sequence having
complementarity to said first sequence, wherein said second sequence is
incapable of
acting as a guide sequence for mediating RNA interference.
In one embodiment, the invention features a double stranded short interfering
nucleic acid (siNA) molecule that comprises a first nucleotide sequence
complementary
to a target RNA sequence or a portion thereof, and a second sequence having
complementarity to said first sequence, wherein said second sequence does not
have a
terminal 5'-hydroxyl (5'-OH) or 5'-phosphate group.
In one embodiment, the invention features a double stranded short interfering
nucleic acid (siNA) molecule that comprises a first nucleotide sequence
complementary
to a target RNA sequence or a portion thereof, and a second sequence having
complementarity to said first sequence, wherein said second sequence comprises
a
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terminal cap moiety at the 5'-end of said second sequence. In one embodiment,
the
terminal cap moiety comprises an inverted abasic, inverted deoxy abasic,
inverted
nucleotide moiety, a group shown in Figure 10, an alkyl or cycloalkyl group, a
heterocycle, or any other group that prevents RNAi activity in which the
second
sequence serves as a guide sequence or template for RNAi.
In one embodiment, the invention features a double stranded short interfering
nucleic acid (siNA) molecule that comprises a first nucleotide sequence
complementary
to a target RNA sequence or a portion thereof, and a second sequence having
complementarity to said first sequence, wherein said second sequence comprises
a
terminal cap moiety at the 5'-end and 3'-end of said second sequence. In one
embodiment, each terminal cap moiety individually comprises an inverted
abasic,
inverted deoxy abasic, inverted nucleotide moiety, a group shown in Figure 10,
an alkyl
or cycloalkyl group, a heterocycle, or any other group that prevents RNAi
activity in
which the second sequence serves as a guide sequence or template for RNAi.
In one embodiment, the invention features a method for generating siNA
molecules of the invention with improved specificity for down regulating or
inhibiting
the expression of a target nucleic acid (e.g., a DNA or RNA such as a gene or
its
corresponding RNA), comprising (a) introducing one or more chemical
modifications
into the structure of a siNA molecule, and (b) assaying the siNA molecule of
step (a)
under conditions suitable for isolating siNA molecules having improved
specificity. In
another embodiment, the chemical modification used to improve specificity
comprises
terminal cap modifications at the 5'-end, 3'-end, or both 5' and 3'-ends of
the siNA
molecule. The terminal cap modifications can comprise, for example, structures
shown
in Figure 10 (e.g. inverted deoxyabasic moieties) or any other chemical
modification
that renders a portion of the siNA molecule (e.g. the sense strand) incapable
of mediating
RNA interference against an off target nucleic acid sequence. In a non-
limiting example,
a siNA molecule is designed such that only the antisense sequence of the siNA
molecule
can serve as a guide sequence for RISC mediated degradation of a corresponding
target
RNA sequence. This can be accomplished by rendering the sense sequence of the
siNA
inactive by introducing chemical modifications to the sense strand that
preclude
recognition of the sense strand as a guide sequence by RNAi machinery. In one
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embodiment, such chemical modifications comprise any chemical group at the ~'-
enn ox
the sense strand of the siNA, or any other group that serves to render the
sense strand
inactive as a guide sequence for mediating RNA interference. These
modifications, for
example, can result in a molecule where the 5'-end of the sense strand no
longer has a
free 5'-hydroxyl (5'-OH) or a free 5'-phosphate group (e.g., phosphate,
diphosphate,
triphosphate, cyclic phosphate etc.). Non-limiting examples of such siNA
constructs are
described herein, such as "Stab 9/10", "Stab 7/8", "Stab 7/19", "Stab 17/22",
"Stab
23/24", "Stab 24/25", and "Stab 24/26" (e.g., any siNA having Stab 7, 9, 17,
23, or 24
sense strands) chemistries and variants thereof (see Table II) wherein the 5'-
end and 3'-
end of the sense strand of the siNA do not comprise a hydroxyl group or
phosphate
group.
In one embodiment, the invention features a method for generating siNA
molecules of the invention with improved specificity for down regulating or
inhibiting
the expression of a target nucleic acid (e.g., a DNA or RNA such as a gene or
its
corresponding RNA), comprising introducing one or more chemical modifications
into
the structure of a siNA molecule that prevent a strand or portion of the siNA
molecule
from acting as a template or guide sequence for RNAi activity. In one
embodiment, the
inactive strand or sense region of the siNA molecule is the sense strand or
sense region
of the siNA molecule, i.e. the strand or region of the siNA that does not have
complementarity to the target nucleic acid sequence. In one embodiment, such
chemical
modifications comprise any chemical group at the 5'-end of the sense strand or
region of
the siNA that does not comprise a 5'-hydroxyl (5'-OH) or 5'-phosphate group,
or any
other group that serves to render the sense strand or sense region inactive as
a guide
sequence for mediating RNA interference. Non-limiting examples of such siNA
constructs are described herein, such as "Stab 9/10", "Stab 7/8", "Stab 7/19",
"Stab
17/22", "Stab 23/24", "Stab 24/25", and "Stab 24/26" (e.g., any siNA having
Stab 7, 9,
17, 23, or 24 sense strands) chemistries and variants thereof (see Table II)
wherein the
5'-end and 3'-end of the sense strand of the siNA do not comprise a hydroxyl
group or
phosphate group.
In one embodiment, the invention features a method for screening siNA
molecules
that are active in mediating RNA interference against a target nucleic acid
sequence
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comprising (a) generating a plurality of unmodified siNA molecules, (b)
screening the
siNA molecules of step (a) under conditions suitable for isolating siNA
molecules that
are active in mediating RNA interference against the target nucleic acid
sequence, and
(c) introducing chemical modifications (e.g. chemical modifications as
described herein
or as otherwise known in the art) into the active siNA molecules of (b). In
one
embodiment, the method further comprises re-screening the chemically modified
siNA
molecules of step (c) under conditions suitable for isolating chemically
modified siNA
molecules that are active in mediating RNA interference against the target
nucleic acid
sequence.
In one embodiment, the invention features a method for screening chemically
modified siNA molecules that are active in mediating RNA interference against
a target
nucleic acid sequence comprising (a) generating a plurality of chemically
modified siNA
molecules (e.g. siNA molecules as described herein or as otherwise known in
the art),
and (b) screening the siNA molecules of step (a) under conditions suitable for
isolating
chemically modified siNA molecules that are active in mediating RNA
interference
against the target nucleic acid sequence.
The term "ligand" refers to any compound or molecule, such as a drug, peptide,
hormone, or neurotransmitter, that is capable of interacting with another
compound, such
as a receptor, either directly or indirectly. The receptor that interacts with
a ligand can be
present on the surface of a cell or can alternately be an intercellular
receptor. Interaction
of the ligand with the receptor can result in a biochemical reaction, or can
simply be a
physical interaction or association.
In another embodiment, the invention features a method for generating siNA
molecules of the invention with improved bioavailability comprising (a)
introducing an
excipient formulation to a siNA molecule, and (b) assaying the siNA molecule
of step (a)
under conditions suitable for isolating siNA molecules having improved
bioavailability.
Such excipients include polymers such as cyclodextrins, lipids, cationic
lipids,
polyamines, phospholipids, nanoparticles, receptors, ligands, and others.
In another embodiment, the invention features a method for generating siNA
molecules of the invention with improved bioavailability comprising (a)
introducing
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nucleotides having any of Formulae I-VII or any combination thereof into a
siNA
molecule, and (b) assaying the siNA molecule of step (a) under conditions
suitable for
isolating siNA molecules having improved bioavailability.
In another embodiment, polyethylene glycol (PEG) can be covalently attached to
siNA compounds of the present invention. The attached PEG can be any molecular
weight, preferably from about 2,000 to about 50,000 daltons (Da).
The present invention can be used alone or as a component of a kit having at
least
one of the reagents necessary to carry out the izz vitz~o or in vivo
introduction of RNA to
test samples and/or subjects. For example, preferred components of the kit
include a
siNA molecule of the invention and a vehicle that promotes introduction of the
siNA into
cells of interest as described herein (e.g., using lipids and other methods of
transfection
known in the art, see for example Beigelman et al, US 6,395,713). The kit can
be used
for target validation, such as in determining gene function and/or activity,
or in drug
optimization, and in drug discovery (see for example Usman et al., USSN
60/402,996).
Such a kit can also include instructions to allow a user of the kit to
practice the invention.
The term "short interfering nucleic acid", "siNA", "short interfering RNA",
"siRNA", "short interfering nucleic acid molecule", "short interfering
oligonucleotide
molecule", or "chemically-modified short interfering nucleic acid molecule" as
used
herein refers to any nucleic acid molecule capable of inhibiting or down
regulating gene
expression or viral replication, for example by mediating RNA interference
"RNAi" or
gene silencing in a sequence-specific manner; see for example Zamore et al.,
2000, Cell,
101, 25-33; Bass, 2001, Nature, 411, 428-429; Elbashir et. al., 2001, Nature,
411, 494-
498; and Kreutzer et al., International PCT Publication No. WO 00/44895;
Zernicka-
Goetz et al., International PCT Publication No. WO 01/36646; Fire,
International PCT
Publication No. WO 99/32619; Plaetinck et al., International PCT Publication
No. WO
00/01846; Mello and Fire, International PCT Publication No. WO 01/29058;
Deschamps-Depaillette, International PCT Publication No. WO 99/07409; and Li
et al.,
International PCT Publication No. WO 00/44914; Allshire, 2002, Sciezzce, 297,
1818-
1819; Volpe et al., 2002, Science, 297, 1833-1837; Jenuwein, 2002, Sciezzce,
297, 2215-
2218; and Hall et al., 2002, Sciezzce, 297, 2232-2237; Hutvagner and Zamore,
2002,
Science, 297, 2056-60; McManus et al., 2002, RNA, 8, 842-850; Reinhart et al.,
2002,
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Gene & Dev., 16, 1616-1626; and Reinhart & Bartel, 2002, Science, 297, 1831).
Non
limiting examples of siNA molecules of the invention are shown in Figures 4-6
herein.
For example the siNA can be a double-stranded polynucleotide molecule
comprising
self complementary sense and antisense regions, wherein the antisense region
comprises
nucleotide sequence that is complementary to nucleotide sequence in a target
nucleic
acid molecule or a portion thereof and the sense region having nucleotide
sequence
corresponding to the target nucleic acid sequence or a portion thereof. The
siNA can be
assembled from two separate oligonucleotides, where one strand is the sense
strand and
the other is the antisense strand, wherein the antisense and sense strands are
self
complementary (i.e. each strand comprises nucleotide sequence that is
complementary to
nucleotide sequence in the other strand; such as where the antisense strand
and sense
strand form a duplex or double stranded structure, for example wherein the
double
stranded region is about 15 to about 30, e.g., about 15, 16, 17, 18, 19, 20,
21, 22, 23, 24,
25, 26, 27, 28, 29 or 30 base pairs; the antisense strand comprises nucleotide
sequence
that is complementary to nucleotide sequence in a target nucleic acid molecule
or a
portion thereof and the sense strand comprises nucleotide sequence
corresponding to the
target nucleic acid sequence or a portion thereof (e.g., about 15 to about 25
or more
nucleotides of the siNA molecule are complementary to the target nucleic acid
or a
portion thereof). Alternatively, the siNA is assembled from a single
oligonucleotide,
where the self complementary sense and antisense regions of the siNA are
linked by
means of a nucleic acid based or non-nucleic acid-based linker(s). The siNA
can be a
polynucleotide with a duplex, asymmetric duplex, hairpin or asymmetric hairpin
secondary structure, having self complementary sense and antisense regions,
wherein the
antisense region comprises nucleotide sequence that is complementary to
nucleotide
sequence in a separate target nucleic acid molecule or a portion thereof and
the sense
region having nucleotide sequence corresponding to the target nucleic acid
sequence or a
portion thereof. The siNA can be a circular single-stranded polynucleotide
having two
or more loop structures and a stem comprising self complementary sense and
antisense
regions, wherein the antisense region comprises nucleotide sequence that is
complementary to nucleotide sequence in a target nucleic acid molecule or a
portion
thereof and the sense region having nucleotide sequence corresponding to the
target
nucleic acid sequence or a portion thereof, and wherein the circular
polynucleotide can
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be processed either in vivo or in vitro to generate an active siNA molecule
capable of
mediating RNAi. The siNA can also comprise a single stranded polynucleotide
having
nucleotide sequence complementary to nucleotide sequence in a target nucleic
acid
molecule or a portion thereof (for example, where such siNA molecule does not
require
the presence within the siNA molecule of nucleotide sequence corresponding to
the
target nucleic acid sequence or a portion thereofj, wherein the single
stranded
polynucleotide can further comprise a terminal phosphate group, such as a 5'-
phosphate
(see for example Martinez et al., 2002, Cell., 110, 563-574 and Schwarz et
al., 2002,
Molecular Cell, 10, 537-568), or 5',3'-diphosphate. In certain embodiments,
the siNA
molecule of the invention comprises separate sense and antisense sequences or
regions,
wherein the sense and antisense regions are covalently linked by nucleotide or
non-
nucleotide linkers molecules as is known in the art, or are alternately non-
covalently
linked by ionic interactions, hydrogen bonding, van der waals interactions,
hydrophobic
interactions, and/or stacking interactions. In certain embodiments, the siNA
molecules
of the invention comprise nucleotide sequence that is complementary to
nucleotide
sequence of a target gene. In another embodiment, the siNA molecule of the
invention
interacts with nucleotide sequence of a target gene in a manner that causes
inhibition of
expression of the target gene. As used herein, siNA molecules need not be
limited to
those molecules containing only RNA, but further encompasses chemically-
modified
nucleotides and non-nucleotides. In certain embodiments, the short interfering
nucleic
acid molecules of the invention lack 2'-hydroxy (2'-OH) containing
nucleotides.
Applicant describes in certain embodiments short interfering nucleic acids
that do not
require the presence of nucleotides having a 2'-hydroxy group for mediating
RNAi and
as such, short interfering nucleic acid molecules of the invention optionally
do not
include any ribonucleotides (e.g., nucleotides having a 2'-OH group). Such
siNA
molecules that do not require the presence of ribonucleotides within the siNA
molecule
to support RNAi can however have an attached linker or linkers or other
attached or
associated groups, moieties, or chains containing one or more nucleotides with
2'-OH
groups. Optionally, siNA molecules can comprise ribonucleotides at about 5,
10, 20, 30,
40, or 50% of the nucleotide positions. The modified short interfering nucleic
acid
molecules of the invention can also be referred to as short interfering
modified
oligonucleotides "siMON." As used herein, the term siNA is meant to be
equivalent to
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other terms used to describe nucleic acid molecules that are capable of
mediating
sequence specific RNAi, for example short interfering RNA (siRNA), double-
stranded
RNA (dsRNA), micro-RNA (miRNA), short hairpin RNA (shRNA), short interfering
oligonucleotide, short interfering nucleic acid, short interfering modified
oligonucleotide,
chemically-modified siRNA, post-transcriptional gene silencing RNA (ptgsRNA),
and
others. In addition, as used herein, the term RNAi is meant to be equivalent
to other
terms used to describe sequence specific RNA interference, such as post
transcriptional
gene silencing, translational inhibition, or epigenetics. For example, siNA
molecules of
the invention can be used to epigenetically silence genes at both the post-
transcriptional
level or the pre-transcriptional level. In a non-limiting example, epigenetic
regulation of
gene expression by siNA molecules of the invention can result from siNA
mediated
modification of chromatin structure or methylation pattern to alter gene
expression (see,
for example, Verdel et al., 2004, Sciey~ce, 303, 672-676; Pal-Bhadra et al.,
2004, Scieyace,
303, 669-672; Allshire, 2002, Science, 297, 1818-1819; Volpe et al., 2002,
Scie~zce, 297,
1833-1837; Jenuwein, 2002, Sciehce, 297, 2215-2218; and Hall et al., 2002,
Scieyace,
297, 2232-2237).
In one embodiment, a siNA molecule of the invention is a duplex forming
oligonucleotide "DFO", (see for example Figures 14-15 and Vaish et al., USSN
10/727,780 filed December 3, 2003 and International PCT Application No.
US04/16390,
filed May 24, 2004).
In one embodiment, a siNA molecule of the invention is a multifunctional siNA,
(see for example Figures 16-21 and Jadhav et al., USSN 60/543,480 filed
February 10,
2004 and International PCT Application No. US04/16390, filed May 24, 2004).
The
multifunctional siNA of the invention can comprise sequence targeting, for
example, two
regions of target RNA.
By "asymmetric hairpin" as used herein is meant a linear siNA molecule
comprising an antisense region, a loop portion that can comprise nucleotides
or non-
nucleotides, and a sense region that comprises fewer nucleotides than the
antisense
region to the extent that the sense region has enough complementary
nucleotides to base
pair with the antisense region and form a duplex with loop. For example, an
asymmetric
hairpin siNA molecule of the invention can comprise an antisense region having
length
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sufficient to mediate RNAi in a cell or in vitro system (e.g. about 15 to
about 30, or
about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30
nucleotides) and a
loop region comprising about 4 to about 12 (e.g., about 4, 5, 6, 7, 8, 9, 10,
11, or 12)
nucleotides, and a sense region having about 3 to about 25 (e.g., about 3, 4,
S, 6, 7, 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25) nucleotides
that are
complementary to the antisense region. The asymmetric hairpin siNA molecule
can also
comprise a 5'-terminal phosphate group that can be chemically modified. The
loop
portion of the asymmetric hairpin siNA molecule can comprise nucleotides, non-
nucleotides, linker molecules, or conjugate molecules as described herein.
By "asymmetric duplex" as used herein is meant a siNA molecule having two
separate strands comprising a sense region and an antisense region, wherein
the sense
region comprises fewer nucleotides than the antisense region to the extent
that the sense
region has enough complementary nucleotides to base pair with the antisense
region and
form a duplex. For example, an asymmetric duplex siNA molecule of the
invention can
comprise an antisense region having length sufficient to mediate RNAi in a
cell or in
vitro system (e.g. about 15 to about 30, or about 15, 16, 17, 18, 19, 20, 21,
22, 23, 24, 25,
26, 27, 28, 29, or 30 nucleotides) and a sense region having about 3 to about
25 (e.g.,
about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,
23, 24, or 25)
nucleotides that are complementary to the antisense region.
By "modulate" is meant that the expression of the gene, or level of RNA
molecule
or equivalent RNA molecules encoding one or more proteins or protein subunits,
or
activity of one or more proteins or protein subunits is up regulated or down
regulated,
such that expression, level, or activity is greater than or less than that
observed in the
absence of the modulator. For example, the term "modulate" can mean "inhibit,"
but the
use of the word "modulate" is not limited to this definition.
By "inhibit", "down-regulate", or "reduce", it is meant that the expression of
the
gene, or level of RNA molecules or equivalent RNA molecules encoding one or
more
proteins or protein subunits, or activity of one or more proteins or protein
subunits, is
reduced below that observed in the absence of the nucleic acid molecules
(e.g., siNA) of
the invention. In one embodiment, inhibition, down-regulation or reduction
with an siNA
molecule is below that level observed in the presence of an inactive or
attenuated
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molecule. In another embodiment, inhibition, down-regulation, or reduction
with siNA
molecules is below that level observed in the presence of, for example, an
siNA
molecule with scrambled sequence or with mismatches. In another embodiment,
inhibition, down-regulation, or reduction of gene expression with a nucleic
acid molecule
of the instant invention is greater in the presence of the nucleic acid
molecule than in its
absence. In one embodiment, inhibition, down regulation, or reduction of gene
expression is associated with post transcriptional silencing, such as RNAi
mediated
cleavage of a target nucleic acid molecule (e.g. RNA) or inhibition of
translation. In one
embodiment, inhibition, down regulation, or reduction of gene expression is
associated
with pretranscriptional silencing.
By "gene", or "target gene", is meant a nucleic acid that encodes an RNA, for
example, nucleic acid sequences including, but not limited to, structural
genes encoding
a polypeptide. A gene or target gene can also encode a functional RNA (fRNA)
or non-
coding RNA (ncRNA), such as small temporal RNA (stRNA), micro RNA (miRNA),
small nuclear RNA (snRNA), short interfering RNA (siRNA), small nucleolar RNA
(snRNA), ribosomal RNA (rRNA), transfer RNA (tRNA) and precursor RNAs thereof.
Such non-coding RNAs can serve as target nucleic acid molecules for siNA
mediated
RNA interference in modulating the activity of fRNA or ncRNA involved in
functional
or regulatory cellular processes. Abberant fRNA or ncRNA activity leading to
disease
can therefore be modulated by siNA molecules of the invention. siNA molecules
targeting fRNA and ncRNA can also be used to manipulate or alter the genotype
or
phenotype of a subject, organism or cell, by intervening in cellular processes
such as
genetic imprinting, transcription, translation, or nucleic acid processing
(e.g.,
transamination, methylation etc.). The target gene can be a gene derived from
a cell, an
endogenous gene, a transgene, or exogenous genes such as genes of a pathogen,
for
example a virus, which is present in the cell after infection thereof. The
cell containing
the target gene can be derived from or contained in any organism, for example
a plant,
animal, protozoan, virus, bacterium, or fungus. Non-limiting examples of
plants include
monocots, dicots, or gymnosperms. Non-limiting examples of animals include
vertebrates or invertebrates. Non-limiting examples of fungi include molds or
yeasts.
For a review, see for example Snyder and Gerstein, 2003, Science, 300, 258-
260.
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By "non-canonical base pair" is meant any non-Watson Crick base pair, such as
mismatches and/or wobble base pairs, including flipped mismatches, single
hydrogen
bond mismatches, trans-type mismatches, triple base interactions, and
quadruple base
interactions. Non-limiting examples of such non-canonical base pairs include,
but are
not limited to, AC reverse Hoogsteen, AC wobble, AU reverse Hoogsteen, GU
wobble,
AA N7 amino, CC 2-carbonyl-amino(H1)-N3-amino(H2), GA sheared, UC 4-carbonyl-
amino, UU imino-carbonyl, AC reverse wobble, AU Hoogsteen, AU reverse Watson
Crick, CG reverse Watson Crick, GC N3-amino-amino N3, AA Nl-amino symmetric,
AA N7-amino symmetric, GA N7-Nl amino-carbonyl, GA+ carbonyl-amino N7-N1,
GG N1-carbonyl symmetric, GG N3-amino symmetric, CC carbonyl-amino symmetric,
CC N3-amino symmetric, UU 2-carbonyl-imino symmetric, UU 4-carbonyl-imino
symmetric, AA amino-N3, AA N1-amino, AC amino 2-carbonyl, AC N3-amino, AC
N7-amino, AU amino-4-carbonyl, AU N1-imino, AU N3-imino, AU N7-imino, CC
carbonyl-amino, GA amino-N1, GA amino-N7, GA carbonyl-amino, GA N3-amino, GC
amino-N3, GC carbonyl-amino, GC N3-amino, GC N7-amino, GG amino-N7, GG
carbonyl-imino, GG N7-amino, GU amino-2-carbonyl, GU carbonyl-imino, GU imino-
2-carbonyl, GU N7-imino, psiU imino-2-carbonyl, UC 4-carbonyl-amino, UC imino-
carbonyl, UU imino-4-carbonyl, AC C2-H-N3, GA carbonyl-C2-H, UU imino-4-
carbonyl 2 carbonyl-CS-H, AC amino(A) N3(C)-carbonyl, GC imino amino-carbonyl,
Gpsi imino-2-carbonyl amino-2- carbonyl, and GU imino amino-2-carbonyl base
pairs.
By "target" as used herein is meant, any target protein, peptide, or
polypeptide,
such as encoded by Genbank Accession Nos. shown in Table I. The term "target"
also
refers to nucleic acid sequences encoding any protein, peptide, or polypeptide
(e.g., DNA
and RNA). The term "target" is also meant to include other target encoding
sequences,
such as other isoforms, mutations, splice variants, and polymorphisms
associated with a
given target.
By "homologous sequence" is meant, a nucleotide sequence that is shared by one
or more polynucleotide sequences, such as genes, gene transcripts and/or non-
coding
polynucleotides. For example, a homologous sequence can be a nucleotide
sequence that
is shared by two or more genes encoding related but different proteins, such
as different
members of a gene family, different protein epitopes, different protein
isoforms or
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completely divergent genes, such as a cytokine and its corresponding
receptors. A
homologous sequence can be a nucleotide sequence that is shared by two or more
non-
coding polynucleotides, such as noncoding DNA or RNA, regulatory sequences,
introns,
and sites of transcriptional control or regulation. Homologous sequences can
also
include conserved sequence regions shared by more than one polynucleotide
sequence.
Homology does not need to be perfect homology (e.g., 100%), as partially
homologous
sequences are also contemplated by the instant invention (e.g., 99%, 98%, 97%,
96%,
95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%,
80% etc.).
By "conserved sequence region" is meant, a nucleotide sequence of one or more
regions in a polynucleotide does not vary significantly between generations or
from one
biological system, subject, or organism to another biological system, subject,
or
organism. The polynucleotide can include both coding and non-coding DNA and
RNA.
By "sense region" is meant a nucleotide sequence of a siNA molecule having
complementarity to an antisense region of the siNA molecule. In addition, the
sense
region of a siNA molecule can comprise a nucleic acid sequence having homology
with
a target nucleic acid sequence.
By "antisense region" is meant a nucleotide sequence of a siNA molecule having
complementarity to a target nucleic acid sequence. In addition, the antisense
region of a
siNA molecule can optionally comprise a nucleic acid sequence having
complementarity
to a sense region of the siNA molecule.
By "target nucleic acid" or "target polynucleotide" is meant any nucleic acid
sequence whose expression or activity is to be modulated. The target nucleic
acid can be
DNA or RNA.
By "complementarity" is meant that a nucleic acid can form hydrogen bonds)
with
another nucleic acid sequence by either traditional Watson-Crick or other non-
traditional
types. In reference to the nucleic molecules of the present invention, the
binding free
energy for a nucleic acid molecule with its complementary sequence is
sufficient to
allow the relevant function of the nucleic acid to proceed, e.g., RNAi
activity.
Determination of binding free energies for nucleic acid molecules is well
known in the
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art (see, e.g., Turner et al., 1987, CSH Symp. Quant. Biol. LII pp.123-133;
Frier et al.,
1986, Proc. Nat. Acad. Sci. USA 83:9373-9377; Turner et al., 1987, J. Ana.
Chem. Soc.
109:3783-3785). A percent complementarity indicates the percentage of
contiguous
residues in a nucleic acid molecule that can form hydrogen bonds (e.g., Watson-
Crick
base pairing) with a second nucleic acid sequence (e.g., 5, 6, 7, 8, 9, or 10
nucleotides
out of a total of 10 nucleotides in the first oligonucleotide being based
paired to a second
nucleic acid sequence having 10 nucleotides represents 50%, 60%, 70%, 80%,
90%, and
100% complementary respectively). "Perfectly complementary" means that all the
contiguous residues of a nucleic acid sequence will hydrogen bond with the
same
number of contiguous residues in a second nucleic acid sequence. In one
embodiment, a
siNA molecule of the invention comprises about 15 to about 30 or more (e.g.,
about 15,
16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or more)
nucleotides that are
complementary to one or more target nucleic acid molecules or a portion
thereof.
In one embodiment, siNA molecules of the invention that down regulate or
reduce
target gene expression are used for preventing or treating diseases, traits,
disorders,
and/or conditions in a subject or organism.
By "proliferative disease" or "cancer" as used herein is meant, any disease
condition, trait, genotype or phenotype characterized by unregulated cell
growth or
replication as is known in the art; including AIDS related cancers such as
I~aposi's
sarcoma; breast cancers; bone cancers such as Osteosarcoma, Chondrosarcomas,
Ewing's
sarcoma, Fibrosarcomas, Giant cell tumors, Adamantinomas, and Chordomas; Brain
cancers such as Meningiomas, Glioblastomas, Lower-Grade Astrocytomas,
Oligodendrocytomas, Pituitary Tumors, Schwannomas, and Metastatic brain
cancers;
cancers of the head and neck including various lymphomas such as mantle cell
lymphoma, non-Hodgkins lymphoma, adenoma, squamous cell carcinoma, laryngeal
carcinoma, gallbladder and bile duct cancers, cancers of the retina such as
retinoblastoma, cancers of the esophagus, gastric cancers, multiple myeloma,
ovarian
cancer, uterine cancer, thyroid cancer, testicular cancer, endometrial cancer,
melanoma,
colorectal cancer, lung cancer, bladder cancer, prostate cancer, lung cancer
(including
non-small cell lung carcinoma), pancreatic cancer, sarcomas, Wilms' tumor,
cervical
cancer, head and neck cancer, skin cancers, nasopharyngeal carcinoma,
liposarcoma,
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epithelial carcinoma, renal cell carcinoma, gallbladder adeno carcinoma,
parotid
adenocarcinoma, endometrial sarcoma, multidrug resistant cancers, and
leukemias such
as acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute
lymphocytic leukemia (ALL), and chronic lymphocytic leukemia,; and
proliferative
diseases and conditions, such as neovascularization associated with tumor
angiogenesis,
macular degeneration (e.g., wet/dry AMD), corneal neovascularization, diabetic
retinopathy, neovascular glaucoma, myopic degeneration and other proliferative
diseases
and conditions such as restenosis and polycystic kidney disease, and any other
cancer or
proliferative disease, condition, trait, genotype or phenotype that can
respond to the
modulation of disease related gene expression in a cell or tissue, alone or in
combination
with other therapies.
By "inflammatory disease" or "inflammatory condition" as used herein is meant
any disease, condition, trait, genotype or phenotype characterized by an
inflammatory or
allergic process as is known in the art, such as inflammation, acute
inflammation,
chronic inflammation, respiratory disease, atherosclerosis, restenosis,
asthma, allergic
rhinitis, atopic dermatitis, septic shock, rheumatoid arthritis, inflammatory
bowl disease,
inflammotory pelvic disease, pain, ocular inflammatory disease, celiac
disease, Leigh
Syndrome, Glycerol Kinase Deficiency, Familial eosinophilia (FE), autosomal
recessive
spastic ataxia, laryngeal inflammatory disease; Tuberculosis, Chronic
cholecystitis,
Bronchiectasis, Silicosis and other pneumoconioses, and any other inflammatory
disease,
condition, trait, genotype or phenotype that can respond to the modulation of
disease
related gene expression in a cell or tissue, alone or in combination with
other therapies.
By "autoimmune disease" or "autoimmune condition" as used herein is meant, any
disease, condition, trait, genotype or phenotype characterized by autoimmunity
as is
known in the art, such as multiple sclerosis, diabetes mellitus, lupus, celiac
disease,
Crohn's disease, ulcerative colitis, Guillain-Barre syndrome, scleroderms,
Goodpasture's
syndrome, Wegener's granulomatosis, autoimmune epilepsy, Rasmussen's
encephalitis,
Primary biliary sclerosis, Sclerosing cholangitis, Autoimmune hepatitis,
Addison's
disease, Hashimoto's thyroiditis, Fibromyalgia, Menier's syndrome;
transplantation
rejection (e.g., prevention of allograft rejection) pernicious anemia,
rheumatoid arthritis,
systemic lupus erythematosus, dermatomyositis, Sjogren's syndrome, lupus
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erythematosus, multiple sclerosis, myasthenia gravis, Reiter's syndrome,
Grave's disease,
and any other autoimmune disease, condition, trait, genotype or phenotype that
can
respond to the modulation of disease related gene expression in a cell or
tissue, alone or
in combination with other therapies.
By "infectious disease" is meant any disease, condition, trait, genotype or
phenotype associated with an infectious agent, such as a virus, bacteria,
fungus, prion, or
parasite. Non-limiting examples of various viral genes that can be targeted
using siNA
molecules of the invention include Hepatitis C Virus (HCV, for example Genbank
Accession Nos: D11168, D50483.1, L38318 and 582227), Hepatitis B Virus (HBV,
for
example GenBank Accession No. AF100308.1), Human Immunodeficiency Virus type 1
(HIV-1, for example GenBank Accession No. U51188), Human Immunodeficiency
Virus type 2 (HIV-2, for example GenBank Accession No. X60667), West Nile
Virus
(WNV for example GenBank accession No. NC 001563), cytomegalovirus (CMV for
example GenBank Accession No. NC 001347), respiratory syncytial virus (RSV for
example GenBank Accession No. NC_001781), influenza virus (for example GenBank
Accession No. AF037412, rhinovirus (for example, GenBank accession numbers:
D00239, X02316, X01087, L24917, M16248, K02121, X01087), papillomavirus (for
example GenBank Accession No. NC_001353), Herpes Simplex Virus (HSV for
example GenBank Accession No. NC 001345), and other viruses such as HTLV (for
example GenBank Accession No. AJ430458). Due to the high sequence variability
of
many viral genomes, selection of siNA molecules for broad therapeutic
applications
would likely involve the conserved regions of the viral genome. Nonlimiting
examples
of conserved regions of the viral genomes include but are not limited to 5'-
Non Coding
Regions (NCR), 3'- Non Coding Regions (NCR) and/or internal ribosome entry
sites
(IRES). siNA molecules designed against conserved regions of various viral
genomes
will enable efficient inhibition of viral replication in diverse patient
populations and may
ensure the effectiveness of the siNA molecules against viral quasi species
which evolve
due to mutations in the non-conserved regions of the viral genome. Non-
limiting
examples of bacterial infections include Actinomycosis, Anthrax,
Aspergillosis,
Bacteremia, Bacterial Infections and Mycoses, Bartonella Infections, Botulism,
Brucellosis, Burkholderia Infections, Campylobacter Infections, Candidiasis,
Cat-Scratch
Disease, Chlamydia Infections, Cholera , Clostridium Infections,
Coccidioidomycosis,
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Cross Infection, Cryptococcosis, Dermatomycoses, Dermatomycoses, Diphtheria,
Ehrlichiosis, Escherichia coli Infections, Fasciitis, Necrotizing,
Fusobacterium
Infections, Gas Gangrene, Gram-Negative Bacterial Infections, Gram-Positive
Bacterial
Infections, Histoplasmosis, Impetigo, Klebsiella Infections, Legionellosis,
Leprosy,
Leptospirosis, Listeria Infections, Lyrne Disease, Maduromycosis, Melioidosis,
Mycobacterium Infections, Mycoplasma Infections, Mycoses, Nocardia Infections,
Onychomycosis, Ornithosis, Plague, Pneumococcal Infections, Pseudomonas
Infections,
Q Fever, Rat-Bite Fever, Relapsing Fever, Rheumatic Fever, Rickettsia
Infections,
Rocky Mountain Spotted Fever, Salmonella Infections, Scarlet Fever, Scrub
Typhus,
Sepsis, Sexually Transmitted Diseases - Bacterial, Bacterial Skin Diseases,
Staphylococcal Infections, Streptococcal Infections, Tetanus, Tick-Borne
Diseases,
Tuberculosis, Tularemia, Typhoid Fever, Typhus, Epidemic Louse-Borne, Vibrio
Infections, Yaws, Yersinia Infections, Zoonoses, and Zygomycosis. Non-limiting
examples of fungal infections include Aspergillosis, Blastomycosis,
Coccidioidomycosis, Cryptococcosis, Fungal Infections of Fingernails and
Toenails,
Fungal Sinusitis, Histoplasmosis, Histoplasmosis, Mucornzycosis, Nail Fungal
Infection,
Paracoccidioidomycosis, Sporotrichosis, Valley Fever (Coccidioidomycosis), and
Mold
Allergy.
By "neurologic disease" or "neurological disease" is meant any disease,
disorder,
or condition affecting the central or peripheral nervous system, inlcuding
ADHD, AIDS -
Neurological Complications, Absence of the Septum Pellucidum, Acquired
Epileptiform
Aphasia, Acute Disseminated Encephalomyelitis, Adrenoleukodystrophy, Agenesis
of
the Corpus Callosum, Agnosia, Aicardi Syndrome, Alexander Disease, Alpers'
Disease,
Alternating Hemiplegia, Alzheimer's Disease, Arnyotrophic Lateral Sclerosis,
Anencephaly, Aneurysm, Angelman Syndrome, Angiomatosis, Anoxia, Aphasia,
Apraxia, Arachnoid Cysts, Arachnoiditis, Arnold-Chiari Malformation,
Arteriovenous
Malformation, Aspartame, Asperger Syndrome, Ataxia Telangiectasia, Ataxia,
Attention
Deficit-Hyperactivity Disorder, Autism, Autonomic Dysfunction, Back Pain,
Barth
Syndrome, Batten Disease, Behcet's Disease, Bell's Palsy, Benign Essential
Blepharospasm, Benign Focal Amyotrophy, Benign Intracranial Hypertension,
Bernhardt-Roth Syndrome, Binswanger's Disease, Blepharospasm, Bloch-Sulzberger
Syndrome, Brachial Plexus Birth Injuries, Brachial Plexus Injuries, Bradbury-
Eggleston
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Syndrome, Brain Aneurysm, Brain Injury, Brain and Spinal Tumors, Brown-Sequard
Syndrome, Bulbospinal Muscular Atrophy, Canavan Disease, Carpal Tunnel
Syndrome,
Causalgia, Cavernomas, Cavernous Angioma, Cavernous Malformation, Central
Cervical Cord Syndrome, Central Cord Syndrome, Central Pain Syndrome, Cephalic
Disorders, Cerebellar Degeneration, Cerebellar Hypoplasia, Cerebral Aneurysm,
Cerebral Arteriosclerosis, Cerebral Atrophy, Cerebral Beriberi, Cerebral
Gigantism,
Cerebral Hypoxia, Cerebral Palsy, Cerebro-Oculo-Facio-Skeletal Syndrome,
Charcot-
Marie-Tooth Disorder, Chiari Malformation, Chorea, Choreoacanthocytosis,
Chronic
Inflammatory Demyelinating Polyneuropathy (CIDP), Chronic Orthostatic
Intolerance,
Chronic Pain, Cockayne Syndrome Type II, Coffin Lowry Syndrome, Coma,
including
Persistent Vegetative State, Complex Regional Pain Syndrome, Congenital Facial
Diplegia, Congenital Myasthenia, Congenital Myopathy, Congenital Vascular
Cavernous
Malformations, Corticobasal Degeneration, Cranial Arteritis, Craniosynostosis,
Creutzfeldt-Jakob Disease, Cumulative Trauma Disorders, Cushing's Syndrome,
Cytomegalic Inclusion Body Disease (CIBD), Cytomegalovirus Infection, Dancing
Eyes-Dancing Feet Syndrome, Dandy-Walker Syndrome, Dawson Disease, De
Morsier's
Syndrome, Dejerine-Klumpke Palsy, Dementia - Multi-Infarct, Dementia -
Subcortical,
Dementia With Lewy Bodies, Dermatomyositis, Developmental Dyspraxia, Devic's
Syndrome, Diabetic Neuropathy, Diffuse Sclerosis, Dravet's Syndrome,
Dysautonomia,
Dysgraphia, Dyslexia, Dysphagia, Dyspraxia, Dystonias, Early Infantile
Epileptic
Encephalopathy, Empty Sella Syndrome, Encephalitis Lethargica, Encephalitis
and
Meningitis, Encephaloceles, Encephalopathy, Encephalotrigeminal Angiomatosis,
Epilepsy, Erb's Palsy, Erb-Duchenne and Dejerine-I~lumpke Palsies, Fabry's
Disease,
Fahr's Syndrome, Fainting, Familial Dysautonomia, Familial Hemangioma,
Familial
Idiopathic Basal Ganglia Calcification, Familial Spastic Paralysis, Febrile
Seizures (e.g.,
GEFS and GEFS plus), Fisher Syndrome, Floppy Infant Syndrome, Friedreich's
Ataxia,
Gaucher's Disease, Gerstmann's Syndrome, Gerstmann-Straussler-Scheinker
Disease,
Giant Cell Arteritis, Giant Cell Inclusion Disease, Globoid Cell
Leukodystrophy,
Glossopharyngeal Neuralgia, Guillain-Barre Syndrome, HTLV-1 Associated
Myelopathy, Hallervorden-Spatz Disease, Head Injury, Headache, Hemicrania
Continua,
Hemifacial Spasm, Hemiplegia Alterans, Hereditary Neuropathies, Hereditary
Spastic
Paraplegia, Heredopathia Atactica Polyneuritiformis, Herpes Zoster Oticus,
Herpes
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Zoster, Hirayama Syndrome, Holoprosencephaly, Huntington's Disease,
Hydranencephaly, Hydrocephalus - Normal Pressure, Hydrocephalus, Hydromyelia,
Hypercortisolism, Hypersomnia, Hypertonia, Hypotonia, Hypoxia, Immune-Mediated
Encephalomyelitis, Inclusion Body Myositis, Incontinentia Pigmenti, Infantile
Hypotonia, Infantile Phytanic Acid Storage Disease, Infantile Refsum Disease,
Infantile
Spasms, Inflammatory Myopathy, Intestinal Lipodystrophy, Intracranial Cysts,
Intracranial Hypertension, Isaac's Syndrome, Joubert Syndrome, Kearns-Sayre
Syndrome, Kennedy's Disease, Kinsbourne syndrome, Kleine-Levin syndrome,
Klippel
Feil Syndrome, Klippel-Trenaunay Syndrome (KTS), Kliiver-Bucy Syndrome,
Korsakoff s Amnesic Syndrome, Krabbe Disease, Kugelberg-Welander Disease,
Kuru,
Lambert-Eaton Myasthenic Syndrome, Landau-Kleffner Syndrome, Lateral Femoral
Cutaneous Nerve Entrapment, Lateral Medullary Syndrome, Learning Disabilities,
Leigh's Disease, Lennox-Gastaut Syndrome, Lesch-Nyhan Syndrome,
Leukodystrophy,
Levine-Critchley Syndrome, Lewy Body Dementia, Lissencephaly, Locked-In
Syndrome, Lou Gehrig's Disease, Lupus - Neurological Sequelae, Lyme Disease -
Neurological Complications, Machado-Joseph Disease, Macrencephaly,
Megalencephaly, Melkersson-Rosenthal Syndrome, Meningitis, Menkes Disease,
Meralgia Paresthetica, Metachromatic Leukodystrophy, Microcephaly, Migraine,
Miller
Fisher Syndrome, Mini-Strokes, Mitochondrial Myopathies, Mobius Syndrome,
Monomelic Amyotrophy, Motor Neuron Diseases, Moyamoya Disease, Mucolipidoses,
Mucopolysaccharidoses, Multi-Infarct Dementia, Multifocal Motor Neuropathy,
Multiple Sclerosis, Multiple System Atrophy with Orthostatic Hypotension,
Multiple
System Atrophy, Muscular Dystrophy, Myasthenia - Congenital, Myasthenia
Gravis,
Myelinoclastic Diffuse Sclerosis, Myoclonic Encephalopathy of Infants,
Myoclonus,
Myopathy - Congenital, Myopathy - Thyrotoxic, Myopathy, Myotonia Congenita,
Myotonia, Narcolepsy, Neuroacanthocytosis, Neurodegeneration with Brain Iron
Accumulation, Neurofibromatosis, Neuroleptic Malignant Syndrome, Neurological
Complications of AIDS, Neurological Manifestations of Pompe Disease,
Neuromyelitis
Optica, Neuromyotonia, Neuronal Ceroid Lipofuscinosis, Neuronal Migration
Disorders, -
Neuropathy - Hereditary, Neurosarcoidosis, Neurotoxicity, Nevus Cavernosus,
Niemann-
Pick Disease, O'Sullivan-McLeod Syndrome, Occipital Neuralgia, Occult Spinal
Dysraphism Sequence, Ohtahara Syndrome, Olivopontocerebellar Atrophy,
Opsoclonus
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Myoclonus, Orthostatic Hypotension, Overuse Syndrome, Pain - Chronic,
Paraneoplastic
Syndromes, Paresthesia, Parkinson's Disease, Parmyotonia Congenita, Paroxysmal
Choreoathetosis, Paroxysmal Hemicrania, Parry-Romberg, Pelizaeus-Merzbacher
Disease, Pena Shokeir II Syndrome, Perineural Cysts, Periodic Paralyses,
Peripheral
Neuropathy, Periventricular Leukornalacia, Persistent Vegetative State,
Pervasive
Developmental Disorders, Phytanic Acid Storage Disease, Pick's Disease,
Piriformis
Syndrome, Pituitary Tumors, Polymyositis, Pompe Disease, Porencephaly, Post-
Polio
Syndrome, Postherpetic Neuralgia, Postinfectious Encephalomyelitis, Postural
Hypotension, Postural Orthostatic Tachycardia Syndrome, Postural Tachycardia
Syndrome, Primary Lateral Sclerosis, Prion Diseases, Progressive Hemifacial
Atrophy,
Progressive Locomotor Ataxia, Progressive Multifocal Leukoencephalopathy,
Progressive Sclerosing Poliodystrophy, Progressive Supranuclear Palsy,
Pseudotumor
Cerebri, Pyridoxine Dependent and Pyridoxine Responsive Siezure Disorders,
Ramsay
Hunt Syndrome Type I, Ramsay Hunt Syndrome Type II, Rasmussen's Encephalitis
and
other autoimmune epilepsies, Reflex Sympathetic Dystrophy Syndrome, Refsum
Disease
- Infantile, Refsum Disease, Repetitive Motion Disorders, Repetitive Stress
Injuries,
Restless Legs Syndrome, Retrovirus-Associated Myelopathy, Rett Syndrome,
Reye's
Syndrome, Riley-Day Syndrome, SUNCT Headache, Sacral Nerve Root Cysts, Saint
Vitus Dance, Salivary Gland Disease, Sandhoff Disease, Schilder's Disease,
Schizencephaly, Seizure Disorders, Septo-Optic Dysplasia, Severe Myoclonic
Epilepsy
of Infancy (SMEI), Shaken Baby Syndrome, Shingles, Shy-Drager Syndrome,
Sjogren's
Syndrome, Sleep Apnea, Sleeping Sickness, Soto's Syndrome, Spasticity, Spina
Bifida,
Spinal Cord Infarction, Spinal Cord Injury, Spinal Cord Tumors, Spinal
Muscular
Atrophy, Spinocerebellar Atrophy, Steele-Richardson-Olszewski Syndrome, Stiff
Person
Syndrome, Striatonigral Degeneration, Stroke, Sturge-Weber Syndrome, Subacute
Sclerosing Panencephalitis, Subcortical Arteriosclerotic Encephalopathy,
Swallowing
Disorders, Sydenham Chorea, Syncope, Syphilitic Spinal Sclerosis,
Syringohydromyelia,
Syringomyelia, Systemic Lupus Erythematosus, Tabes Dorsalis, Tardive
Dyskinesia,
Tarlov Cysts, Tay-Sachs Disease, Temporal Arteritis, Tethered Spinal Cord
Syndrome,
Thomsen Disease, Thoracic Outlet Syndrome, Thyrotoxic Myopathy, Tic
Douloureux,
Todd's Paralysis, Tourette Syndrome, Transient Ischemic Attack, Transmissible
Spongiform Encephalopathies, Transverse Myelitis, Traumatic Brain Injury,
Tremor,
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Trigeminal Neuralgia, Tropical Spastic Paraparesis, Tuberous Sclerosis,
Vascular
Erectile Tumor, Vasculitis including Temporal Arteritis, Von Economo's
Disease, Von
Hippel-Lindau disease (VHL), Von Recklinghausen's Disease, Wallenberg's
Syndrome,
Werdnig-Hoffman Disease, Wernicke-I~orsakoff Syndrome, West Syndrome,
Whipple's
Disease, Williams Syndrome, Wilson's Disease, X-Linked Spinal and Bulbar
Muscular
Atrophy, and Zellweger Syndrome.
By "respiratory disease" is meant, any disease or condition affecting the
respiratory tract, such as asthma, chronic obstructive pulmonary disease or
"COPD",
allergic rhinitis, sinusitis, pulmonary vasoconstriction, inflammation,
allergies, impeded
respiration, respiratory distress syndrome, cystic fibrosis, pulmonary
hypertension,
pulmonary vasoconstriction, emphysema, and any other respiratory disease,
condition,
trait, genotype or phenotype that can respond to the modulation of disease
related gene
expression in a cell or tissue, alone or in combination with other therapies.
By "cardiovascular disease" is meant and disease or condition affecting the
heart
and vasculature, inlcuding but not limited to, coronary heart disease (CHD),
cerebrovascular disease (CVD), aortic stenosis, peripheral vascular disease,
atherosclerosis, arteriosclerosis, myocardial infarction (heart attack),
cerebrovascular
diseases (stroke), transient ischaemic attacks (TIA), angina (stable and
unstable), atrial
fibrillation, arrhythmia, vavular disease, congestive heart failure,
hypercholoesterolemia,
type I hyperlipoproteinemia, type II hyperlipoproteinemia, type III
hyperlipoproteinemia,
type IV hyperlipoproteinemia, type V hyperlipoproteinemia, secondary
hyperirigliceridemia, and familial lecithin cholesterol acyltransferase
deficiency.
By "ocular disease" as used herein is meant, any disease, condition, trait,
genotype
or phenotype of the eye and related structures as is known in the art, such as
Cystoid
Macular Edema, Asteroid Hyalosis, Pathological Myopia and Posterior
Staphyloma,
Toxocariasis (Ocular Larva Migrans), Retinal Vein Occlusion, Posterior
Vitreous
Detachment, Tractional Retinal Tears, Epiretinal Membrane, Diabetic
Retinopathy,
Lattice Degeneration, Retinal Vein Occlusion, Retinal Artery Occlusion,
Macular
Degeneration (e.g., age related macular degeneration such as wet AMD or dry
AMD),
Toxoplasmosis, Choroidal Melanoma, Acquired Retinoschisis, Hollenhorst Plaque,
Idiopathic Central Serous Chorioretinopathy, Macular Hole, Presumed Ocular
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Histoplasmosis Syndrome, Retinal Macroaneursym, Retinitis Yigmentosa, ttetinai
Detachment, Hypertensive Retinopathy, Retinal Pigment Epithelium (RPE)
Detachment,
Papillophlebitis, Ocular Ischemic Syndrome, Coats' Disease, Leber's Miliary
Aneurysm,
Conjunctival Neoplasms, Allergic Conjunctivitis, Vernal Conjunctivitis, Acute
Bacterial
Conjunctivitis, Allergic Conjunctivitis Vernal Keratoconjunctivitis, Viral
Conjunctivitis, Bacterial Conjunctivitis, Chlamydial & Gonococcal
Conjunctivitis,
Conjunctival Laceration, Episcleritis, Scleritis, Pingueculitis, Pterygium,
Superior
Limbic Keratoconjunctivitis (SLK of Theodore), Toxic Conjunctivitis,
Conjunctivitis
with Pseudomembrane, Giant Papillary Conjunctivitis, Ternen's Marginal
Degeneration,
Acanthamoeba Keratitis, Fungal Keratitis, Filamentary Keratitis, Bacterial
Keratitis,
Keratitis Sicca/Dry Eye Syndrome, Bacterial Keratitis, Herpes Simplex
Keratitis, Sterile
Corneal Infiltrates, Phlyctenulosis, Corneal Abrasion & Recurrent Corneal
Erosion,
Corneal Foreign Body, Chemical Burs, Epithelial Basement Membrane Dystrophy
(EBMD), Thygeson's Superficial Punctate Keratopathy, Corneal Laceration,
Salzmann's
Nodular Degeneration, Fuchs' Endothelial Dystrophy, Crystalline Lens
Subluxation,
Ciliary-Block Glaucoma, Primary Open-Angle Glaucoma, Pigment Dispersion
Syndrome and Pigmentary Glaucoma, Pseudoexfoliation Syndrom and
Pseudoexfoliative
Glaucoma, Anterior Uveitis, Primary Open Angle Glaucoma, Uveitic Glaucoma &
Glaucomatocyclitic Crisis, Pigment Dispersion Syndrome & Pigmentary Glaucoma,
Acute Angle Closure Glaucoma, Anterior Uveitis, Hyphema, Angle Recession
Glaucoma, Lens Induced Glaucoma, Pseudoexfoliation Syndrome and
Pseudoexfoliative
Glaucoma, Axenfeld-Rieger Syndrome, Neovascular Glaucoma, Pars Planitis,
Choroidal
Rupture, Duane's Retraction Syndrome, Toxic/Nutritional Optic Neuropathy,
Aberrant
Regeneration of Cranial Nerve III, Intracranial Mass Lesions, Carotid-
Cavernous Sinus
Fistula, Anterior Ischemic Optic Neuropathy, Optic Disc Edema & Papilledema,
Cranial
Nerve III Palsy, Cranial Nerve IV Palsy, Cranial Nerve VI Palsy, Cranial Nerve
VII
(Facial Nerve) Palsy, Homer's Syndrome, Internuclear Ophthalmoplegia, Optic
Nerve
Head Hypoplasia, Optic Pit, Tonic Pupil, Optic Nerve Head Drusen,
Demyelinating
Optic Neuropathy (Optic Neuritis, Retrobulbar Optic Neuritis), Amaurosis Fugax
and
Transient Ischemic Attack, Pseudotumor Cerebri, Pituitary Adenoma, Molluscum
Contagiosum, Canaliculitis, Verruca and Papilloma, Pediculosis and Pthiriasis,
Blepharitis, Hordeolum, Preseptal Cellulitis, Chalazion, Basal Cell Carcinoma,
Herpes
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Zoster Ophthalmicus, Pediculosis ~ Phthiriasis, Blow-out Fracture, Chronic
Epiphora,
Dacryocystitis, Herpes Simplex Blepharitis, Orbital Cellulitis, Senile
Entropion, and
Squamous Cell Carcinoma.
By "metabolic disease" is meant any disease or condition affecting metabolic
pathways as in known in the art. Metabolic disease can result in an abnormal
metabolic
process, either congenital due to inherited enzyme abnormality (inborn errors
of
metabolism) or acquired due to disease of an endocrine organ or failure of a
metabolically important organ such as the liver. In one embodiment, metabolic
disease
includes obesity, insulin resistance, and diabetes (e.g., type I and/or type
II diabetes).
In one embodiment of the present invention, each sequence of a siNA molecule
of
the invention is independently about 15 to about 30 nucleotides in length, in
specific
embodiments about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,
or 30
nucleotides in length. In another embodiment, the siNA duplexes of the
invention
independently comprise about 15 to about 30 base pairs (e.g., about 15, 16,
17, 18, 19,
20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30). In another embodiment, one or
more strands
of the siNA molecule of the invention independently comprises about 15 to
about 30
nucleotides (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,
28, 29, or 30)
that are complementary to a target nucleic acid molecule. In yet another
embodiment,
siNA molecules of the invention comprising hairpin or circular structures are
about 35 to
about 55 (e.g., about 35, 40, 45, 50 or 55) nucleotides in length, or about 38
to about 44
(e.g., about 38, 39, 40, 41, 42, 43, or 44) nucleotides in length and
comprising about 15
to about 25 (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25) base
pairs.
Exemplary siNA molecules of the invention are shown in Figures 4-5.
As used herein "cell" is used in its usual biological sense, and does not
refer to an
entire multicellular organism, e.g., specifically does not refer to a human.
The cell can
be present in an organism, e.g., birds, plants and mammals such as humans,
cows, sheep,
apes, monkeys, swine, dogs, and cats. The cell can be prokaryotic (e.g.,
bacterial cell) or
eukaryotic (e.g., mammalian or plant cell). The cell can be of somatic or germ
line
origin, totipotent or pluripotent, dividing or non-dividing. The cell can also
be derived
from or can comprise a gamete or embryo, a stem cell, or a fully
differentiated cell.
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The siNA molecules of the invention are added directly, or can be complexed
with
cationic lipids, packaged within liposomes, or otherwise delivered to target
cells or
tissues. The nucleic acid or nucleic acid complexes can be locally
administered to
relevant tissues ex vivo, or in. vivo through direct dermal application,
transdermal
application, or injection, with or without their incorporation in biopolymers.
In another aspect, the invention provides mammalian cells containing one or
more
siNA molecules of this invention. The one or more siNA molecules can
independently
be targeted to the same or different sites.
By "RNA" is meant a molecule comprising at least one ribonucleotide residue.
By
"ribonucleotide" is meant a nucleotide with a hydroxyl group at the 2'
position of a ~i-D-
ribofuranose moiety. The terms include double-stranded RNA, single-stranded
RNA,
isolated RNA such as partially purified RNA, essentially pure RNA, synthetic
RNA,
recombinantly produced RNA, as well as altered RNA that differs from naturally
occurnng RNA by the addition, deletion, substitution and/or alteration of one
or more
nucleotides. Such alterations can include addition of non-nucleotide material,
such as to
the ends) of the siNA or internally, for example at one or more nucleotides of
the RNA.
Nucleotides in the RNA molecules of the instant invention can also comprise
non-
standard nucleotides, such as non-naturally occurring nucleotides or
chemically
synthesized nucleotides or deoxynucleotides. These altered RNAs can be
referred to as
analogs or analogs of naturally-occurnng RNA.
By "subject" is meant an organism, which is a donor or recipient of explanted
cells
or the cells themselves. "Subject" also refers to an organism to which the
nucleic acid
molecules of the invention can be administered. A subject can be a mammal or
mammalian cells, including a human or human cells.
The term "phosphorothioate" as used herein refers to an internucleotide
linkage
having Formula I, wherein Z and/or W comprise a sulfur atom. Hence, the term
phosphorothioate refers to both phosphorothioate and phosphorodithioate
internucleotide
linkages.
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The term "phosphonoacetate" as used herein refers to an internucleotide
linkage
having Formula I, wherein Z and/or W comprise an acetyl or protected acetyl
group.
The term "thiophosphonoacetate" as used herein refers to an internucleotide
linkage having Formula I, wherein Z comprises an acetyl or protected acetyl
group and
W comprises a sulfur atom or alternately W comprises an acetyl ox protected
acetyl
group and Z comprises a sulfur atom.
The term "universal base" as used herein refers to nucleotide base analogs
that
form base pairs with each of the natural DNA/RNA bases with little
discrimination
between them. Non-limiting examples of universal bases include C-phenyl, C-
naphthyl
and other aromatic derivatives, inosine, azole carboxamides, and nitroazole
derivatives
such as 3-nitropyrrole, 4-nitroindole, S-nitroindole, and 6-nitroindole as
known in the art
(see for example Loakes, 2001, Nucleic Acids Research, 29, 2437-2447).
The term "acyclic nucleotide" as used herein refers to any nucleotide having
an
acyclic ribose sugar, for example where any of the ribose carbons (C1, C2, C3,
C4, or
CS), are independently or in combination absent from the nucleotide.
The nucleic acid molecules of the instant invention, individually, or in
combination
or in conjunction with other drugs, can be used to for preventing or treating
diseases,
traits, disorders, and/or conditions described herein or otherwise known in
the art, in a
subject or organism. For example, the siNA molecules can be administered to a
subject
or can be administered to other appropriate cells evident to those skilled in
the art,
individually or in combination with one or more drugs under conditions
suitable for the
treatment.
In a further embodiment, the siNA molecules can be used in combination with
other known treatments to prevent or treat preventing ox treating diseases,
traits,
disorders, and/or conditions described herein or otherwise known in the art,
in a subject
or organism. For example, the described molecules could be used in combination
with
one or more known compounds, treatments, or procedures to prevent or treat
diseases,
traits, disorders, and/or conditions described herein or otherwise known in
the art, in a
subject or organism.
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In one embodiment, the invention features an expression vector comprising a
nucleic acid sequence encoding at least one siNA molecule of the invention, in
a manner
which allows expression of the siNA molecule. For example, the vector can
contain
sequences) encoding both strands of a siNA molecule comprising a duplex. The
vector
can also contain sequences) encoding a single nucleic acid molecule that is
self
complementary and thus forms a siNA molecule. Non-limiting examples of such
expression vectors are described in Paul et al., 2002, Natuf~e Biotechnology,
19, 505;
Miyagishi and Taira, 2002, Nature Biotech~aology, 19, 497; Lee et al., 2002,
Nature
Biotechnology, 19, 500; and Novina et al., 2002, Nature Medicine, advance
online
publication doi:10.1038/nm725.
In another embodiment, the invention features a mammalian cell, for example, a
human cell, including an expression vector of the invention.
In yet another embodiment, the expression vector of the invention comprises a
sequence for a siNA molecule having complementarity to a RNA molecule referred
to by
Genbank Accession numbers, for example Genbank Accession Nos. shown in Table
I.
In one embodiment, an expression vector of the invention comprises a nucleic
acid
sequence encoding two or more siNA molecules, which can be the same or
different.
In another aspect of the invention, siNA molecules that interact with target
RNA
molecules and down-regulate gene encoding target RNA molecules (for example
target
RNA molecules referred to by Genbank Accession numbers herein) are expressed
from
transcription units inserted into DNA or RNA vectors. The recombinant vectors
can be
DNA plasrnids or viral vectors. siNA expressing viral vectors can be
constructed based
on, but not limited to, adeno-associated virus, retrovirus, adenovirus, or
alphavirus. The
recombinant vectors capable of expressing the siNA molecules can be delivered
as
described herein, and persist in target cells. Alternatively, viral vectors
can be used that
provide for transient expression of siNA molecules. Such vectors can be
repeatedly
administered as necessary. Once expressed, the siNA molecules bind and down-
regulate
gene function or expression via RNA interference (RNAi). Delivery of siNA
expressing
vectors can be systemic, such as by intravenous or intramuscular
administration, by
administration to target cells ex-planted from a subject followed by
reintroduction into
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the subject, or by any other means that would allow for introduction into the
desired
target cell.
By "vectors" is meant any nucleic acid- and/or viral-based technique used to
deliver a desired nucleic acid.
Other features and advantages of the invention will be apparent from the
following
description of the preferred embodiments thereof, and from the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows a non-limiting example of a scheme for the synthesis of siNA
molecules. The complementary siNA sequence strands, strand 1 and strand 2, are
synthesized in tandem and are connected by a cleavable linkage, such as a
nucleotide
succinate or abasic succinate, which can be the same or different from the
cleavable
linker used for solid phase synthesis on a solid support. The synthesis can be
either solid
phase or solution phase, in the example shown, the synthesis is a solid phase
synthesis.
The synthesis is performed such that a protecting group, such as a
dimethoxytrityl group,
remains intact on the terminal nucleotide of the tandem oligonucleotide. Upon
cleavage
and deprotection of the oligonucleotide, the two siNA strands spontaneously
hybridize to
form a siNA duplex, which allows the purification of the duplex by utilizing
the
properties of the terminal protecting group, for example by applying a trityl
on
purification method wherein only duplexes/oligonucleotides with the terminal
protecting
group are isolated.
Figure 2 shows a MALDI-TOF mass spectrum of a purified siNA duplex
synthesized by a method of the invention. The two peaks shown correspond to
the
predicted mass of the separate siNA sequence strands. This result demonstrates
that the
siNA duplex generated from tandem synthesis can be purified as a single entity
using a
simple trityl-on purification methodology.
Figure 3 shows a non-limiting proposed mechanistic representation of target
RNA
degradation involved in RNAi. Double-stranded RNA (dsRNA), which is generated
by
RNA-dependent RNA polymerase (RdRP) from foreign single-stranded RNA, for
example viral, transposon, or other exogenous RNA, activates the DICER enzyme
that in
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turn generates siNA duplexes. Alternately, synthetic or expressed siNA can be
introduced directly into a cell by appropriate means. An active siNA complex
forms
which recognizes a target RNA, resulting in degradation of the target RNA by
the RISC
endonuclease complex or in the synthesis of additional RNA by RNA-dependent
RNA
polymerase (RdRP), which can activate DICER and result in additional siNA
molecules,
thereby amplifying the RNAi response.
Figure 4A-F shows non-limiting examples of chemically-modified siNA
constructs of the present invention. In the figure, N stands for any
nucleotide (adenosine,
guanosine, cytosine, uridine, or optionally thymidine, for example thymidine
can be
substituted in the overhanging regions designated by parenthesis (N N).
Various
modifications are shown for the sense and antisense strands of the siNA
constructs.
Figure 4A: The sense strand comprises 21 nucleotides wherein the two terminal
3'-nucleotides are optionally base paired and wherein all nucleotides present
are
ribonucleotides except for (N N) nucleotides, which can comprise
ribonucleotides,
deoxynucleotides, universal bases, or other chemical modifications described
herein.
The antisense strand comprises 21 nucleotides, optionally having a 3'-terminal
glyceryl
moiety wherein the two terminal 3'-nucleotides are optionally complementary to
the
target RNA sequence, and wherein all nucleotides present are ribonucleotides
except for
(N N) nucleotides, which can comprise ribonucleotides, deoxynucleotides,
universal
bases, or other chemical modifications described herein. A modified
internucleotide
linkage, such as a phosphorothioate, phosphorodithioate or other modified
internucleotide linkage as described herein, shown as "s", optionally connects
the (N N)
nucleotides in the antisense strand.
Figure 4B: The sense strand comprises 21 nucleotides wherein the two terminal
3'-nucleotides are optionally base paired and wherein all pyrimidine
nucleotides that may
be present are 2'deoxy-2'-fluoro modified nucleotides and all purine
nucleotides that may
be present are 2'-O-methyl modified nucleotides except for (N N) nucleotides,
which can
comprise ribonucleotides, deoxynucleotides, universal bases, or other chemical
modifications described herein. The antisense strand comprises 21 nucleotides,
optionally having a 3'-terminal glyceryl moiety and wherein the two terminal
3'
nucleotides are optionally complementary to the target RNA sequence, and
wherein all
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pyrimidine nucleotides that may be present are 2'-deoxy-2'-fluoro modified
nucleotides
and all purine nucleotides that may be present are 2'-O-methyl modified
nucleotides
except for (N N) nucleotides, which can comprise ribonucleotides,
deoxynucleotides,
universal bases, or other chemical modifications described herein. A modified
internucleotide linkage, such as a phosphorothioate, phosphorodithioate or
other
modified internucleotide linkage as described herein, shown as "s", optionally
connects
the (N N) nucleotides in the sense and antisense strand.
Figure 4C: The sense strand comprises 21 nucleotides having 5'- and 3'-
terminal
cap moieties wherein the two terminal 3'-nucleotides are optionally base
paired and
wherein all pyrimidine nucleotides that may be present are 2'-O-methyl or 2'-
deoxy-2'-
fluoro modified nucleotides except for (N N) nucleotides, which can comprise
ribonucleotides, deoxynucleotides, universal bases, or other chemical
modifications
described herein. The antisense strand comprises 21 nucleotides, optionally
having a 3'-
terminal glyceryl moiety and wherein the two terminal 3'-nucleotides are
optionally
complementary to the target RNA sequence, and wherein all pyrimidine
nucleotides that
may be present are 2'-deoxy-2'-fluoro modified nucleotides except for (N N)
nucleotides,
which can comprise ribonucleotides, deoxynucleotides, universal bases, or
other
chemical modifications described herein. A modified internucleotide linkage,
such as a
phosphorothioate, phosphorodithioate or other modified internucleotide linkage
as
described herein, shown as "s", optionally connects the (N N) nucleotides in
the
antisense strand.
Figure 4D: The sense strand comprises 21 nucleotides having 5'- and 3'-
terminal
cap moieties wherein the two terminal 3'-nucleotides are optionally base
paired and
wherein all pyrimidine nucleotides that may be present are 2'-deoxy-2'-fluoro
modified
nucleotides except for (N N) nucleotides, which can comprise ribonucleotides,
deoxynucleotides, universal bases, or other chemical modifications described
herein and
wherein and all purine nucleotides that may be present are 2'-deoxy
nucleotides. The
antisense strand comprises 21 nucleotides, optionally having a 3'-terminal
glyceryl
moiety and wherein the two terminal 3'-nucleotides are optionally
complementary to the
target RNA sequence, wherein all pyrimidine nucleotides that may be present
are 2'-
deoxy-2'-fluoro modified nucleotides and all purine nucleotides that may be
present are
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2'-O-methyl modified nucleotides except for (N N) nucleotides, which can
comprise
ribonucleotides, deoxynucleotides, universal bases, or other chemical
modifications
described herein. A modified internucleotide linkage, such as a
phosphorothioate,
phosphorodithioate or other modified internucleotide linkage as described
herein, shown
as "s", optionally connects the (N N) nucleotides in the antisense strand.
Figure 4E: The sense strand comprises 21 nucleotides having 5'- and 3'-
terminal
cap moieties wherein the two terminal 3'-nucleotides are optionally base
paired and
wherein all pyrimidine nucleotides that rnay be present are 2'-deoxy-2'-fluoro
modified
nucleotides except for (N N) nucleotides, which can comprise ribonucleotides,
deoxynucleotides, universal bases, or other chemical modifications described
herein.
The antisense strand comprises 21 nucleotides, optionally having a 3'-terminal
glyceryl
moiety and wherein the two terminal 3'-nucleotides are optionally
complementary to the
target RNA sequence, and wherein all pyrimidine nucleotides that may be
present are 2'-
deoxy-2'-fluoro modified nucleotides and all purine nucleotides that may be
present are
2'-O-methyl modified nucleotides except for (N N) nucleotides, which can
comprise
ribonucleotides, deoxynucleotides, universal bases, or other chemical
modifications
described herein. A modified internucleotide linkage, such as a
phosphorothioate,
phosphorodithioate or other modified internucleotide linkage as described
herein, shown
as "s", optionally connects the (N N) nucleotides in the antisense strand.
Figure 4F: The sense strand comprises 21 nucleotides having 5'- and 3'-
terminal
cap moieties wherein the two terminal 3'-nucleotides are optionally base
paired and
wherein all pyrimidine nucleotides that may be present are 2'-deoxy-2'-fluoro
modified
nucleotides except for (N N) nucleotides, which can comprise ribonucleotides,
deoxynucleotides, universal bases, or other chemical modifications described
herein and
wherein and all purine nucleotides that may be present are 2'-deoxy
nucleotides. The
antisense strand comprises 21 nucleotides, optionally having a 3'-terminal
glyceryl
moiety and wherein the two terminal 3'-nucleotides are optionally
complementary to the
target RNA sequence, and having one 3'-terminal phosphorothioate
internucleotide
linkage and wherein all pyrimidine nucleotides that may be present are 2'-
deoxy-2'-fluoro
modified nucleotides and all purine nucleotides that may be present are 2'-
deoxy
nucleotides except for (N N) nucleotides, which can comprise ribonucleotides,
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deoxynucleotides, universal bases, or other chemical modifications described
herein. A
modified internucleotide linkage, such as a phosphorothioate,
phosphorodithioate or
other modified internucleotide linkage as described herein, shown as "s",
optionally
connects the (N N) nucleotides in the antisense strand. The antisense strand
of
constructs A-F comprise sequence complementary to any target nucleic acid
sequence of
the invention. Furthermore, when a glyceryl moiety (L) is present at the 3'-
end of the
antisense strand for any construct shown in Figure 4 A-F, the modified
internucleotide
linkage is optional.
Figure 5A-F shows non-limiting examples of specific chemically-modified siNA
sequences of the invention. A-F applies the chemical modifications described
in Figure
4A-F to a target siNA sequence. Such chemical modifications can be applied to
any
target sequence and/or target polymorphism sequence.
Figure 6 shows non-limiting examples of different siNA constructs of the
invention. The examples shown (constructs 1, 2, and 3) have 19 representative
base
pairs; however, different embodiments of the invention include any number of
base pairs
described herein. Bracketed regions represent nucleotide overhangs, for
example,
comprising about 1, 2, 3, or 4 nucleotides in length, preferably about 2
nucleotides.
Constructs 1 and 2 can be used independently for RNAi activity. Construct 2
can
comprise a polynucleotide or non-nucleotide linker, which can optionally be
designed as
a biodegradable linker. In one embodiment, the loop structure shown in
construct 2 can
comprise a biodegradable linker that results in the formation of construct 1
ih vivo and/or
ifi vitro. In another example, construct 3 can be used to generate construct 2
under the
same principle wherein a linker is used to generate the active siNA construct
2 ih vivo
and/or ah vitro, which can optionally utilize another biodegradable linker to
generate the
active siNA construct 1 in vivo and/or in vitro. As such, the stability and/or
activity of
the siNA constructs can be modulated based on the design of the siNA construct
for use
ih vivo or iya vitro and/or ifa vitro.
Figure 7A-C is a diagrammatic representation of a scheme utilized in
generating
an expression cassette to generate siNA hairpin constructs.
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Figure 7A: A DNA oligomer is synthesized with a 5'-restriction site (R1)
sequence followed by a region having sequence identical (sense region of siNA)
to a
predetermined target sequence, wherein the sense region comprises, for
example, about
19, 20, 21, or 22 nucleotides (I~ in length, which is followed by a loop
sequence of
defined sequence (X), comprising, for example, about 3 to about 10
nucleotides.
Figure 7B: The synthetic construct is then extended by DNA polymerase to
generate a hairpin structure having self complementary sequence that will
result in a
siNA transcript having specificity for a target sequence and having self
complementary
sense and antisense regions.
Figure 7C: The construct is heated (for example to about 95°C) to
linearize the
sequence, thus allowing extension of a complementary second DNA strand using a
primer to the 3'-restriction sequence of the first strand. The double-stranded
DNA is then
inserted into an appropriate vector for expression in cells. The construct can
be designed
such that a 3'-terminal nucleotide overhang results from the transcription,
for example,
by engineering restriction sites and/or utilizing a poly-U termination region
as described
in Paul et al., 2002, Nature Bioteclahology, 29, 505-508.
Figure 8A-C is a diagrammatic representation of a scheme utilized in
generating
an expression cassette to generate double-stranded siNA constructs.
Figure 8A: A DNA oligomer is synthesized with a 5'-restriction (R1) site
sequence
followed by a region having sequence identical (sense region of siNA) to a
predetermined target sequence, wherein the sense region comprises, for
example, about
19, 20, 21, or 22 nucleotides (N) in length, and which is followed by a 3'-
restriction site
(R2) which is adjacent to a loop sequence of defined sequence (X).
Figure 8B: The synthetic construct is then extended by DNA polymerase to
generate a hairpin structure having self complementary sequence.
Figure 8C: The construct is processed by restriction enzymes specific to Rl
and
R2 to generate a double-stranded DNA which is then inserted into an
appropriate vector
for expression in cells. The transcription cassette is designed such that a U6
promoter
region flanks each side of the dsDNA which generates the separate sense and
antisense
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strands of the siNA. Poly T termination sequences can be added to the
constructs to
generate U overhangs in the resulting transcript.
Figure 9A-E is a diagrammatic representation of a method used to determine
target sites for siNA mediated RNAi within a particular target nucleic acid
sequence,
such as messenger RNA.
Figure 9A: A pool of siNA oligonucleotides are synthesized wherein the
antisense
region of the siNA constructs has complementarity to target sites across the
target
nucleic acid sequence, and wherein the sense region comprises sequence
complementary
to the antisense region of the siNA.
Figure 9B&C: (Figure 9B) The sequences are pooled and are inserted into
vectors such that (Figure 9C) transfection of a vector into cells results in
the expression
of the siNA.
Figure 9D: Cells are sorted based on phenotypic change that is associated with
modulation of the target nucleic acid sequence.
Figure 9E: The siNA is isolated from the sorted cells and is sequenced to
identify
efficacious target sites within the target nucleic acid sequence.
Figure 10 shows non-limiting examples of different stabilization chemistries
(1-
10) that can be used, for example, to stabilize the 3'-end of siNA sequences
of the
invention, including (1) [3-3']-inverted deoxyribose; (2) deoxyribonucleotide;
(3) [5'-3']-
3'-deoxyribonucleotide; (4) [5'-3']-ribonucleotide; (5) [S'-3']-3'-O-methyl
ribonucleotide;
(6) 3'-glyceryl; (7) [3'-5']-3'-deoxyribonucleotide; (8) [3'-3']-
deoxyribonucleotide; (9) [5'-
2']-deoxyribonucleotide; and (10) [5-3']-dideoxyribonucleotide. In addition to
modified
and unmodified backbone chemistries indicated in the figure, these chemistries
can be
combined with different backbone modifications as described herein, for
example,
backbone modifications having Formula I. In addition, the 2'-deoxy nucleotide
shown 5'
to the terminal modifications shown can be another modified or unmodified
nucleotide
or non-nucleotide described herein, for example modifications having any of
Formulae I-
VIT or any combination thereof
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Figure 11 shows a non-limiting example of a strategy used to identify
chemically
modified siNA constructs of the invention that are nuclease resistance while
preserving
the ability to mediate RNAi activity. Chemical modifications are introduced
into the
siNA construct based on educated design parameters (e.g. introducing 2'-
mo~cations,
base modifications, backbone modifications, terminal cap modifications etc).
The
modified construct in tested in an appropriate system (e.g. human serum for
nuclease
resistance, shown, or an animal model fox PK/delivery parameters). In
parallel, the siNA
construct is tested for lZNAi activity, for example in a cell culture system
such as a
luciferase reporter assay). Lead siNA constructs are then identified which
possess a
particular characteristic while maintaining lRNAi activity, and can be further
modified
and assayed once again. This same approach can be used to identify siNA-
conjugate
molecules with improved pharmacokinetic profiles, delivery, and RNAi activity.
Figure 12 shows non-limiting examples of phosphorylated siNA molecules of the
invention, including linear and duplex constructs and asymmetric derivatives
thereof
Figure 13 shows non-limiting examples of chemically modified terminal
phosphate groups of the invention.
Figure 14A shows a non-limiting example of methodology used to design self
complementary DFO constructs utilizing palidrome and/or repeat nucleic acid
sequences
that are identified in a target nucleic acid sequence. (i) A palindrome or
repeat sequence
is identified in a nucleic acid target sequence. (ii) A sequence is designed
that is
complementary to the target nucleic acid sequence and the palindrome sequence.
(iii) An
inverse repeat sequence of the non-palindrome/repeat portion of the
complementary
sequence is appended to the 3'-end of the complementary sequence to generate a
self
complementary DFO molecule comprising sequence complementary to the nucleic
acid
target. (iv) The DFO molecule can self assemble to form a double stranded
oligonucleotide. Figure 14B shows a non-limiting representative example of a
duplex
forming oligonucleotide sequence. Figure 14C shows a non-limiting example of
the self
assembly schematic of a representative duplex forming oligonucleotide
sequence.
Figure 14D shows a non-limiting example of the self assembly schematic of a
representative duplex forming oligonucleotide sequence followed by interaction
with a
target nucleic acid sequence resulting in modulation of gene expression.
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Figure 15 shows a non-limiting example of the design of self complementary DFO
constructs utilizing palidrome and/or repeat nucleic acid sequences that are
incorporated
into the DFO constructs that have sequence complementary to any target nucleic
acid
sequence of interest. Incorporation of these palindrome/repeat sequences allow
the
design of DFO constructs that form duplexes in which each strand is capable of
mediating modulation of target gene expression, for example by RNAi. First,
the target
sequence is identified. A complementary sequence is then generated in which
nucleotide
or non-nucleotide modifications (shown as X or Y) are introduced into the
complementary sequence that generate an artificial palindrome (shown as XYXYXY
in
the Figure). An inverse repeat of the non-palindrome/repeat complementary
sequence is
appended to the 3'-end of the complementary sequence to generate a self
complementary
DFO comprising sequence complementary to the nucleic acid target. The DFO can
self
assemble to form a double stranded oligonucleotide.
Figure 16 shows non-limiting examples of multifunctional siNA molecules of the
invention comprising two separate polynucleotide sequences that are each
capable of
mediating RNAi directed cleavage of differing target nucleic acid sequences.
Figure
16A shows a non-limiting example of a multifunctional siNA molecule having a
first
region that is complementary to a first target nucleic acid sequence
(complementary
region 1) and a second region that is complementary to a second target nucleic
acid
sequence (complementary region 2), wherein the first and second complementary
regions
are situated at the 3'-ends of each polynucleotide sequence in the
multifunctional siNA.
The dashed portions of each polynucleotide sequence of the multifunctional
siNA
construct have complementarity with regard to corresponding portions of the
siNA
duplex, but do not have complementarity to the target nucleic acid sequences.
Figure
16B shows a non-limiting example of a multifunctional siNA molecule having a
first
region that is complementary to a first target nucleic acid sequence
(complementary
region 1) and a second region that is complementary to a second target nucleic
acid
sequence (complementary region 2), wherein the first and second complementary
regions
are situated at the 5'-ends of each polynucleotide sequence in the
multifunctional siNA.
The dashed portions of each polynucleotide sequence of the multifunctional
siNA
construct have complementarily with regard to corresponding portions of the
siNA
duplex, but do not have complementarity to the target nucleic acid sequences.
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Figure 17 shows non-limiting examples of multifunctional siNA molecules of the
invention comprising a single polynucleotide sequence comprising distinct
regions that
are each capable of mediating RNAi directed cleavage of differing target
nucleic acid
sequences. Figure 17A shows a non-limiting example of a multifunctional siNA
molecule having a first region that is complementary to a first target nucleic
acid
sequence (complementary region 1) and a second region that is complementary to
a
second target nucleic acid sequence (complementary region 2), wherein the
second
complementary region is situated at the 3'-end of the polynucleotide sequence
in the
multifunctional siNA. The dashed portions of each polynucleotide sequence of
the
multifunctional siNA construct have complernentarity with regard to
corresponding
portions of the siNA duplex, but do not have complementarity to the target
nucleic acid
sequences. Figure 17B shows a non-limiting example of a multifunctional siNA
molecule having a first region that is complementary to a first target nucleic
acid
sequence (complementary region 1) and a second region that is complementary to
a
second target nucleic acid sequence (complementary region 2), wherein the
first
complementary region is situated at the 5'-end of the polynucleotide sequence
in the
multifunctional siNA. The dashed portions of each polynucleotide sequence of
the
multifunctional siNA construct have complementarily with regard to
corresponding
portions of the siNA duplex, but do not have complementarity to the target
nucleic acid
sequences. In one embodiment, these multifunctional siNA constructs are
processed in
vivo or in vitro to generate multifunctional siNA constructs as shown in
Figure 16.
Figure 18 shows non-limiting examples of multifunctional siNA molecules of the
invention comprising two separate polynucleotide sequences that are each
capable of
mediating RNAi directed cleavage of differing target nucleic acid sequences
and wherein
the multifunctional siNA construct further comprises a self complementary,
palindrome,
or repeat region, thus enabling shorter bifuctional siNA constructs that can
mediate RNA
interference against differing target nucleic acid sequences. Figure 18A shows
a non-
limiting example of a multifunctional siNA molecule having a first region that
is
complementary to a first target nucleic acid sequence (complementary region 1)
and a
second region that is complementary to a second target nucleic acid sequence
(complementary region 2), wherein the first and second complementary regions
are
situated at the 3' -ends of each polynucleotide sequence in the
multifunctional siNA, and
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wherein the first and second complementary regions further comprise a self
complementary, palindrome, or repeat region. The dashed portions of each
polynucleotide sequence of the multifunctional siNA construct have
complementarity
with regard to corresponding portions of the siNA duplex, but do not have
complernentarity to the target nucleic acid sequences. Figure 18B shows a non-
limiting
example of a multifunctional siNA molecule having a first region that is
complementary
to a first target nucleic acid sequence (complementary region I) and a second
region that
is complementary to a second target nucleic acid sequence (complementary
region 2),
wherein the first and second complementary regions are situated at the 5'-ends
of each
polynucleotide sequence in the multifunctional siNA, and wherein the first and
second
complementary regions further comprise a self complementary, palindrome, or
repeat
region. The dashed portions of each polynucleotide sequence of the
multifunctional
siNA construct have complementarity with regard to corresponding portions of
the siNA
duplex, but do not have complementarity to the target nucleic acid sequences.
Figure 19 shows non-limiting examples of multifunctional siNA molecules of the
invention comprising a single polynucleotide sequence comprising distinct
regions that
are each capable of mediating RNAi directed cleavage of differing target
nucleic acid
sequences and wherein the multifunctional siNA construct further comprises a
self
complementary, palindrome, or repeat region, thus enabling shorter bifuctional
siNA
constructs that can mediate RNA interference against differing target nucleic
acid
sequences. Figure 19A shows a non-limiting example of a multifunctional siNA
molecule having a first region that is complementary to a first target nucleic
acid
sequence (complementary region I) and a second region that is complementary to
a
second target nucleic acid sequence (complementary region 2), wherein the
second
complementary region is situated at the 3'-end of the polynucleotide sequence
in the
multifunctional siNA, and wherein the first and second complementary regions
further
comprise a self complementary, palindrome, or repeat region. The dashed
portions of
each polynucleotide sequence of the multifunctional siNA construct have
complementarity with regard to corresponding portions of the siNA duplex, but
do not
have complementarity to the target nucleic acid sequences. Figure 19B shows a
non-
limiting example of a multifunctional siNA molecule having a first region that
is
complementary to a first target nucleic acid sequence (complementary region 1)
and a
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second region that is complementary to a second target nucleic acid sequence
(complementary region 2), wherein the first complementary region is situated
at the 5'-
end of the polynucleotide sequence in the multifunctional siNA, and wherein
the first
and second complementary regions further comprise a self complementary,
palindrome,
or repeat region. The dashed portions of each polynucleotide sequence of the
multifunctional siNA construct have complementarity with regard to
corresponding
portions of the siNA duplex, but do not have complementarity to the target
nucleic acid
sequences. In one embodiment, these multifunctional siNA constructs are
processed in
vivo or in vitro to generate multifunctional siNA constructs as shown in
Figure 18.
Figure 20 shows a non-limiting example of how multifunctional siNA molecules
of the invention can target two separate target nucleic acid molecules, such
as separate
RNA molecules encoding differing proteins, for example, a cytokine and its
corresponding receptor, differing viral strains, a virus and a cellular
protein involved in
viral infection or replication, or differing proteins involved in a common or
divergent
biologic pathway that is implicated in the maintenance of progression of
disease. Each
strand of the multifunctional siNA construct comprises a region having
complementarity
to separate target nucleic acid molecules. The multifunctional siNA molecule
is
designed such that each strand of the siNA can be utilized by the RISC complex
to
initiate RNA interference mediated cleavage of its corresponding target. These
design
parameters can include destabilization of each end of the siNA construct (see
for
example Schwarz et al., 2003, Cell, 115, 199-20S). Such destabilization can be
accomplished for example by using guanosine-cytidine base pairs, alternate
base pairs
(e.g., wobbles), or destabilizing chemically modified nucleotides at terminal
nucleotide
positions as is known in the art.
Figure 21 shows a non-limiting example of how multifunctional siNA molecules
of the invention can target two separate target nucleic acid sequences within
the same
target nucleic acid molecule, such as alternate coding regions of a RNA,
coding and non-
coding regions of a RNA, or alternate splice variant regions of a RNA. Each
strand of
the multifunctional siNA construct comprises a region having complementarity
to the
separate regions of the target nucleic acid molecule. The multifunctional siNA
molecule
is designed such that each strand of the siNA can be utilized by the RISC
complex to
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initiate RNA interference mediated cleavage of its corresponding target
region. These
design parameters can include destabilization of each end of the siNA
construct (see for
example Schwarz et al., 2003, Cell, 115, 199-208). Such destabilization can be
accomplished for ea~ample by using guanosine-cytidine base pairs, alternate
base pairs
(e.g., wobbles), or destabilizing chemically modified nucleotides at terminal
nucleotide
positions as is known in the art.
DETAILED DESCRTPTION OF THE INVENTION
Mechanism of Action of Nucleic Acid Molecules of the Invention
The discussion that follows discusses the proposed mechanism of RNA
interference mediated by short interfering RNA as is presently known, and is
not meant
to be limiting and is not an admission of prior art. Applicant demonstrates
herein that
chemically-modified short interfering nucleic acids possess similar or
improved capacity
to mediate RNAi as do siRNA molecules and are expected to possess improved
stability
and activity ira vivo; therefore, this discussion is not meant to be limiting
only to siRNA
and can be applied to siNA as a whole. By "improved capacity to mediate RNAi"
or
"improved RNAi activity" is meant to include RNAi activity measured in vitro
and/or in
vivo where the RNAi activity is a reflection of both the ability of the siNA
to mediate
RNAi and the stability of the siNAs of the invention. In this invention, the
product of
these activities can be increased in vitro and/or ira vivo compared to an all
RNA siRNA
or a siNA containing a plurality of ribonucleotides. In some cases, the
activity or stability
of the siNA molecule can be decreased (i.e., less than ten-fold), but the
overall activity of
the siNA molecule is enhanced in vitro and/or isa vivo.
RNA interference refers to the process of sequence specific post-
transcriptional
gene silencing in animals mediated by short interfering RNAs (siRNAs) (Fire et
al.,
1998, Nature, 391, 806). The corresponding process in plants is commonly
referred to as
post-transcriptional gene silencing or RNA silencing and is also referred to
as quelling in
fungi. The process of post-transcriptional gene silencing is thought to be an
evolutionarily-conserved cellular defense mechanism used to prevent the
expression of
foreign genes which is commonly shared by diverse flora and phyla (Fire et
al., 1999,
Trends Genet., 1 S, 358). Such protection from foreign gene expression may
have
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evolved in response to the production of double-stranded RNAs (dsRNAs) derived
from
viral infection or the random integration of transposon elements into a host
genome via a
cellular response that specifically destroys homologous single-stranded RNA or
viral
genomic RNA. The presence of dsRNA in cells triggers the RNAi response though
a
mechanism that has yet to be fully characterized. This mechanism appears to be
different from the interferon response that results from dsRNA-mediated
activation of
protein kinase PKR and 2', 5'-oligoadenylate synthetase resulting in non-
specific
cleavage of mRNA by ribonuclease L.
The presence of long dsRNAs in cells stimulates the activity of a ribonuclease
III
enzyme referred to as Dicer. Dicer is involved in the processing of the dsRNA
into short
pieces of dsRNA known as short interfering RNAs (siRNAs) (Berstein et al.,
2001,
Nature, 409, 363). Short interfering RNAs derived from Dicer activity are
typically
about 21 to about 23 nucleotides in length and comprise about 19 base pair
duplexes.
Dicer has also been implicated in the excision of 21- and 22-nucleotide small
temporal
RNAs (stRNAs) from precursor RNA of conserved structure that are implicated in
translational control (Hutvagner et al., 2001, Science, 293, 834). The RNAi
response
also features an endonuclease complex containing a siRNA, commonly referred to
as an
RNA-induced silencing complex (RISC), which mediates cleavage of single-
stranded
RNA having sequence homologous to the siRNA. Cleavage of the target RNA takes
place in the middle of the region complementary to the guide sequence of the
siRNA
duplex (Elbashir et al., 2001, Genes Dev., 15, 188). In addition, RNA
interference can
also involve small RNA (e.g., micro-RNA or miRNA) mediated gene silencing,
presumably though cellular mechanisms that regulate chromatin structure and
thereby
prevent transcription of target gene sequences (see for example Allshire,
2002, Science,
297, 1818-1819; Volpe et al., 2002, Science, 297, 1833-1837; Jenuwein, 2002,
Science,
297, 2215-2218; and Hall et al., 2002, Science, 297, 2232-2237). As such, siNA
molecules of the invention can be used to mediate gene silencing via
interaction with
RNA transcripts or alternately by interaction with particular gene sequences,
wherein
such interaction results in gene silencing either at the transcriptional level
or post-
transcriptionallevel.
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RNAi has been studied in a variety of systems. Fire et al., 1998, Nature, 391,
806,
were the first to observe RNAi in C. elegans. Wianny and Goetz, 1999, Nature
Cell
Biol., 2, 70, describe RNAi mediated by dsRNA in mouse embryos. Hammond et
al.,
2000, Nature, 404, 293, describe RNAi in Drosophila cells transfected with
dsRNA.
Elbashir et al., 2001, Nature, 411, 494, describe RNAi induced by introduction
of
duplexes of synthetic 21-nucleotide RNAs in cultured mammalian cells including
human
embryonic kidney and HeLa cells. Recent work in Drosophila embryonic lysates
has
revealed certain requirements for siRNA length, structure, chemical
composition, and
sequence that are essential to mediate efficient RNAi activity. These studies
have shown
that 21 nucleotide siRNA duplexes are most active when containing two 2-
nucleotide 3'-
terminal nucleotide overhangs. Furthermore, substitution of one or both siRNA
strands
with 2'-deoxy or 2'-O-methyl nucleotides abolishes RNAi activity, whereas
substitution
of 3'-terminal siRNA nucleotides with deoxy nucleotides was shown to be
tolerated.
Mismatch sequences in the center of the siRNA duplex were also shown to
abolish RNAi
activity. In addition, these studies also indicate that the position of the
cleavage site in
the target RNA is defined by the 5'-end of the siRNA guide sequence rather
than the 3'-
end (Elbashir et al., 2001, EMBO .L, 20, 6877). Other studies have indicated
that a 5'-
phosphate on the target-complementary strand of a siRNA duplex is required for
siRNA
activity and that ATP is utilized to maintain the 5'-phosphate moiety on the
siRNA
(Nykanen et al., 2001, Cell, 107, 309); however, siRNA molecules lacking a 5'-
phosphate are active when introduced exogenously, suggesting that 5'-
phosphorylation of
siRNA constructs may occur i~a vivo.
~nthesis of Nucleic Acid Molecules
Synthesis of nucleic acids greater than 100 nucleotides in length is difficult
using
automated methods, and the therapeutic cost of such molecules is prohibitive.
In this
invention, small nucleic acid motifs ("small" refers to nucleic acid motifs no
more than
100 nucleotides in length, preferably no more than 80 nucleotides in length,
and most
preferably no more than 50 nucleotides in length; e.g., individual siNA
oligonucleotide
sequences or siNA sequences synthesized in tandem) are preferably used for
exogenous
delivery. The simple structure of these molecules increases the ability of the
nucleic acid
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to invade targeted regions of protein and/or RNA structure. Exemplary
molecules of the
instant invention are chemically synthesized, and others can similarly be
synthesized.
Oligonucleotides (e.g., certain modified oligonucleotides or portions of
oligonucleotides lacking ribonucleotides) are synthesized using protocols
known in the
art, for example as described in Caruthers et al., 1992, MetJzods ira
E~azynaology 211, 3-
19, Thompson et al., International PCT Publication No. WO 99/54459, Wincott et
al.,
1995, Nucleic Acids Res. 23, 2677-2684, Wincott et al., 1997, Methods Mol.
Bio., 74,
59, Brennan et ezl., 1998, Biotechnol Bioeng., 61, 33-45, and Brennan, U,S,
Pat. No.
6,001,311. All of these references are incorporated herein by reference. The
synthesis of
oligonucleotides makes use of common nucleic acid protecting and coupling
groups,
such as dimethoxytrityl at the 5'-end, and phosphoramidites at the 3'-end. In
a non-
limiting example, small scale syntheses are conducted on a 394 Applied
Biosystems, Inc.
synthesizer using a 0.2 p.mol scale protocol with a 2.5 min coupling step for
2'-O-
methylated nucleotides and a 45 second coupling step for 2'-deoxy nucleotides
or 2'-
deoxy-2'-fluoro nucleotides. Table III outlines the amounts and the contact
times of the
reagents used in the synthesis cycle. Alternatively, syntheses at the 0.2 wmol
scale can
be performed on a 96-well plate synthesizer, such as the instrument produced
by
Protogene (Palo Alto, CA) with minimal modification to the cycle. A 33-fold
excess (60
~L of 0.11 M = 6.6 pmol) of 2'-O-methyl phosphoramidite and a 105-fold excess
of S-
ethyl tetrazole (60 p,L of 0.25 M = 15 pmol) can be used in each coupling
cycle of 2'-O-
methyl residues relative to polymer-bound 5'-hydroxyl. A 22-fold excess (40 pL
of 0.11
M = 4.4 p.mol) of deoxy phosphoramidite and a 70-fold excess of S-ethyl
tetrazole (40
pL of 0.25 M = 10 ~,mol) can be used in each coupling cycle of deoxy residues
relative
to polymer-bound 5'-hydroxyl. Average coupling yields on the 394 Applied
Biosystems,
Inc. synthesizer, determined by colorimetric quantitation of the trityl
fractions, are
typically 97.5-99%. Other oligonucleotide synthesis reagents for ,the 394
Applied
Biosystems, Inc. synthesizer include the following: detritylation solution is
3% TCA in
methylene chloride (ABI); capping is performed with 16% N methyl imidazole in
THF
(ABI) and 10% acetic anhydridell0% 2,6-lutidine in THF (ABI); and oxidation
solution
is 16.9 mM I2, 49 mM pyridine, 9% water in THF (PerSeptive Biosystems, Inc.).
Burdick & Jackson Synthesis Grade acetonitrile is used directly from the
reagent bottle.
S-Ethyltetrazole solution (0.25 M in acetonitrile) is made up from the solid
obtained
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ii~om American International Chemical, Inc. Alternately, for the introduction
of
phosphorothioate linkages, Beaucage reagent (3H-1,2-Benzodithiol-3-one 1,1-
dioxide,
0.05 M in acetonitrile) is used.
Deprotection of the DNA-based oligonucleotides is performed as follows: the
polymer-bound trityl-on oligoribonucleotide is transferred to a 4 mL glass
screw top vial
and suspended in a solution of 40% aqueous methylamine (1 rnL) at 65 °C
for 10
minutes. After cooling to -20 °C, the supernatant is removed from the
polymer support.
The support is washed three times with 1.0 mL of EtOH:MeCN:H20/3:1:1, vortexed
arid
the supernatant is then added to the first supernatant. The combined
supernatants,
containing the oligoribonucleotide, are dried to a white powder.
The method of synthesis used for RNA including certain siNA molecules of the
invention follows the procedure as described in Usman et al., 1987, .I. Arn.
Chem. Soc.,
109, 7845; Scaringe et al., 1990, Nucleic Acids Res., 18, 5433; and Wincott et
al., 1995,
Nucleic Acids Res. 23, 2677-2684 Wincott et al., 1997, Methods Mol. Bio., 74,
59, and
makes use of common nucleic acid protecting and coupling groups, such as
dimethoxytrityl at the 5'-end, and phosphoramidites at the 3'-end. In a non-
limiting
example, small scale syntheses are conducted on a 394 Applied Biosystems, Inc.
synthesizer using a 0.2 ~mol scale protocol with a 7.5 min coupling step for
alkylsilyl
protected nucleotides and a 2.5 min coupling step for 2'-O-methylated
nucleotides.
Table III outlines the amounts and the contact times of the reagents used in
the synthesis
cycle. Alternatively, syntheses at the 0.2 pmol scale can be done on a 96-well
plate
synthesizer, such as the instrument produced by Protogene (Palo Alto, CA) with
minimal
modification to the cycle. A 33-fold excess (60 ~L of 0.11 M = 6.6 ~,mol) of
2'-O-
methyl phosphoramidite and a 75-fold excess of S-ethyl tetrazole (60 pL of
0.25 M = 15
~,mol) can be used in each coupling cycle of 2'-O-methyl residues relative to
polymer-
bound 5'-hydroxyl. A 66-fold excess (120 p.L of 0.11 M = 13.2 pmol) of
alkylsilyl (ribo)
protected phosphoramidite and a 150-fold excess of S-ethyl tetrazole (120 ~.L
of 0.25 M
= 30 ~mol) can be used in each coupling cycle of ribo residues relative to
polymer-
bound 5'-hydroxyl. Average coupling yields on the 394 Applied Biosystems, Inc.
synthesizer, determined by colorimetric quantitation of the trityl fractions,
are typically
97.5-99%. Other oligonucleotide synthesis reagents for the 394 Applied
Biosystems,
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Inc. synthesizer include the following: detritylation solution is 3% TCA in
methylene
chloride (ABI); capping is performed with 16% N methyl imidazole in THF (ABI)
and
10% acetic anhydride/10% 2,6-lutidine in THF (ABI); oxidation solution is 16.9
mM I2,
49 mM pyridine, 9% water in THF (PerSeptive Biosystems, Inc.). Burdick &
Jackson
Synthesis Grade acetonitrile is used directly from the reagent bottle. S-
Ethyltetrazole
solution (0.25 M in acetonitrile) is made up from the solid obtained from
American
International Chemical, Inc. Alternately, for the introduction of
phosphorothioate
linkages, Beaucage reagent (3H-1,2-Benzodithiol-3-one 1,1-dioxide0.05 M in
acetonitrile) is used.
Deprotection of the RNA is performed using either a two-pot or one-pot
protocol.
For the two-pot protocol, the polymer-bound trityl-on oligoribonucleotide is
transferred
to a 4 mL glass screw top vial and suspended in a solution of 40% aq,
methylamine (1
mL) at 65 °C for 10 min. After cooling to -20 °C, the
supernatant is removed from the
polymer support. The support is washed three times with 1.0 mL of
EtOH:MeCN:H20/3:1:1, vortexed and the supernatant is then added to the first
supernatant. The combined supernatants, containing the oligoribonucleotide,
are dried to
a white powder. The base deprotected oligoribonucleotide is resuspended in
anhydrous
TEA/HF/NMP solution (300 p.L of a solution of 1.5 mL N-methylpyrrolidinone,
750 p.L
TEA and 1 mL TEA~3HF to provide a 1.4 M HF concentration) and heated to 65
°C.
After 1.5 h, the oligomer is quenched with 1.5 M NHqHC03.
Alternatively, for the one-pot protocol, the polymer-bound trityl-on
oligoribonucleotide is transferred to a 4 mL glass screw top vial and
suspended in a
solution of 33% ethanolic methylamine/DMSO: 1/1 (0.8 mL) at 65 °C for
15 minutes.
The vial is brought to room temperature TEA~3HF (0.1 mL) is added and the vial
is
heated at 65 °C for 15 minutes. The sample is cooled at -20 °C
and then quenched with
1.5 M NH~HCO~.
For purification of the trityl-on oligomers, the quenched NHqHC03 solution is
loaded onto a C-I8 containing cartridge that had been prewashed with
acetonitrile
followed by 50 mM TEAA. After washing the loaded cartridge with water, the RNA
is
detritylated with 0.5% TFA for 13 minutes. The cartridge is then washed again
with
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water, salt exchanged with 1 M NaCI and washed with water again. The
oligonucleotide
is then eluted with 30% acetonitrile.
The average stepwise coupling yields are typically >98% (Wincott et al., 1995
Nucleic Acids Res. 23, 2677-2684). Those of ordinary skill in the art will
recognize that
the scale of synthesis can be adapted to be larger or smaller than the example
described
above including but not limited to 96-well format.
Alternatively, the nucleic acid molecules of the present invention can be
synthesized separately and joined together post-synthetically, for example, by
ligation
(Moore et al., 1992, Science 256, 9923; Draper et al., International PCT
publication No,
WO 93/23569; Shabarova et al,, 1991, Nucleic Acids ReseaYClz 19, 4247; Bellon
et al.,
1997, Nucleosides & Nucleotides, 16, 951; Bellon et al., 1997, Biocohjugate
Chena. 8,
204), or by hybridization following synthesis and/or deprotection.
The siNA molecules of the invention can also be synthesized via a tandem
synthesis methodology as described in Example 1 herein, wherein both siNA
strands are
I S synthesized as a single contiguous oligonucleotide fragment or strand
separated by a
cleavable linker which is subsequently cleaved to provide separate siNA
fragments or
strands that hybridize and permit purification of the siNA duplex. The linker
can be a
polynucleotide linker or a non-nucleotide linker. The tandem synthesis of siNA
as
described herein can be readily adapted to both multiwell/multiplate synthesis
platforms
such as 96 well or similarly larger mufti-well platforms. The tandem synthesis
of siNA as
described herein can also be readily adapted to large scale synthesis
platforms employing
batch reactors, synthesis columns and the like.
A siNA molecule can also be assembled from two distinct nucleic acid strands
or
fragments wherein one fragment includes the sense region and the second
fragment
includes the antisense region of the RNA molecule.
The nucleic acid molecules of the present invention can be modified
extensively to
enhance stability by modification with nuclease resistant groups, for example,
2'-amino,
2'-C-allyl, 2'-fluoro, 2'-O-methyl, 2'-H (for a xeview see Usman and
Cedergren, 1992,
TIBS 17, 34; Usman et al., 1994, Nucleic Acids Syynp. Ser. 31, 163). siNA
constructs can
be purified by gel electrophoresis using general methods or can be purified by
high
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pressure liquid chromatography (HPLC; see Wincott et al., supra, the totality
of which is
hereby incorporated herein by reference) and re-suspended in water.
In another aspect of the invention, siNA molecules of the invention are
expressed
from transcription units inserted into DNA ox RNA vectors. The recombinant
vectors can
be DNA plasmids or viral vectors. siNA expressing viral vectors can be
constructed
based on, but not limited to, adeno-associated virus, retrovirus, adenovirus,
or alphavirus.
The recombinant vectors capable of expressing the siNA molecules can be
delivered as
described herein, and persist in target cells. Alternatively, viral vectors
can be used that
provide for transient expression of siNA molecules.
Optimizing_Activity of the nucleic acid molecule of the invention.
Chemically synthesizing nucleic acid molecules with modifications (base, sugar
andfor phosphate) can prevent their degradation by serum ribonucleases, which
can
increase their potency (see e.g., Eckstein et al., International Publication
No. WO
92/07065; Perrault et al., 1990 NatuYe 344, 565; Pielcen et al., 1991, Science
253, 314;
Usman and Cedergren, 1992, Trehels irr Biochem. Sci. 17, 334; Usman et al.,
International Publication No. WO 93/15187; and Rossi et al., International
Publication
No. WO 91/03162; Sproat, U.S. Pat. No. 5,334,711; Gold et al., U.S. Pat. No.
6,300,074;
and Burgin et al., supra; all of which are incorporated by reference herein).
All of the
above references describe various chemical modifications that can be made to
the base,
phosphate and/or sugar moieties of the nucleic acid molecules described
herein.
Modifications that enhance their efficacy in cells, and removal of bases from
nucleic acid
molecules to shorten oligonucleotide synthesis times and reduce chemical
requirements
are desired.
There are several examples in the art describing sugar, base and phosphate
modifications that can be introduced into nucleic acid molecules with
significant
enhancement in their nuclease stability and efficacy. For example,
oligonucleotides are
modified to enhance stability and/or enhance biological activity by
modification with
nuclease resistant groups, for example, 2'-amino, 2'-~'-allyl, 2'-fluoro, 2'-O-
methyl, 2'-O-
allyl, 2'-H, nucleotide base modifications (for a review see Usman and
Cedergren, 1992,
TIBS. 17, 34; Usman et al., 1994, Nucleic Acids Syrnp. Ser. 31, 163; Burgin et
al., 1996,
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Biochemistry, 35, 14090). Sugar modification of nucleic acid molecules have
been
extensively described in the art (see Eckstein et al., International
Publication PCT No.
WO 92/07065; Perrault et al. Nature, 1990, 344, 565-568; Pieken et al.
Science, 1991,
253, 314-317; Usman and Cedergren, Trends in Biochem. Sci., 1992, 17, 334-339;
Usman et al. International Publication PCT No. WO 93/15187; Sproat, U.S. Pat.
No.
5,334,711 and Beigelman et al., 1995, J. Biol. Chem., 270, 25702; Beigelman et
al.,
International PCT publication No. WO 97/26270; Beigelman et al., U.S. Pat. No.
5,716,824; Usman et al., U.S. Pat. No. 5,627,053; Woolf et al., International
PCT
Publication No. WO 98/13526; Thompson et al., USSN 60/082,404 which was filed
on
April 20, 1998; Karpeisky et al., 1998, Tetralzedron Lett., 39, 1131; Earnshaw
and Gait,
1998, Biopolymers (Nucleic Acid Sciezzces), 48, 39-55; Verma and Eckstein,
1998, Annu.
Rev. Biochem., 67, 99-134; and Burlina et al., 1997, Bioorg. Med. Clzenz., 5,
1999-2010;
all of the references are hereby incorporated in their totality by reference
herein). Such
publications describe general methods and strategies to determine the location
of
incorporation of sugar, base and/or phosphate modifications and the like into
nucleic acid
molecules without modulating catalysis, and are incorporated by reference
herein. In
view of such teachings, similar modifications can be used as described herein
to modify
the siNA nucleic acid molecules of the instant invention so long as the
ability of siNA to
promote RNAi is cells is not significantly inhibited.
While chemical modification of oligonucleotide internucleotide linkages with
phosphorothioate, phosphorodithioate, and/or 5'-methylphosphonate linkages
improves
stability, excessive modifications can cause some toxicity or decreased
activity.
Therefore, when designing nucleic acid molecules, the amount of these
internucleotide
linkages should be minimized. The reduction in the concentration of these
linkages
should lower toxicity, resulting in increased efficacy and higher specificity
of these
molecules.
Short interfering nucleic acid (siNA) molecules having chemical modifications
that
maintain or enhance activity are provided. Such a nucleic acid is also
generally more
resistant to nucleases than an unmodified nucleic acid. Accordingly, the in
vitro and/or
in vivo activity should not be significantly lowered. In cases in which
modulation is the
goal, therapeutic nucleic acid molecules delivered exogenously should
optimally be
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stable within cells until translation of the target RNA has been modulated
long enough to
reduce the levels of the undesirable protein. This period of time varies
between hours to
days depending upon the disease state. Improvements in the chemical synthesis
of RNA
and DNA (Wincott et al., 1995, Nucleic Acids Res. 23, 2677; Caruthers et al.,
1992,
Methods in Enzynzology 21 l, 3-19 (incorporated by reference herein)) have
expanded the
ability to modify nucleic acid molecules by introducing nucleotide
modifications to
enhance their nuclease stability, as described above.
In one embodiment, nucleic acid molecules of the invention include one or more
(e.g., about l, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) G-clamp nucleotides. A G-
clamp
nucleotide is a modified cytosine analog wherein the modifications confer the
ability to
hydrogen bond both Watson-Crick and Hoogsteen faces of a complementary guanine
within a duplex, see for example Lin and Matteucci, 1998, J. Am. Chem. Soc.,
120, 8531-
8532. A single G-clamp analog substitution within an oligonucleotide can
result in
substantially enhanced helical thermal stability and mismatch discrimination
when
hybridized to complementary oligonucleotides. The inclusion of such
nucleotides in
nucleic acid molecules of the invention results in both enhanced affinity and
specificity
to nucleic acid targets, complementary sequences, or template strands. In
another
embodiment, nucleic acid molecules of the invention include one or more (e.g.,
about 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, or more) LNA "locked nucleic acid" nucleotides
such as a 2', 4'-
C rnethylene bicyclo nucleotide (see for example Wengel et al., International
PCT
Publication No, WO 00/66604 and WO 99/14226).
In another embodiment, the invention features conjugates and/or complexes of
siNA molecules of the invention. Such conjugates and/or complexes can be used
to
facilitate delivery of siNA molecules into a biological system, such as a
cell. The
conjugates and complexes provided by the instant invention can impart
therapeutic
activity by transfernng therapeutic compounds across cellular membranes,
altering the
pharmacokinetics, and/or modulating the localization of nucleic acid molecules
of the
invention. The present invention encompasses the design and synthesis of novel
conjugates and complexes for the delivery of molecules, including, but not
limited to,
small molecules, lipids, cholesterol, phospholipids, nucleosides, nucleotides,
nucleic
acids, antibodies, toxins, negatively charged polymers and other polymers, for
example
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proteins, peptides, hormones, carbohydrates, polyethylene glycols, or
polyamines, across
cellular membranes. In general, the transporters described are designed to be
used either
individually or as part of a mufti-component system, with or without
degradable linkers.
These compounds are expected to improve delivery and/or localization of
nucleic acid
molecules of the invention into a number of cell types originating from
different tissues,
in the presence or absence of serum (see Sullenger and Cech, U.S. Pat. No.
5,854,038).
Conjugates of the molecules described herein can be attached to biologically
active
molecules via linkers that are biodegradable, such as biodegradable nucleic
acid linker
molecules.
The term "biodegradable linker" as used herein, refers to a nucleic acid or
non-
nucleic acid linker molecule that is designed as a biodegradable linker to
connect one
molecule to another molecule, for example, a biologically active molecule to a
siNA
molecule of the invention or the sense and antisense strands of a siNA
molecule of the
invention. The biodegradable linker is designed such that its stability can be
modulated
for a particular purpose, such as delivery to a particular tissue or cell
type. The stability
of a nucleic acid-based biodegradable linker molecule can be modulated by
using various
chemistries, for example combinations of ribonucleotides,
deoxyribonucleotides, and
chemically-modified nucleotides, such as 2'-O-methyl, 2'-fluoro, 2'-amino, 2'-
O-amino,
2'-C-allyl, 2'-0-allyl, and other 2'-modified or base modified nucleotides.
The
biodegradable nucleic acid linker molecule can be a dimer, trimer, tetramer or
longer
nucleic acid molecule, for example, an oligonucleotide of about 2, 3, 4, 5, 6,
7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleotides in length, or can
comprise a single
nucleotide with a phosphorus-based linkage, for example, a phosphoramidate or
phosphodiester linkage. The biodegradable nucleic acid linker molecule can
also
comprise nucleic acid backbone, nucleic acid sugar, or nucleic acid base
modifications.
The term "biodegradable" as used herein, refers to degradation in a biological
system, for example, enzymatic degradation or chemical degradation.
The term "biologically active molecule" as used herein refers to compounds or
molecules that are capable of eliciting or modifying a biological response in
a system.
Non-limiting examples of biologically active siNA molecules either alone or in
combination with other molecules contemplated by the instant invention include
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therapeutically active molecules such as antibodies, cholesterol, hormones,
antivirals,
peptides, proteins, chemotherapeutics, small molecules, vitamins, co-factors,
nucleosides, nucleotides, oligonucleotides, enzymatic nucleic acids, antisense
nucleic
acids, triplex forming oligonucleotides, 2,5-A chimeras, siNA, dsRNA,
allozymes,
aptamers, decoys and analogs thereof. Biologically active molecules of the
invention
also include molecules capable of modulating the pharmacokinetics and/or
pharmacodynamics of other biologically active molecules, for example, lipids
and
polymers such as polyamines, polyamides, polyethylene glycol and other
polyethers.
The term "phospholipid" as used herein, refers to a hydrophobic molecule
comprising at least one phosphorus group. For example, a phospholipid can
comprise a
phosphorus-containing group and saturated or unsaturated alkyl group,
optionally
substituted with OH, COOH, oxo, amine, or substituted or unsubstituted aryl
groups.
Therapeutic nucleic acid molecules (e.g., siNA molecules) delivered
exogenously
optimally are stable within cells until reverse transcription of the RNA has
been
modulated long enough to reduce the levels of the RNA transcript. The nucleic
acid
molecules are resistant to nucleases in order to function as effective
intracellular
therapeutic agents. Improvements in the chemical synthesis of nucleic acid
molecules
described in the instant invention and in the art have expanded the ability to
modify
nucleic acid molecules by introducing nucleotide modifications to enhance
their nuclease
stability as described above.
In yet another embodiment, siNA molecules having chemical modifications that
maintain or enhance enzymatic activity of proteins involved in RNAi are
provided. Such
nucleic acids are also generally more resistant to nucleases than unmodified
nucleic
acids. Thus, ih vitro and/or isa vivo the activity should not be significantly
lowered.
Use of the nucleic acid-based molecules of the invention will lead to better
treatments by affording the possibility of combination therapies (e.g.,
multiple siNA
molecules targeted to different genes; nucleic acid molecules coupled with
known small
molecule modulators; or intermittent treatment with combinations of molecules,
including different motifs and/or other chemical or biological molecules). The
treatment
of subjects with siNA molecules can also include combinations of different
types of
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nucleic acid molecules, such as enzymatic nucleic acid molecules (ribozymes),
allozymes, antisense, 2,5-A oligoadenylate, decoys, and aptamers.
In another aspect a siNA molecule of the invention comprises one or more 5'
and/or a 3'- cap structure, for example, on only the sense siNA strand, the
antisense siNA
strand, or both siNA strands.
By "cap structure" is meant chemical modifications, which have been
incorporated
at either terminus of the oligonucleotide (see, for example, Adamic et al.,
U.S. Pat. No.
5,998,203, incorporated by reference herein). These terminal modifications
protect the
nucleic acid molecule from exonuclease degradation, and may help in delivery
and/or
localization within a cell. The cap may be present at the 5'-terminus (5'-cap)
or at the 3'-
terminal (3'-cap) or may be present on both termini. In non-limiting examples,
the 5'-cap
includes, but is not limited to, glyceryl, inverted deoxy abasic residue
(moiety); 4',5'-
methylene nucleotide; 1-(beta-D-erythrofuranosyl) nucleotide, 4'-thio
nucleotide;
carbocyclic nucleotide; 1,5-anhydrohexitol nucleotide; L-nucleotides; alpha-
nucleotides;
modified base nucleotide; phosphorodithioate linkage; tlzreo-pentofuranosyl
nucleotide;
acyclic 3',4'-seco nucleotide; acyclic 3,4-dihydroxybutyl nucleotide; acyclic
3,5-
dihydroxypentyl nucleotide, 3'-3'-inverted nucleotide moiety; 3'-3'-inverted
abasic
moiety; 3'-2'-inverted nucleotide moiety; 3'-2'-inverted abasic moiety; 1,4-
butanediol
phosphate; 3'-phosphoramidate; hexylphosphate; aminohexyl phosphate; 3'-
phosphate;
3'-phosphorothioate; phosphorodithioate; or bridging or non-bridging
methylphosphonate moiety. Non-limiting examples of cap moieties are shown in
Figure
10.
Non-limiting examples of the 3'-cap include, but are not limited to, glyceryl,
inverted deoxy abasic residue (moiety), 4', 5'-methylene nucleotide; 1-(beta-D-
erythrofuranosyl) nucleotide; 4'-thio nucleotide, carbocyclic nucleotide; 5'-
amino-alkyl
phosphate; 1,3-diamino-2-propyl phosphate; 3-aminopropyl phosphate; 6-
aminohexyl
phosphate; 1,2-aminododecyl phosphate; hydroxypropyl phosphate; 1,5-
anhydrohexitol
nucleotide; L-nucleotide; alpha-nucleotide; modified base nucleotide;
phosphorodithioate; tlzreo-pentofuranosyl nucleotide; acyclic 3',4'-seco
nucleotide; 3,4-
dihydroxybutyl nucleotide; 3,5-dihydroxypentyl nucleotide, 5'-5'-inverted
nucleotide
moiety; 5'-5'-inverted abasic moiety; 5'-phosphoramidate; 5'-phosphorothioate;
1,4
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butanediol phosphate; 5'-amino; bridging and/or non-bridging 5'-
phosphoramidate,
phosphorothioate and/or phosphorodithioate, bridging or non bridging
methylphosphonate and 5'-mercapto moieties (for more details see Beaucage and
Iyer,
1993, Tetralaedrofa 49, 1925; incorporated by reference herein).
By the term "non-nucleotide" is meant any group or compound which can be
incorporated into a nucleic acid chain in the place of one or more nucleotide
units,
including either sugar and/or phosphate substitutions, and allows the
remaining bases to
exhibit their enzymatic activity. The group or compound is abasic in that it
does not
contain a commonly recognized nucleotide base, such as adenosine, guanine,
cytosine,
uracil or thymine and therefore lacks a base at the 1'-position.
An "alkyl" group refers to a saturated aliphatic hydrocarbon, including
straight-
chain, branched-chain, and cyclic alkyl groups. Preferably, the alkyl group
has 1 to 12
carbons. More preferably, it is a lower alkyl of from 1 to 7 carbons, more
preferably 1 to
4 carbons. The alkyl group can be substituted or unsubstituted. When
substituted the
substituted groups) is preferably, hydroxyl, cyano, alkoxy, =O, =S, N02 or
N(CH3)2,
amino, or SH. The term also includes alkenyl groups that are unsaturated
hydrocarbon
groups containing at least one carbon-carbon double bond, including straight-
chain,
branched-chain, and cyclic groups. Preferably, the alkenyl group has 1 to 12
carbons.
More preferably, it is a lower alkenyl of from 1 to 7 carbons, more preferably
1 to 4
carbons. The alkenyl group may be substituted or unsubstituted. When
substituted the
substituted groups) is preferably, hydroxyl, cyano, alkoxy, =O, =S, N02,
halogen,
N(CH3)2, amino, or SH. The term "alkyl" also includes alkynyl groups that have
an
unsaturated hydrocarbon group containing at least one carbon-carbon triple
bond,
including straight-chain, branched-chain, and cyclic groups. Preferably, the
alkynyl
group has 1 to 12 carbons. More preferably, it is a lower alkynyl of from 1 to
7 carbons,
more preferably 1 to 4 carbons. The alkynyl group may be substituted or
unsubstituted.
When substituted the substituted groups) is preferably, hydroxyl, cyano,
alkoxy, =O,
=S, N02 or N(CH3)2, amino or SH.
Such alkyl groups can also include aryl, alkylaryl, carbocyclic aryl,
heterocyclic
aryl, amide and ester groups. An "aryl" group refers to an aromatic group that
has at
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least one ring having a conjugated pi electron system and includes carbocyclic
aryl,
heterocyclic aryl and biaryl groups, all of which may be optionally
substituted. The
preferred substituent(s) of aryl groups are halogen, trihalomethyl, hydroxyl,
SH, OH,
cyano, alkoxy, alkyl, alkenyl, alkynyl, and amino groups _ An "alkylaryl"
group refers to
an alkyl group (as described above) covalently joined to an aryl group (as
described
above). Carbocyclic aryl groups are groups wherein the ring atoms on the
aromatic ring
are all carbon atoms. The carbon atoms are optionally substituted.
Heterocyclic aryl
groups are groups having from 1 to 3 heteroatoms as ring atoms in the aromatic
ring and
the remainder of the ring atoms are carbon atoms. Suitable heteroatoms include
oxygen,
sulfur, and nitrogen, and include furanyl, thienyl, pyridyl, pyrrolyl, N-lower
alkyl
pyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like, all optionally
substituted. An
"amide" refers to an -C(O)-NH-R, where R is either all~yl, aryl, alkylaryl or
hydrogen.
An "ester" refers to an -C(O)-OR', where R is either alkyl, aryl, alkylaryl or
hydrogen.
By "nucleotide" as used herein is as recognized in the art to include natural
bases
(standard), and modified bases well known in the art. Such bases are generally
located at
the 1' position of a nucleotide sugar moiety. Nucleotides generally comprise a
base,
sugar and a phosphate group. The nucleotides can be unmodified or modified at
the
sugar, phosphate and/or base moiety, (also referred to interchangeably as
nucleotide
analogs, modified nucleotides, non-natural nucleotides, non-standard
nucleotides arid
other; see, for example, Usman and McSwiggen, supra; Eckstein et al.,
International
PCT Publication No. WO 92/07065; Usman et al., International PCT Publication
No.
WO 93/15187; Uhlman & Peyman, supra, all are hereby incorporated by reference
herein). There are several examples of modified nucleic acid bases known in
the art as
summarized by Limbach et al., 1994, Nucleic Acids Res. 22, 2183. Some of the
non-
limiting examples of base modifications that can be introduced into nucleic
acid
molecules include, inosine, purine, pyridin-4-one, pyridin-2-one, phenyl,
pseudouracil, 2,
4, 6-trimethoxy benzene, 3-methyl uracil, dihydrouridine, naphthyl,
aminophenyl,
5-alkylcytidines (e.g., 5-rnethylcytidine), 5-alkyluridines (e.g.,
ribothymidine),
5-halouridine (e.g., 5-bromouridine) or 6-azapyrimidines or 6-alkylpyrimidines
(e.g. 6-
methyluridine), propyne, and others (Burgin et al., 1996, Biochemistry, 35,
14090;
Uhlman & Peyman, supra). By "modified bases" in this aspect is meant
nucleotide bases
other than adenine, guanine, cytosine and uracil at 1' position or their
equivalents.
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In one embodiment, the invention features modified siNA molecules, with
phosphate backbone modifications comprising one or more phosphorothioate,
phosphorodithioate, methylphosphonate, phosphotriester, morpholino, amidate
carbamate, carboxymethyl, acetamidate, polyamide, sulfonate, sulfonamide,
sulfamate,
formacetal, thioformacetal, and/or alkylsilyl, substitutions. For a review of
oligonucleotide backbone modifications, see Hunziker and Leumann, 1995,
Nucleic Acid
Analogues: Synthesis and Properties, in Modern Synthetic Methods, VCH, 331-
417, and
Mesmaeker et al., 1994, Novel Backbone Replacements for Oligozzucleotides, in
Carbohydrate Modifications izz Antisense Research, ACS, 24-39.
By "abasic" is meant sugar moieties lacking a base or having other chemical
groups in place of a base at the 1' position, see for example Adamic et al.,
U.S. Pat. No.
5,998,203.
By "unmodified nucleoside" is meant one of the bases adenine, cytosine,
guanine,
thymine, or uracil joined to the 1' carbon of (3-D-ribo-furanose.
By "modified nucleoside" is meant any nucleotide base which contains a
modification in the chemical structure of an unmodified nucleotide base, sugar
and/or
phosphate. Non-limiting examples of modified nucleotides are shown by Formulae
I-VII
and/or other modifications described herein.
In connection with f-modified nucleotides as described for the present
invention,
by "amino" is meant f-NH2 or f-O- NH2, which can be modified or unmodified.
Such
modified groups are described, for example, in Eckstein et al., U.S. Pat. No.
5,672,695
and Matulic-Adamic et al., U.S. Pat. No. 6,248,878, which are both
incorporated by
reference in their entireties.
Various modifications to nucleic acid siNA structure can be made to enhance
the
utility of these molecules. Such modifications will enhance shelf life, half
life in vitro,
stability, and ease of introduction of such oligonucleotides to the target
site, e.g., to
enhance penetration of cellular membranes, and confer the ability to recognize
and bind
to targeted cells.
Administration of Nucleic Acid Molecules
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A siNA molecule of the invention can be adapted for use to prevent or treat
diseases, traits, disorders, and/or conditions described herein or otherwise
known in the
art to be related to gene expression, and/or any other trait, disease,
disorder or condition
that is related to or will respond to the levels of a target polynucleotide in
a cell or tissue,
alone or in combination with other therapies. For example, a siNA molecule can
comprise a delivery vehicle, including liposomes, for administration to a
subject, carriers
and diluents and their salts, and/or can be present in pharmaceutically
acceptable
formulations. Methods for the delivery of nucleic acid molecules are described
in
Akhtar et al., 1992, Trezzds Cell Bio., 2, 139; Delivezy Strategies for
Antisenzse
Oligonucleotide Therapeutics, ed. Akhtar, 1995, Maurer et al., 1999, Mol.
Meznbr. Biol.,
16, 129-140; Hofland and Huang, 1999, Handb. Exp. Phaz-zrzacol., 137, 165-192;
and Lee
et al., 2000, ACS Symp. Ser., 752, 184-192, all of which are incorporated
herein by
reference. Beigelman et al., U.S. Pat. No. 6,395,713 and Sullivan et al., PCT
WO
94/02595 further describe the general methods for delivery of nucleic acid
molecules.
These protocols can be utilized for the delivery of virtually any nucleic acid
molecule.
Nucleic acid molecules can be administered to cells by a variety of methods
known to
those of skill in the art, including, but not restricted to, encapsulation in
liposomes, by
iontophoresis, or by incorporation into other vehicles, such as biodegradable
polymers,
hydrogels, cyclodextrins (see for example Gonzalez et al., 1999, Biocoy jugate
Clzenz.,
10, 1068-1074; Wang et al., International PCT publication Nos. WO 03/47518 and
WO
03/46185), poly(lactic-co-glycolic)acid (PLGA) and PLCA microspheres (see for
example US Patent 6,447,796 and US Patent Application Publication No. US
2002130430), biodegradable nanocapsules, and bioadhesive microspheres, or by
proteinaceous vectors (O'Hare and Normand, International PCT Publication No.
WO
00/53722). Alternatively, the nucleic acid/vehicle combination is locally
delivered by
direct injection or by use of an infusion pump. Direct injection of the
nucleic acid
molecules of the invention, whether subcutaneous, intramuscular, or
intradermal, can
take place using standard needle and syringe methodologies, or by needle-free
technologies such as those described in Conry et al., 1999, Clin. Cancez~
Res., 5, 2330-
2337 and Barry et al., International PCT Publication No. WO 99/31262. The
molecules
of the instant invention can be used as pharmaceutical agents. Pharmaceutical
agents
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prevent, modulate the occurrence, or treat (alleviate a symptom to some
extent,
preferably all of the symptoms) of a disease state in a subject.
In another embodiment, the nucleic acid molecules of the invention can also be
formulated or complexed with polyethyleneimine and derivatives thereof, such
as
polyethyleneimine-polyethyleneglycol-N-acetylgalactosamine (PEI-PEG-GAL) or
polyethyleneimine-polyethyleneglycol-tri-N-acetylgalactosamine (PEI-PEG-
triGAL)
derivatives. In one embodiment, the nucleic acid molecules of the invention
are
formulated as described in United States Patent Application Publication No.
20030077829, incorporated by reference herein in its entirety.
In one embodiment, a siNA molecule of the invention is complexed with
membrane disruptive agents such as those described in U.S. Patent Application
Publication No. 20010007666, incorporated by reference herein in its entirety
including
the drawings. In another embodiment, the membrane disruptive agent or agents
and the
siNA molecule are also complexed with a cationic lipid or helper lipid
molecule, such as
those lipids described in U.S. Patent No. 6,235,310, incorporated by reference
herein in
its entirety including the drawings.
In vne embodiment, a siNA molecule of the invention is complexed with delivery
systems as described in U.S. Patent Application Publication No. 2003077829 and
International PCT Publication Nos. WO 00/03683 and WO 02/087541, all
incorporated
by reference herein in their entirety including the drawings.
In one embodiment, the nucleic acid molecules of the invention are
administered
via pulmonary delivery, such as by inhalation of an aerosol or spray dried
formulation
administered by an inhalation device or nebulizer, providing rapid local
uptake of the
nucleic acid molecules into relevant pulmonary tissues. Solid particulate
compositions
containing respirable dry particles of micronized nucleic acid compositions
can be
prepared by grinding dried or lyophilized nucleic acid compositions, and then
passing the
micronized composition through, for example, a 400 mesh screen to break up or
separate
out large agglomerates. A solid particulate composition comprising the nucleic
acid
compositions of the invention can optionally contain a dispersant which serves
to
facilitate the formation of an aerosol as well as other therapeutic compounds.
A suitable
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dispersant is lactose, which can be blended with the nucleic acid compound in
any
suitable ratio, such as a 1 to 1 ratio by weight.
Aerosols of liquid particles comprising a nucleic acid composition of the
invention
can be produced by any suitable means, such as with a nebulizer (see for
example US
4,501,729). Nebulizers are commercially available devices which transform
solutions or
suspensions of an active ingredient into a therapeutic aerosol mist either by
means of
acceleration of a compressed gas, typically air or oxygen, through a narrow
venturi
orifice or by means of ultrasonic agitation. Suitable formulations for use in
nebulizers
comprise the active ingredient in a liquid carrier in an amount of up to 40%
w/w
preferably less than 20% w/w of the formulation. The carrier is typically
water or a
dilute aqueous alcoholic solution, preferably made isotonic with body fluids
by the
addition of, for example, sodium chloride or other suitable salts. Optional
additives
include preservatives if the formulation is not prepared sterile, for example,
methyl
hydroxybenzoate, anti-oxidants, flavorings, volatile oils, buffering agents
and emulsifiers
and other formulation surfactants. The aerosols of solid particles comprising
the active
composition and surfactant can likewise be produced with any solid particulate
aerosol
generator. Aerosol generators for administering solid particulate therapeutics
to a subject
produce particles which are respirable, as explained above, and generate a
volume of
aerosol containing a predetermined metered dose of a therapeutic composition
at a rate
suitable for human administration. One illustrative type of solid particulate
aerosol
generator is an insufflator. Suitable formulations for administration by
insufflation
include finely comrninuted powders which can be delivered by means of an
insufflator.
In the insufflator, the powder, e.g., a metered dose thereof effective to
carry out the
treatments described herein, is contained in capsules or cartridges, typically
made of
gelatin or plastic, which are either pierced or opened in situ and the powder
delivered by
air drawn through the device upon inhalation or by means of a manually-
operated pump.
The powder employed in the insufflator consists either solely of the active
ingredient or
of a powder blend comprising the active ingredient, a suitable powder diluent,
such as
lactose, and an optional surfactant. The active ingredient typically comprises
from 0.1 to
100 w/w of the formulation. A second type of illustrative aerosol generator
comprises a
metered dose inhaler. Metered dose inhalers are pressurized aerosol
dispensers, typically
containing a suspension or solution formulation of the active ingredient in a
liquifled
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propellant. During use these devices discharge the formulation through a valve
adapted
to deliver a metered volume to produce a fine particle spray containing the
active
ingredient. Suitable propellants include certain chlorofluorocarbon compounds,
for
example, dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane
and mixtures thereof. The formulation can additionally contain one or more co-
solvents,
for example, ethanol, emulsifiers and other formulation surfactants, such as
oleic acid or
sorbitan trioleate, anti-oxidants and suitable flavoring agents. Other methods
for
pulmonary delivery are described in, for example US Patent Application No.
20040037780, and US Patent Nos. 6,592,904; 6,582,728; 6,565,885.
In one embodiment, the invention features the use of methods to deliver the
nucleic
acid molecules of the instant invention to the central nervous system and/or
peripheral
nervous system. Experiments have demonstrated the efficient in vivo uptake of
nucleic
acids by neurons. As an example of local administration of nucleic acids to
nerve cells,
Sommer et al., 1998, Ahtisehse Nuc. Acid Drug Dev., 8, 75, describe a study in
which a
l5mer phosphorothioate antisense nucleic acid molecule to c-fos is
administered to rats
via microinjection into the brain. Antisense molecules labeled with
tetramethylrhodamine-isothiocyanate (TRITC) or fluorescein isothiocyanata
(FITC) were
taken up by exclusively by neurons thirty minutes post-injection. A diffuse
cytoplasmic
staining and nuclear staining was observed in these cells. As an example of
systemic
administration of nucleic acid to nerve cells, Epa et al., 2000, AntiseTase
Nuc. Acid Drug
Dev., 10, 469, describe an ira vivo mouse study in which beta-cyclodextrin-
adamantane-
oligonucleotide conjugates were used to target the p75 neurotrophin receptor
in
neuronally differentiated PC12 cells. Following a two week course of IP
administration,
pronounced uptake of p75 neurotrophin receptor antisense was observed in
dorsal root
ganglion (DRG) cells. In addition, a marked and consistent down-regulation of
p75 was
observed in DRG neurons. Additional approaches to the targeting of nucleic
acid to
neurons are described in Broaddus et al., 1998, J. Neurosufg., 88(4), 734,
Karle et al.,
1997, Eur. .I. Pha~mocol., 340(2/3), 153; Bannai et al., 1998, Brairz
ReseaYCh, 784(1,2),
304; Rajakumar et al., 1997, Synapse, 26(3), 199; Wu-pong et al., 1999,
BioPhar~a,
12(1), 32; Bannai et al., 1998, BYairz Res. Protoc., 3(1), 83; Simantov et
al., 1996,
Neuroscience, 74(1), 39. Nucleic acid molecules of the invention are therefore
amenable
to delivery to and uptake by cells that express repeat expansion allelic
variants for
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modulation of RE gene expression. The delivery of nucleic acid molecules of
the
invention, targeting RE is provided by a variety of different strategies.
Traditional
approaches to CNS delivery that can be used include, but are not limited to,
intrathecal
and intracerebroventricular administration, implantation of catheters and
pumps, direct
injection or perfusion at the site of injury or lesion, injection into the
brain arterial
system, or by chemical or osmotic opening of the blood-brain barrier. Other
approaches
can include the use of various transport and carrier systems, for example
though the use
of conjugates and biodegradable polymers. Furthermore, gene therapy
approaches, for
example as described in Kaplitt et al., US 6,180,613 and Davidson, WO
04/013280, can
be used to express nucleic acid molecules in the CNS.
In one embodiment, nucleic acid molecules of the invention are administered to
the
central nervous system (CNS) or peripheral nervous system (PNS). Experiments
have
demonstrated the efficient in vivo uptake of nucleic acids by neurons. As an
example of
local administration of nucleic acids to nerve cells, Sommer et al., 1998,
Antisense Nuc.
Acid Drug Dev., 8, 75, describe a study in which a l5mer phosphorothioate
antisense
nucleic acid molecule to c-fos is administered to rats via microinjection into
the brain.
Antisense molecules labeled with tetramethylrhodamine-isothiocyanate (TRITC)
or
fluorescein isothiocyanate (FITC) were taken up by exclusively by neurons
thirty
minutes post-injection. A diffuse cytoplasmic staining and nuclear staining
was
observed in these cells. As an example of systemic administration of nucleic
acid to
nerve cells, Epa et al., 2000, Antisense Nuc. Acid Drug Dev., 10, 469,
describe an in vivo
mouse study in which beta-cyclodextrin-adamantane-oligonucleotide conjugates
were
used to target the p75 neurotrophin receptor in neuronally differentiated PC12
cells.
Following a two week course of IP administration, pronounced uptake of p75
neurotrophin receptor antisense was observed in dorsal root ganglion (DRG)
cells. In
addition, a marked and consistent down-regulation of p75 was observed in DRG
neurons. Additional approaches to the targeting of nucleic acid to neurons are
described
in Broaddus et al., 1998, J. Neurosurg., 88(4), 734; Karle et al., 1997, Eur.
J.
PhaYmocol., 340(2/3), 153; Bannai et al., 1998, Brain Research, 784(1,2), 304;
Rajakurnar et al., 1997, Synapse, 26(3), 199; Wu-pong et al., 1999, BioPlaarm,
12(1), 32;
Bannai et al., 1998, Brain Res. Protoc., 3(1), 83; Simantov et al., 1996,
Neuroscience,
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74(1), 39. Nucleic acid molecules of the invention are therefore amenable to
delta ery to
and uptake by cells in the CNS and/or PNS.
The delivery of nucleic acid molecules of the invention to the CNS is provided
by
a variety of different strategies. Traditional approaches to CNS delivery that
can be used
include, but are not limited to, intrathecal and intracerebroventricular
administration,
implantation of catheters and pumps, direct injection or perfusion at the site
of injury or
lesion, injection into the brain arterial system, or by chemical or osmotic
opening of the
blood-brain barrier. Other approaches can include the use of various transport
and
carrier systems, for example though the use of conjugates and biodegradable
polymers.
Furthermore, gene therapy approaches, for example as described in Kaplitt et
al., US
6,180,613 and Davidson, WO 04/013280, can be used to express nucleic acid
molecules
in the CNS.
In one embodiment, delivery systems of the invention include, for example,
aqueous and nonaqueous gels, creams, multiple emulsions, microemulsions,
liposomes,
ointments, aqueous and nonaqueous solutions, lotions, aerosols, hydrocarbon
bases and
powders, and can contain excipients such as solubilizers, permeation enhancers
(e.g.,
fatty acids, fatty acid estexs, fatty alcohols and amino acids), and
hydrophilic polymers
(e.g., polycarbophil and polyvinylpyrolidone). In one embodiment, the
pharmaceutically
acceptable carrier is a liposome or a transdermal enhancer. Examples of
liposomes Which
can be used in this invention include the following: (1) CellF'ectin, 1:1.5
(M/M) Iiposome
formulation of the cationic lipid N,NI,NII,NIII-tetramethyl-N,NI,NII,NIII-
tetrapalmit-y-
spermine and dioleoyl phosphatidylethanolamine (DOPE) (GIBCO BRL); (2)
Cytofectin
GSV, 2:1 (M/M) liposome formulation of a cationic lipid and DOPE (Glen
Research);
(3) DOTAP (N-[1-(2,3-dioleoyloxy)-N,N,N-tri-methyl-ammoniummethylsulfate)
(Boehringer Manheim); and (4) Lipofectamine, 3:1 (M/M) liposome formulation of
the
polycationic lipid DOSPA and the neutral lipid DOPE (GIBCO BRL).
In one embodiment, delivery systems of the invention include patches, tablets,
suppositories, pessaries, gels and creams, and can contain excipients such as
solubilizers
and enhancers (e.g., propylene glycol, bile salts and amino acids), and other
vehicles
(e.g., polyethylene glycol, fatty acid esters and derivatives, and hydrophilic
polymers
such as hydroxypropylmethylcellulose and hyaluronic acid).
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In one embodiment, siNA molecules of the invention are formulated or complexed
with polyethylenimine (e.g., linear or branched PEI) and/or polyethylenimine
derivatives, including for example grafted PEIs such as galactose PEI,
cholesterol PEI,
antibody derivatized PEI, and polyethylene glycol PEI (PEG-PEI) derivatives
thereof
(see for example Ogris et al., 2001, ~4APA PlaarrnSci, 3, 1-11; Furgeson et
al., 2003,
Bioconjugate Chem., 14, 840-847; Kunath et al., 2002, Phramaceutical Research,
19,
810-817; Choi et al., 2001, Bull. Korean Chem. Soc., 22, 46-52; Bettinger et
al., 1999,
Bioconjugate Chem., 10, 558-561; Peterson et al., 2002, Bioconjugate Chem., 13
, 845-
854; Erbacher et al., 1999, Journal of Gene Medicine Preprint, 1, 1-18; Godbey
et al.,
1999., PNAS USA, 96, 5177-5181; Godbey et al., 1999, Journal of Controlled
Release,
60, 149-160; Diebold et al., 1999, Journal of Biological Chemistry, 274, 19087-
19094;
Thomas and Klibanov, 2002, PNAS USA, 99, 14640-14645; and Sagara, US
6,586,524,
incorporated by reference herein.
In one embodiment, a siNA molecule of the invention comprises a bioconjugate,
for example a nucleic acid conjugate as described in Vargeese et aL, USSN
10/427,160,
filed April 30, 2003; US 6,528,631; US 6,335,434; US 6, 235,886; US 6,153,737;
US
5,214,136; US 5,138,045, all incorporated by reference herein.
Thus, the invention features a pharmaceutical composition comprising one or
more
nucleic acids) of the invention in an acceptable carrier, such as a
stabilizer, buffer, and
the like. The polynucleotides of the invention can be administered (e.g., RNA,
DNA or
protein) and introduced to a subject by any standard means, with or without
stabilizers,
buffers, and the like, to form a pharmaceutical composition. When it is
desired to use a
liposome delivery mechanism, standard protocols for formation of liposomes can
be
followed. The compositions of the present invention can also be formulated and
used as
creams, gels, sprays, oils and other suitable compositions for topical,
dermal, or
transdermal administration as is known in the art.
The present invention also includes pharmaceutically acceptable formulations
of
the compounds described. These formulations include salts of the above
compounds,
e.g., acid addition salts, for example, salts of hydrochloric, hydxobromic,
acetic acid, and
benzene sulfonic acid.
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A pharmacological composition or formulation refers to a composition or
formulation in a form suitable for administration, e.g., systemic or local
administration,
into a cell or subject, including for example a human. Suitable forms, in
part, depend
upon the use or the route of entry, for example oral, transdermal, or by
injection. Such
forms should not prevent the composition or formulation from reaching a target
cell (i.e.,
a cell to which the negatively charged nucleic acid is desirable for
delivery). For
example, pharmacological compositions injected into the blood stream should be
soluble.
Other factors are known in the art, and include considerations such as
toxicity and forms
that prevent the composition or formulation from exerting its effect.
In one embodiment, siNA molecules of the invention are administered to a
subject
by systemic administration in a pharmaceutically acceptable composition or
formulation.
By "systemic administration" is meant in vivo systemic absorption or
accumulation of
drugs in the blood stream followed by distribution throughout the entire body.
Administration routes that lead to systemic absorption include, without
limitation:
intravenous, subcutaneous, intraperitoneal, inhalation, oral, intrapulmonary
and
intramuscular. Each of these administration routes exposes the siNA molecules
of the
invention to an accessible diseased tissue. The rate of entry of a drug into
the
circulation has been shown to be a function of molecular weight or size. The
use of a
liposome or other drug carrier comprising the compounds of the instant
invention can
potentially localize the drug, for example, in certain tissue types, such as
the tissues of
the reticular endothelial system (RES). A liposome formulation that can
facilitate the
association of drug with the surface of cells, such as, lymphocytes and
macrophages is
also useful. This approach can provide enhanced delivery of the drug to target
cells by
taking advantage of the specificity of macrophage and lymphocyte immune
recognition
of abnormal cells, such as cancer cells.
By "pharmaceutically acceptable formulation" or "pharmaceutically acceptable
composition" is meant, a composition or formulation that allows for the
effective
distribution of the nucleic acid molecules of the instant invention in the
physical location
most suitable for their desired activity. Non-limiting examples of agents
suitable for
formulation with the nucleic acid molecules of the instant invention include:
P-
glycoprotein inhibitors (such as Pluronic P85),; biodegradable polymers, such
as poly
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(DL-lactide-coglycolide) microspheres for sustained release delivery (Emerich,
DF et al,
1999, Cell Trahsplan.t, 8, 47-58); and loaded nanoparticles, such as those
made of
polybutylcyanoacrylate. Other non-limiting examples of delivery strategies for
the
nucleic acid molecules of the instant invention include material described in
Boado et aZ ,
1998, J. Pharnz. Sci., 87, 1308-1315; Tyler et al., 1999, FEBS Lett., 421, 280-
284;
Pardridge et al., 1995, PNAS USA., 92, 5592-5596; Boado, 1995, Adv. Drug
Delivery
Rev., 15, 73-107; Aldrian-Herrada et al., 1998, Nucleic Acids Res., 26, 4910-
4916; and
Tyler et al., 1999, PNAS USA., 96, 7053-7058.
The invention also features the use of the composition comprising surface-
modified liposomes containing poly (ethylene glycol) lipids (PEG-modified, or
long-
circulating liposomes or stealth liposomes). These formulations offer a method
for
increasing the accumulation of drugs in target tissues. This class of drug
Garners resists
opsonization and elimination by the mononuclear phagocytic system (MPS or
REST,
thereby enabling longer blood circulation times and enhanced tissue exposure
for the
15. encapsulated drug (Lasic et al. CIZem. Rev. 1995, 95, 2601-2627; Ishiwata
et al., Chena.
Pharm. Bull. 1995, 43, 1005-1011). Such liposomes have been shown to
accumulate
selectively in tumors, presumably by extravasation and capture in the
neovascularized
target tissues (Lasic et al., Science 1995, 267, 1275-1276; Oku et a1.,1995,
Biochim.
Biophys. Acta, 1238, 86-90). The long-circulating liposomes enhance the
pharmacokinetics and pharmacodynamics of DNA and RNA, particularly compared to
conventional cationic liposomes which are known to accumulate in tissues of
the MPS
(Liu et al., J. Biol. Claem. 1995, 42, 24864-24870; Choi et al., International
PCT
Publication No. WO 96/10391; Ansell et al., International PCT Publication No.
WO
96/10390; Holland et al., International PCT Publication No. WO 96/10392). Long-
circulating liposomes are also likely to protect drugs from nuclease
degradation to a
greater extent compared to cationic liposomes, based on their ability to avoid
accumulation in metabolically aggressive MPS tissues such as the liver and
spleen.
The present invention also includes compositions prepared for storage or
administration that include a pharmaceutically effective amount of the desired
compounds in a pharmaceutically acceptable Garner or diluent. Acceptable
carriers or
diluents for therapeutic use are well known in the pharmaceutical art, and are
described,
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for example, in Reznizzgtoh's Plaamzaceutical Sciezzces, Mack Publishing Co.
(A.R.
Gennaro edit. 1985), hereby incorporated by reference herein. Fox example,
preservatives, stabilizers, dyes and flavoring agents can be provided. These
include
sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. In addition,
S antioxidants and suspending agents can be used.
A pharmaceutically effective dose is that dose required to prevent, inhibit
the
occurrence, or treat (alleviate a symptom to some extent, preferably all of
the symptoms)
of a disease state. The pharmaceutically effective dose depends on the type of
disease,
the composition used, the route of administration, the type of mammal being
treated, the
physical characteristics of the specific mammal under consideration,
concurrent
medication, and other factors that those skilled in the medical arts will
recognize.
Generally, an amount between 0.1 mg/kg and 100 mg/kg body weightlday of active
ingredients is administered dependent upon potency of the negatively charged
polymer.
The nucleic acid molecules of the invention and formulations thereof can be
administered orally, topically, parenterally, by inhalation or spray, or
rectally in dosage
unit formulations containing conventional non-toxic pharmaceutically
acceptable
carriers, adjuvants and/or vehicles. The term parenteral as used herein
includes
percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular,
or
intrathecal injection or infusion techniques and the like. In addition, there
is provided a
pharmaceutical formulation comprising a nucleic acid molecule of the invention
and a
pharmaceutically acceptable carrier. One ox more nucleic acid molecules of the
invention can be present in association with one or more non-toxic
pharmaceutically
acceptable carriers and/or diluents and/or adjuvants, and if desired other
active
ingredients. The pharmaceutical compositions containing nucleic acid molecules
of the
invention can be in a form suitable for oral use, for example, as tablets,
troches,
lozenges, aqueous or oily suspensions, dispersible powders or granules,
emulsion, hard
or soft capsules, or syrups or elixirs.
Compositions intended for oral use can be pxepared according to any method
known to the art for the manufacture of pharmaceutical compositions and such
compositions can contain one or more such sweetening agents, flavoring agents,
coloring
agents or preservative agents in order to provide pharmaceutically elegant and
palatable
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preparations. Tablets contain the active ingredient in admixture with non-
toxic
pharmaceutically acceptable excipients that are suitable for the manufacture
of tablets.
These excipients can be, for example, inert diluents; such as calcium
carbonate, sodium
carbonate, lactose, calcium phosphate or sodium phosphate; granulating and
disintegrating agents, for example, corn starch, or alginic acid; binding
agents, for
example starch, gelatin or acacia; and lubricating agents, for example
magnesium
stearate, stearic acid or talc. The tablets can be uncoated or they can be
coated by known
techniques. In some cases such coatings can be prepared by known techniques to
delay
disintegration and absorption in the gastrointestinal tract and thereby
provide a sustained
action over a longer period. For example, a time delay material such as
glyceryl
monosterate or glyceryl distearate can be employed.
Formulations for oral use can also be presented as hard gelatin capsules
wherein
the active ingredient is mixed with an inert solid diluent, for example,
calcium carbonate,
calcium phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is
mixed with water or an oil medium, for example peanut oil, liquid paraffin or
olive oil.
Aqueous suspensions contain the active materials in a mixture with excipients
suitable for the manufacture of aqueous suspensions. Such excipients are
suspending
agents, for example sodium carboxymethylcellulose, methylcellulose,
hydropropyl-
methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum
acacia;
dispersing or wetting agents can be a naturally-occurring phosphatide, for
example,
lecithin, or condensation products of an alkylene oxide with fatty acids, for
example
polyoxyethylene stearate, or condensation products of ethylene oxide with long
chain
aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation
products
of ethylene oxide with partial esters derived from fatty acids and a hexitol
such as
polyoxyethylene sorbitol monooleate, or condensation products of ethylene
oxide with
partial esters derived from fatty acids and hexitol anhydrides, for example
polyethylene
soxbitan monooleate. The aqueous suspensions can also contain one or more
preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more
coloring
agents, one or more flavoring agents, and one or more sweetening agents, such
as
sucrose or saccharin.
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Oily suspensions can be formulated by suspending the active ingredients in a
vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil,
or in a mineral
oil such as liquid paraffin. The oily suspensions can contain a thickening
agent, for
example beeswax, hard paraffin or cetyl alcohol. Sweetening agents and
flavoring
agents can be added to provide palatable oral preparations. These compositions
can be
preserved by the addition of an anti-oxidant such as ascorbic acid
Dispersible powders and granules suitable for preparation of an aqueous
suspension by the addition of water provide the active ingredient in admixture
with a
dispersing or wetting agent, suspending agent and one or more preservatives.
Suitable
dispersing or wetting agents or suspending agents are exemplified by those
already
mentioned above. Additional excipients, for example sweetening, flavoring and
coloring
agents, can also be present.
Pharmaceutical compositions of the invention can also be in the form of oil-in-
water emulsions. The oily phase can be a vegetable oil or a mineral oil or
mixtures of
these. Suitable emulsifying agents can be naturally-occurnng gums, for example
gum
acacia or gum tragacanth, naturally-occurring phosphatides, for example soy
bean,
lecithin, and esters or partial esters derived from fatty acids and hexitol,
anhydrides, for
example sorbitan monooleate, and condensation products of the said partial
esters with
ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions
can
also contain sweetening and flavoring agents.
Syrups and elixirs can be formulated with sweetening agents, for example
glycerol,
propylene glycol, sorbitol, glucose or sucrose. Such formulations can also
contain a
demulcent, a preservative and flavoring and coloring agents. The
pharmaceutical
compositions can be in the form of a sterile injectable aqueous or oleaginous
suspension.
This suspension can be formulated according to the known art using those
suitable
dispersing or wetting agents and suspending agents that have been mentioned
above.
The sterile injectable preparation can also be a sterile injectable solution
or suspension in
a non-toxic parentally acceptable diluent or solvent, for example as a
solution in 1,3-
butanediol. Among the acceptable vehicles and solvents that can be employed
are water,
Ringer's solution and isotonic sodium chloride solution. In addition, sterile,
fixed oils
are conventionally employed as a solvent or suspending medium. For this
purpose, any
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bland fixed oil can be employed including synthetic mono-or diglycerides. In
addition,
fatty acids such as oleic acid find use in the preparation of injectables.
The nucleic acid molecules of the invention can also be administered in the
form of
suppositories, e.g., for rectal administration of the drug. These compositions
can be
prepared by mixing the drug with a suitable non-irritating excipient that is
solid at
ordinary temperatures but liquid at the rectal temperature and will therefore
melt in the
rectum to release the drug. Such materials include cocoa butter and
polyethylene
glycols.
Nucleic acid molecules of the invention can be administered parenterally in a
sterile medium. The drug, depending on the vehicle and concentration used, can
either
be suspended or dissolved in the vehicle. Advantageously, adjuvants such as
local
anesthetics, preservatives and buffering agents can be dissolved in the
vehicle.
Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram
of
body weight per day are useful in the treatment of the above-indicated
conditions (about
0.5 mg to about 7 g per subject per day). The amount of active ingredient that
can be
combined with the carrier materials to produce a single dosage form varies
depending
upon the host treated and the particular mode of administration. Dosage unit
forms
generally contain between from about 1 mg to about 500 mg of an active
ingredient.
It is understood that the specific dose level for any particular subject
depends upon
a variety of factors including the activity of the specific compound employed,
the age,
body weight, general health, sex, diet, time of administration, route of
administration,
and rate of excretion, drug combination and the severity of the particular
disease
undergoing therapy.
For administration to non-human animals, the composition can also be added to
the
animal feed or drinking water. It can be convenient to formulate the animal
feed and
drinking water compositions so that the animal takes in a therapeutically
appropriate
quantity of the composition along with its diet. It can also be convenient to
present the
composition as a premix for addition to the feed or drinking water.
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The nucleic acid molecules of the present invention can also be administered
to a
subject in combination with other therapeutic compounds to increase the
overall
therapeutic effect. The use of multiple compounds to treat an indication can
increase the
beneficial effects while reducing the presence of side effects.
S In one embodiment, the invention comprises compositions suitable for
administering nucleic acid molecules of the invention to specific cell types.
For
example, the asialoglycoprotein receptor (ASGPr) (Wu and Wu, 1987, J. Biol.
Chem.
262, 4429-4432) is unique to hepatocytes and binds branched galactose-terminal
glycoproteins, such as asialoorosomucoid (ASOR). In another example, the
folate
receptor is overexpressed in many cancer cells. Binding of such glycoproteins,
synthetic
glycoconjugates, or folates to the receptor takes place with an affinity that
strongly
depends on the degree of branching of the oligosaccharide chain, for example,
triatennary structures are bound with greater affinity than biatenarry or
monoatennary
chains (Baenziger and Fiete, 1980, Cell, 22, 611-620; Connolly et al., 1982,
J. Biol.
Claern., 257, 939-945). Lee and Lee, 1987, Glycocor jugate J., 4, 317-328,
obtained this
high specificity through the use of N-acetyl-D-galactosamine as the
carbohydrate moiety,
which has higher affinity for the receptor, compared to galactose. This
"clustering effect"
has also been described for the binding and uptake of mannosyl-terminating
glycoproteins or glycoconjugates (Ponpipom et al., 1981, J. Med. Ch.ern., 24,
1388-
1395). The use of galactose, galactosamine, or folate based conjugates to
transport
exogenous compounds across cell membranes can provide a targeted delivery
approach
to, for example, the treatment of liver disease, cancers of the liver, or
other cancers. The
use of bioconjugates can also provide a reduction in the required dose of
therapeutic
compounds required for treatment. Furthermore, therapeutic bioavailability,
pharmacodynamics, and pharmacokinetic parameters can be modulated through the
use
of nucleic acid bioconjugates of the invention. Non-limiting examples of such
bioconjugates are described in Vargeese et al., USSN 10/201,394, filed August
13, 2001;
and Matulic-Adamic et al., USSN 60/362,016, filed March 6, 2002.
Alternatively, certain siNA molecules of the instant invention can be
expressed
within cells from eukaryotic promoters (e.g., Izant and Weintraub, 1985,
Science, 229,
345; McGarry and Lindquist, 1986, Proc. Natl. Acad. Sci., USA 83, 399; Scanlon
et al.,
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1991, Proc. Natl. Acad. Sci. USA, 88, 10591-5; Kashani-Sabet et al., 1992,
Antisense
Res. Dev., 2, 3-15; Dropulic et al., 1992, J. Yiz-ol., 66, 1432-41;
Weerasinghe et al.,
1991, J. Viz-ol., 65, 5531-4; Ojwang et al., 1992, Pz°oc. Natl. Acad.
Sci. USA, 89, 10802-
6; Chen et al., 1992, Nucleic Acids Res., 20, 4581-9; Sarver et al., 1990
Sciezzce, 247,
1222-1225; °Thompson et al., 1995, Nucleic Acids Res., 23, 2259; Good
et al., 1997,
Gezze Tlzerapy, 4, 45. Those skilled in the art realize that any nucleic acid
can be
expressed in eukaryotic cells from the appropriate DNA/RNA vector. The
activity of
such nucleic acids can be augmented by their release from the primary
transcript by a
enzymatic nucleic acid (Draper et al., PCT WO 93/23569, and Sullivan et al.,
PCT WO
94/02595; Ohkawa et al., 1992, Nucleic Acids Synzp. Ser., 27, 15-6; Taira et
al., 1991,
Nucleic Acids Res., 19, 5125-30; Ventura et al., 1993, Nucleic Acids Res., 21,
3249-55;
Chowrira et al., 1994, J. Biol. Clzem., 269, 25856.
In another aspect of the invention, RNA molecules of the present invention can
be
expressed from transcription units (see for example Couture et al., 1996,
TIG., 12, 510)
inserted into DNA or RNA vectors. The recombinant vectors can be DNA plasmids
or
viral vectors. siNA expressing viral vectors can be constructed based on, but
not limited
to, adeno-associated virus, retrovirus, adenovirus, or alphavirus. In another
embodiment,
pol III based constructs are used to express nucleic acid molecules of the
invention (see
for example Thompson, U.S. Pats. Nos. 5,902,880 and 6,146,886). The
recombinant
vectors capable of expressing the siNA molecules can be delivered as described
above,
and persist in target cells. Alternatively, viral vectors can be used that
provide for
transient expression of nucleic acid molecules. Such vectors can be repeatedly
administered as necessary. Once expressed, the siNA molecule interacts with
the target
mRNA and generates an RNAi response. Delivery of siNA molecule expressing
vectors
can be systemic, such as by intravenous or infra-muscular administration, by
administration to target cells ex-planted from a subject followed by
reintroduction into
the subject, or by any other means that would allow for introduction into the
desired
target cell (for a review see Couture et al., 1996, TIG., 12, 510).
In one aspect the invention features an expression vector comprising a nucleic
acid
sequence encoding at least one siNA molecule of the instant invention. The
expression
vector can encode one or both strands of a siNA duplex, or a single self
complementary
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strand that self hybridizes into a siNA duplex. The nucleic acid sequences
encoding the
siNA molecules of the instant invention can be operably linked in a manner
that allows
expression of the siNA molecule (see for example Paul et al., 2002, Nature
Biotechnology, 19, 505; Miyagishi and Taira, 2002, Nature Biotechnology, 19,
497; Lee
et al., 2002, Nature Biotechnology, 19, 500; and Novina et al., 2002, Nature
Medicine,
advance online publication doi:10.1038/nm725).
In another aspect, the invention features an expression vector comprising: a)
a
transcription initiation region (e.g., eukaryotic pol I, II or III initiation
region); b) a
transcription termination region (e.g., eukaryotic pol I, II or III
termination region); and
c) a nucleic acid sequence encoding at least one of the siNA molecules of the
instant
invention, wherein said sequence is operably linked to said initiation region
and said
termination region in a manner that allows expression and/or delivery of the
siNA
molecule. The vector can optionally include an open reading frame (ORF) for a
protein
operably linked on the 5' side or the 3'-side of the sequence encoding the
siNA of the
invention; and/or an intron (intervening sequences).
Transcription of the siNA molecule sequences can be driven from a promoter for
eukaryotic RNA polymerase I (pol I), RNA polymerase II (pol II), or RNA
polymerase
III (pol III). Transcripts from pol II or pol III promoters are expressed at
high levels in
all cells; the levels of a given pol II promoter in a given cell type depends
on the nature
of the gene regulatory sequences (enhancers, silencers, etc.) present nearby.
Prokaryotic
RNA polymerase promoters are also used, providing that the prokaryotic RNA
polyrnerase enzyme is expressed in the appropriate cells (Elroy-Stein and
Moss, 1990,
Proc. Natl. Acad. Sci. U S A, 87, 6743-7; Gao and Huang 1993, Nucleic Acids
Res., 21,
2867-72; Lieber et al., 1993, Methods Enzyrnol., 217, 47-66; Zhou et al.,
1990, Mol.
Cell. Biol., 10, 4529-37). Several investigators have demonstrated that
nucleic acid
molecules expressed from such promoters can function in mammalian cells (e.g.
Kashani-Sabet et al., 1992, A~atisense Res. Dev., 2, 3-15; Ojwang et al.,
1992, Proc.
Natl. Acad. Sci. U S A, 89, 10802-6; Chen et al., 1992, Nucleic Acids Res.,
20, 4581-9;
Yu et al., 1993, Proc. Natl. Acad. Sci. U S A, 90, 6340-4; L'Huillier et al.,
1992, EMBO
J., 11, 4411-8; Lisziewicz et al., 1993, Proc. Natl. Acad. Sci. U. S. A, 90,
8000-4;
Thompson et al., 1995, Nucleic Acids Res., 23, 2259; Sullenger & Cech, 1993,
Scieface,
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262, 1566). More specifically, transcription units such as the ones derived
from genes
encoding U6 small nuclear (snRNA), transfer RNA (tRNA) and adenovirus VA RNA
are
useful in generating high concentrations of desired RNA molecules such as siNA
in cells
(Thompson et al., supra; Couture and Stinchcomb, 1996, supra; Noonberg et al.,
1994,
Nucleic Acid Res., 22, 2830; Noonberg et al., U.S. Pat. No. 5,624,803; Good et
al., 1997,
Gefae Ther., 4, 45; Beigelman et al., International PCT Publication No. WO
96118736.
The above siNA transcription units can be incorporated into a variety of
vectors for
introduction into mammalian cells, including but not restricted to, plasmid
DNA vectors,
viral DNA vectors (such as adenovirus or adeno-associated virus vectors), or
viral RNA
vectors (such as retroviral or alphavirus vectors) (for a review see Couture
and
Stinchcomb, 1996, supra).
In another aspect the invention features an expression vector comprising a
nucleic
acid sequence encoding at least one of the siNA molecules of the invention in
a manner
that allows expression of that siNA molecule. The expression vector comprises
in one
embodiment; a) a transcription initiation region; b) a transcription
termination region;
and c) a nucleic acid sequence encoding at least one strand of the siNA
molecule,
wherein the sequence is operably linked to the initiation region and the
termination
region in a manner that allows expression and/or delivery of the siNA
molecule.
In another embodiment the expression vector comprises: a) a transcription
initiation region; b) a transcription termination region; c) an open reading
frame; and d) a
nucleic acid sequence encoding at least one strand of a siNA molecule, wherein
the
sequence is operably linked to the 3'-end of the open reading frame and
wherein the
sequence is operably linked to the initiation region, the open reading frame
and the
termination region in a manner that allows expression and/or delivery of the
siNA
molecule. In yet another embodiment, the expression vector comprises: a) a
transcription initiation region; b) a transcription termination region; c) an
intron; and d) a
nucleic acid sequence encoding at least one siNA molecule, wherein the
sequence is
operably linked to the initiation region, the intron and the termination
region in a manner
which allows expression and/or delivery of the nucleic acid molecule.
In another embodiment, the expression vector comprises: a) a transcription
initiation region; b) a transcription termination region; c) an intron; d) an
open reading
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frame; and e) a nucleic acid sequence encoding at least one strand of a siNA
molecule,
wherein the sequence is operably linked to the 3'-end of the open reading
frame and
wherein the sequence is operably linked to the initiation region, the intron,
the open
reading frame and the termination region in a manner which allows expression
and/or
delivery of the siNA molecule.
Expressed pseudogene tar e~ t biology and biochemistry
Pseudogenes have been considered as nonfunctional sequences of genomic DNA
originally derived from functional genes. The assumption follows that alI
pseudogene
mutations are selectively neutral and have equal probability to become fixed
in the
population. Howevex, pseudogenes that have been suitably investigated often
exhibit
functional roles, such as gene expression, gene regulation, generation of
genetic (e.g.,
antibody, antigenic, and other) diversity (see for example Balakirev et al.,
2003, A~nu.
Rev. Gefaet., 37, 123-51). A pseudogene is an evolutionary conserved gene copy
that
does not produce a functional, full-length protein. The human genome is
estimated to
contain upwards of 20,000 pseudogenes. Although much effort has been devoted
to
understanding the function of such pseudogenes, their biological roles remain
largely
unknown. Some psuedogenes that are expressed have been associated with disease
or
developmental conditions. For example, Hirotsune et al., 2003, NatuJ°e,
423, 91-96,
report the role of an expressed pseudogene, specifically regulation of
messenger-RNA
stability, in a transgene-insertion mouse mutant exhibiting polyeystic kidneys
and bone
deformity. The transgene was integrated into the vicinity of the expressing
pseudogene
of Makorinl, referred to as Makorinl-pl. This insertion attenuated
transcription of
Makorinl-pl, resulting in destabilization of Makorinl mRNA in trans by way of
a cis-
acting RNA decay element within the 5' region of Makorinl that is homologous
between
Makorinl and Makorinl-pl. Either Makorinl or Makorinl-pl transgenes could
rescue
the expressed pseudogene phenotypes. These findings demonstrate a specific
regulatory
role of an expressed pseudogene, and point to the functional signiftcance of
non-coding
RNAs (Hirotsune et al., 2003, Nature, 423, 91-96). In a subsequent study, it
was
determined that 2-3% of human processed pseudogenes are expressed (Yano et
al., 2004,
J. Mol. Med., 82(7), 414-22). Other reports of expressed pseudogenes are
described in,
for example I~andouz et al., 2004, Oncoge~re, 23, 4763-70 (Connexin43);
Yoshida et al.,
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2003, Hung Cell, 16, 65-72 (Makorinl); and Perez Jurado et al., 1998, Hum Mol
Genet,
7, 325-34).
Examples:
The following are non-limiting examples showing the selection, isolation,
synthesis and activity of nucleic acids of the instant invention.
Example 1: Tandem synthesis of siNA constructs
Exemplary siNA molecules of the invention are synthesized in tandem using a
cleavable linker, for example, a succinyl-based linker. Tandem synthesis as
described
herein is followed by a one-step purification process that provides RNAi
molecules in
high yield. This approach is highly amenable to siNA synthesis in support of
high
throughput RNAi scxeening, and can be readily adapted to mufti-column or mufti-
well
synthesis platforms.
After completing a tandem synthesis of a siNA oligo and its complement in
which
the 5'-terminal dimethoxytrityl (5'-O-DMT) group remains intact (trityl on
synthesis), the
oligonucleotides are deprotected as described above. Following deprotection,
the siNA
sequence strands are allowed to spontaneously hybridize. This hybridization
yields a
duplex in which one strand has retained the 5'-O-DMT group while the
complementary
strand comprises a terminal 5'-hydroxyl. The newly formed duplex behaves as a
single
molecule during routine solid-phase extraction puriftcation (Trityl-On
purification) even
though only one molecule has a dimethoxytrityl group. Because the strands form
a
stable duplex, this dimethoxytrityl group (or an equivalent group, such as
other trityl
groups ox other hydrophobic moieties) is all that is required to purify the
pair of oligos,
for example, by using a C 18 cartridge.
Standard phosphoramidite synthesis chemistry is used up to the point of
introducing a tandem linker, such as an inverted deoxy abasic succinate or
glyceryl
succinate linker (see Figure 1) or an equivalent cleavable linker. A non-
limiting
example of linker coupling conditions that can be used includes a hindered
base such as
diisopropylethylamine (DIPA) and/or DMAP in the presence of an activator
reagent such
as Bromotripyrrolidinophosphoniumhexaflurorophosphate (PyBrOP). After the
linker is
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coupled, standard synthesis chemistry is utilized to complete synthesis of the
second
sequence leaving the terminal the 5'-O-DMT intact. Following synthesis, the
resulting
oligonucleotide is deprotected according to the procedures described herein
and
quenched with a suitable buffer, for example with SOmM NaOAc or 1.5M
NH4H~,C03.
Purification of the siNA duplex can be readily accomplished using solid phase
extraction, for example, using a Waters C18 SepPak 1g cartridge conditioned
with 1
column volume (CV) of acetonitrile, 2 CV H20, and 2 CV SOmM NaOAc. The sample
is loaded and then washed with 1 CV H20 or SOmM NaOAc. Failure sequences are
eluted with 1 CV 14% ACN (Aqueous with SOmM NaOAc and SOmM NaCI). The
column is then washed, for example with 1 CV H20 followed by on-column
detritylation, for example by passing 1 CV of 1% aqueous trifluoroacetic acid
(TFA)
over the column, then adding a second CV of 1% aqueous TFA to the column and
allowing to stand for approximately 10 minutes. The remaining TFA solution is
removed and the column washed with H20 followed by 1 CV 1M NaCl and additional
H20. The siNA duplex product is then eluted, for example, using 1 CV 20%
aqueous
CAN.
Figure 2 provides an example of MALDI-TOF mass spectrometry analysis of a
purified siNA construct in which each peak corresponds to the calculated mass
of an
individual siNA strand of the siNA duplex. The same purified siNA provides
three
peaks when analyzed by capillary gel electrophoresis (CGE), one peak
presumably
corresponding to the duplex siNA, and two peaks presumably corresponding to
the
separate siNA sequence strands. Ion exchange HPLC analysis of the same siNA
contract
only shows a single peak. Testing of the purified siNA construct using a
luciferase
reporter assay described below demonstrated the same RNAi activity compared to
siNA
constructs generated from separately synthesized oligonucleotide sequence
strands.
Example 2: Identification of potential siNA target sites in any RNA sequence
The sequence of an RNA target of interest, such as a viral or human mRNA
transcript, is screened for target sites, for example by using a computer
folding
algorithm. In a non-limiting example, the sequence of a gene or RNA gene
transcript
derived from a database, such as Genbank, is used to generate siNA targets
having
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complementarity to the target. Such sequences can be obtained from a database,
or can
be determined experimentally as known in the art. Target sites that are known,
for
example, those target sites determined to be effective target sites based on
studies with
other nucleic acid molecules, for example ribozymes or antisense, or those
targets known
to be associated with a disease or condition such as those sites containing
mutations or
deletions, can be used to design siNA molecules targeting those sites. Various
parameters can be used to determine which sites are the most suitable target
sites within
the target RNA sequence. These parameters include but are not limited to
secondary or
tertiary RNA structure, the nucleotide base composition of the target
sequence, the
degree of homology between various regions of the target sequence, or the
relative
position of the target sequence within the RNA transcript. Based on these
determinations, any number of target sites within the RNA transcript can be
chosen to
screen siNA molecules for efficacy, for example by using ira vitro RNA
cleavage assays,
cell culture, or animal models. In a non-limiting example, anywhere from 1 to
1000
target sites are chosen within the transcript based on the size of the siNA
construct to be
used. High throughput screening assays can be developed for screening siNA
molecules
using methods known in the art, such as with mufti-well or mufti-plate assays
to
determine efficient reduction in target gene expression.
Example 3: Selection of siNA molecule target sites in a RNA
The following non-limiting steps can be used to carry out the selection of
siNAs
targeting a given gene sequence or transcript.
1. The target sequence is parsed ira silico into a list of all fragments or
subsequences of a
particular length, for example 23 nucleotide fragments, contained within the
target
sequence. This step is typically carried out using a custom Perl script, but
commercial
sequence analysis programs such as Oligo, MacVector, or the GCG Wisconsin
Package can be employed as well.
2. In some instances the siNAs correspond to more than one target sequence;
such
would be the case for example in targeting different transcripts of the same
gene,
targeting different transcripts of more than one gene, or for targeting both
the human
gene and an animal homolog. In this case, a subsequence list of a particular
length is
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generated for each of the targets, and then the lists are compared to find
matching
sequences in each list. The subsequences are then ranked according to the
number of
target sequences that contain the given subsequence; the goal is to find
subsequences
that are present in most or all of the target sequences. Alternately, the
ranking can
identify subsequences that are unique to a target sequence, such as a mutant
target
sequence. Such an approach would enable the use of siNA to target specifically
the
mutant sequence and not effect the expression of the normal sequence.
3. In some instances the siNA subsequences are absent in one or more sequences
while
present in the desired target sequence; such would be the case if the siNA
targets a
gene with a paralogous family member that is to remain untargeted. As in case
2
above, a subsequence list of a particular length is generated for each of the
targets,
and then the lists are compared to find sequences that are present in the
target gene
but are absent in the untargeted paralog.
4. The ranked siNA subsequences can be further analyzed and ranked according
to GC
content. A preference can be given to sites containing 30-70% GC, with a
further
preference to sites containing 40-60% GC.
5. The ranked siNA subsequences can be further analyzed and ranked according
to self
folding and internal hairpins. Weaker internal folds are preferred; strong
hairpin
structures are to be avoided.
6. The ranked siNA subsequences can be further analyzed and ranked according
to
whether they have runs of GGG or CCC in the sequence. GGG (or even more Gs) in
either strand can make oligonucleotide synthesis problematic and can
potentially
interfere with RNAi activity, so it is avoided whenever better sequences are
available.
CCC is searched in the target strand because that will place GGG in the
antisense
strand.
7. The ranleed siNA subsequences can be further analyzed and ranked according
to
whether they have the dinucleotide UU (uritdine dinucleotide) on the 3'-end of
the
sequence, and/or AA on the S'-end of the sequence (to yield 3' UU on the
antisense
sequence). These sequences allow one to design siNA molecules with terminal TT
thymidine dinucleotides.
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8. Four or five target sites are chosen from the ranked list of subsequences
as described
above. For example, in subsequences having 23 nucleotides, the right 21
nucleotides
of each chosen 23-mer subsequence are then designed and synthesized for the
upper
(sense) strand of the siNA duplex, while the reverse complement of the left 21
nucleotides of each chosen 23-mer subsequence are then designed and
synthesized for
the lower (antisense) strand of the siNA duplex. If terminal TT residues are
desired
for the sequence (as described in paragraph 7), then the two 3' terminal
nucleotides of
both the sense and antisense strands are replaced by TT prior to synthesizing
the
oligos.
9. The siNA molecules are screened in an in vitno, cell culture or animal
model system
to identify the most active siNA molecule or the most preferred target site
within the
target RNA sequence.
10. Other design considerations can be used when selecting target nucleic acid
sequences, see, for example, Reynolds et al., 2004, Nature Biotechnology
Advanced
Online Publication, 1 February 2004, doi:10.1038/nbt936 and Ui-Tei et al.,
2004,
Nucleic Acids Research, 32, doi:10.1093/nar/gkh247.
In an alternate approach, a pool of siNA constructs specific to a target
polynucloetide sequence is used to screen for target sites in cells expressing
target RNA.
The general strategy used in this approach is shown in Figure 9. Cells
expressing target
RNA are transfected with the pool of siNA constructs and cells that
demonstrate a
phenotype associated with target inhibition are sorted. The pool of siNA
constructs can
be expressed from transcription cassettes inserted into appropriate vectors
(see for
example Figure 7 and Figure 8). The siNA from cells demonstrating a positive
phenotypic change (e.g., decreased proliferation, decreased RNA levels,
decreased
protein expression), are sequenced to determine the most suitable target
sites) within the
target RNA sequence.
Example 4: Targeted siNA design
siNA target sites were chosen by analyzing sequences of the target
polynucleotide
and optionally prioritizing the target sites on the basis of folding
(structure of any given
sequence analyzed to determine siNA accessibility to the target), by using a
library of
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siNA molecules as described in Example 3, or alternately by using an ira vitro
siNA
system as described in Example 6 herein. siNA molecules are designed that
could bind
each target and are optionally individually analyzed by computer folding to
assess
whether the siNA molecule can interact with the target sequence. Varying the
length of
the siNA molecules can be chosen to optimize activity. Generally, a sufficient
number
of complementary nucleotide bases are chosen to bind to, or otherwise interact
with, the
target RNA, but the degree of complementarity can be modulated to accommodate
siNA
duplexes or varying length or base composition. By using such methodologies,
siNA
molecules can be designed to target sites within any known RNA sequence, for
example
those RNA sequences corresponding to the any gene transcript.
Chemically modified siNA constructs are designed to provide nuclease stability
for
systemic administration in vivo and/or improved pharmacokinetic, localization,
and
delivery properties while preserving the ability to mediate RNAi activity
Chemical
modifications as described herein are introduced synthetically using synthetic
methods
described herein and those generally known in the art. The synthetic siNA
constructs are
then assayed for nuclease stability in serum and/or cellular/tissue extracts
(e.g. liver
extracts). The synthetic siNA constructs are also tested in parallel for RNAi
activity
using an appropriate assay, such as a luciferase reporter assay as described
herein or
another suitable assay that can quantity RNAi activity. Synthetic siNA
constructs that
possess both nuclease stability and RNAi activity can be further modified and
re-
evaluated in stability and activity assays. The chemical modifications of the
stabilized
active siNA constructs can then be applied to any siNA sequence targeting any
chosen
RNA and used, for example, in target screening assays to pick lead siNA
compounds for
therapeutic development (see for example Figure 11).
Example 5: Chemical Synthesis and Purification of siNA
siNA molecules can be designed to interact with various sites in the RNA
message,
for example, target sequences within the RNA sequences described herein. The
sequence of one strand of the siNA molecules) is complementary to the target
site
sequences described above. The siNA molecules can be chemically synthesized
using
methods described herein. Inactive siNA molecules that are used as control
sequences
can be synthesized by scrambling the sequence of the siNA molecules such that
it is not
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complementary to the target sequence. Generally, siNA constructs can by
synthesized
using solid phase oligonucleotide synthesis methods as described herein (see
for example
Usman et al., US Patent Nos. 5,804,683; 5,831,071; 5,998,203; 6,117,657;
6,353,098;
6,362,323; 6,437,117; 6,469,158; Scaringe et al., US Patent Nos. 6,111,086;
6,008,400;
6,111,086 all incorporated by reference herein in their entirety).
In a non-limiting example, RNA oligonucleotides are synthesized in a stepwise
fashion using the phosphoramidite chemistry as is known in the art. Standard
phosphoramidite chemistry involves the use of nucleosides comprising any of 5'-
O-
dimethoxytrityl, 2'-O-tert-butyldimethylsilyl, 3'-O-2-Cyanoethyl N,N-
diisopropylphos-
phoroamidite groups, and exocyclic amine protecting groups (e.g. N6-benzoyl
adenosine,
N4 acetyl cytidine, and N2-isobutyryl guanosine). Alternately, 2'-O-Silyl
Ethers can be
used in conjunction with acid-labile 2'-O-orthoester protecting groups in the
synthesis of
RNA as described by Scaringe supYa. Differing 2' chemistries can require
different
protecting groups, for example 2'-deoxy-2'-amino nucleosides can utilize N-
phthaloyl
protection as described by Usman et al., US Patent 5,631,360, incorporated by
reference
herein in its entirety).
During solid phase synthesis, each nucleotide is added sequentially (3
°- to 5'-
direction) to the solid support-bound oligonucleotide. The first nucleoside at
the 3'-end
of the chain is covalently attached to a solid support (e.g., controlled pore
glass or
polystyrene) using various linkers. The nucleotide precursor, a ribonucleoside
phosphoramidite, and activator are combined resulting in the coupling of the
second
nucleoside phosphoramidite onto the 5'-end of the first nucleoside. The
support is then
washed and any unreacted 5°-hydroxyl groups are capped with a capping
reagent such as
acetic anhydride to yield inactive 5 °-acetyl moieties. The trivalent
phosphorus linkage is
then oxidized to a more stable phosphate linkage. At the end of the nucleotide
addition
cycle, the 5'-O-protecting group is cleaved under suitable conditions (e.g.,
acidic
conditions for trityl-based groups and Fluoride for silyl-based groups). The
cycle is
repeated for each subsequent nucleotide.
Modification of synthesis conditions can be used to optimize coupling
efficiency,
for example by using differing coupling times, differing
reagent/phosphoramidite
concentrations, differing contact times, differing solid supports and solid
support linker
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chemistries depending on the particular chemical composition of the siNA to be
synthesized. Deprotection and purification of the siNA can be performed as is
generally
described in Usman et al., US 5,831,071, US 6,353,098, US 6,437,117, and
Bellon et al.,
US 6,054,576, US 6,162,909, US 6,303,773, or Scaringe supra, incorporated by
reference herein in their entireties. Additionally, deprotection conditions
can be
modified to provide the best possible yield and purity of siNA constructs. For
example,
applicant has observed that oligonucleotides comprising 2'-deoxy-2'-fluoro
nucleotides
can degrade under inappropriate deprotection conditions. Such oligonucleotides
are
deprotected using aqueous methylamine at about 35°C for 30 minutes. If
the 2'-deoxy-
2'-fluoro containing oligonucleotide also comprises ribonucleotides, after
deprotection
with aqueous methylamine at about 35°C for 30 minutes, TEA-HF is added
and the
reaction maintained at about 65°C for an additional 15 minutes.
Example 6: RNAi in vitro assay to assess siNA activity
An if2 vitro assay that recapitulates RNAi in a cell-free system is used to
evaluate
siNA constructs targeting target RNA. The assay comprises the system described
by
Tuschl et al., 1999, Geiaes and Development, 13, 3191-3197 and Zamore et al.,
2000,
Cell, 101, 25-33 adapted for use with target RNA. A Drosophila extract derived
from
syncytial blastoderm is used to reconstitute RNAi activity in vitro. Target
RNA is
generated via iyt. vitro transcription from an appropriate target expressing
plasmid using
T7 RNA polymerase or via chemical synthesis as described herein. Sense and
antisense
siNA strands (for example 20 uM each) are annealed by incubation in buffer
(such as
100 mM potassium acetate, 30 mM HEPES-KOH, pH 7.4, 2 mM magnesium acetate) for
1 minute at 90°C followed by 1 hour at 37°C , then diluted in
lysis buffer (for example
100 mM potassium acetate, 30 mM HEPES-KOH at pH 7.4, 2mM magnesium acetate).
Annealing can be monitored by gel electrophoresis on an agarose gel in TBE
buffer and
stained with ethidium bromide. The Drosophila lysate is prepared using zero to
two-
hour-old embryos from Oregon R flies collected on yeasted molasses agar that
are
dechorionated and lysed. The lysate is centrifuged and the supernatant
isolated. The
assay comprises a reaction mixture containing 50% lysate [vol/vol~, RNA (10-50
pM
final concentration), and 10% [vollvol] lysis buffer containing siNA (10 nM
final
concentration). The reaction mixture also contains 10 mM creatine phosphate,
10 ug/ml
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creatine phosphokinase, 100 um GTP, 100 uM UTP, 100 uM CTP, 500 uM ATP, 5 mM
DTT, 0.1 U/uL RNasin (Promega), and 100 uM of each amino acid. The final
concentration of potassium acetate is adjusted to 100 mM. The reactions are
pre-
assembled on ice and preincubated at 25° C for 10 minutes before adding
RNA, then
incubated at 25° C for an additional 60 minutes. Reactions are quenched
with 4 volumes
of 1.25 x Passive Lysis Buffer (Promega). Target RNA cleavage is assayed by RT-
PCR
analysis or other methods known in the art and are compared to control
reactions in
which siNA is omitted from the reaction.
Alternately, internally-labeled target RNA for the assay is prepared by in
vitro
transcription in the presence of [alpha-32p] CTP, passed over a G50 Sephadex
column by
spin chromatography and used as target RNA without further purification.
Optionally,
target RNA is 5' 32P-end labeled using T4 polynucleotide kinase enzyme. Assays
are
performed as described above and target RNA and the specific RNA cleavage
products
generated by RNAi are visualized on an autoradiograph of a gel. The percentage
of
cleavage is determined by PHOSPHOR IMAGER~ (autoradiography) quantitation of
bands representing intact control RNA or RNA from control reactions without
siNA and
the cleavage products generated by the assay.
In one embodiment, this assay is used to determine target sites in the target
RNA
target for siNA mediated RNAi cleavage, wherein a plurality of siNA constructs
are
screened for RNAi mediated cleavage of the target RNA, for example, by
analyzing the
assay reaction by electrophoresis of labeled target RNA, or by northern
blotting, as well
as by other methodology well known in the art.
Example 7: Nucleic acid inhibition of target RNA
siNA molecules targeted to the human target RNA are designed and synthesized
as
described above. These nucleic acid molecules can be tested for cleavage
activity ira
vivo, for example, using the following procedure.
Two formats are used to test the efficacy of siNAs of the invention. First,
the
reagents are tested in cell culture to determine the extent of RNA and protein
inhibition.
siNA reagents are selected against the target as described herein. RNA
inhibition is
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measured alter delivery of these reagents by a suitable transfection agent to
cells.
Relative amounts of target RNA are measured versus actin using real-time PCR
monitoring of amplification (eg., ABI 7700 TAQMAN~ real-time PCR monitoring
of amplification)). A comparison is made to a mixture of oligonucleotide
sequences
made to unrelated targets or to a randomized siNA control with the same
overall length
and chemistry, but randomly substituted at each position. Primary and
secondary lead
reagents are chosen for the target and optimization performed. After an
optimal
transfection agent concentration is chosen, a RNA time-course of inhibition is
performed
with the lead siNA molecule. In addition, a cell-plating format can be used to
determine
RNA inhibition.
Delivery of siNA to Cells
Cells (e.g., HEKn/HEKa, HeLa, A549, A375 cells) are seeded, for example, at
1x105 cells per well of a six-well dish in EGM-2 (BioWhittaker) the day before
transfection. siNA (final concentration, for example 20nM) and cationic lipid
(e.g., final
concentration 2p,g/ml) are complexed in EGM basal media (Bio Whittaker) at
37°C.' for
30 minutes in polystyrene tubes. Following vortexing, the complexed siNA is
added to
each well and incubated for the times indicated. For initial optimization
experiments,
cells are seeded, for example, at 1x103 in 96 well plates and siNA complex
added as
described. Efficiency of delivery of siNA to cells is determined using a
fluorescent siNA
complexed with lipid. Cells in 6-well dishes are incubated with siNA for 24
hours,
rinsed with PBS and fixed in 2% paraformaldehyde for 15 minutes at room
temperature.
Uptake of siNA is visualized using a fluorescent microscope.
TAOMAN~ (real-time PCR monitorin og f amplification) and Li~htcycler
quantiftcation
of mRNA
Total RNA is prepared from cells following siNA delivery, for example, using
Qiagen RNA purification kits for 6-well or Rneasy extraction kits for 96-well
assays. For
TAQMAN~ analysis (real-time PCR monitoring of amplification), dual-labeled
probes
are synthesized with the reporter dye, FAM or JOE, covalently linked at the 5'-
end and
the quencher dye TAMRA conjugated to the 3'-end. One-step RT-PCR
amplifications
are performed on, for example, an ABI PRISM 7700 Sequence Detector using 50
p.1
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reactions consisting of 10 ~.1 total RNA, 100 nM forward primer, 900 nM
reverse primer,
100 nM probe, 1X TaqMan PCR reaction buffer (PE-Applied Biosystems), 5.5 mM
MgCl2, 300 ~,M each dATP, dCTP, dGTP, and dTTP, lOIJ RNase Inhibitor
(Prornega),
1.25LT AMPLITAQ GOLD~ (DNA polymerase) (PE-Applied Biosystems) and lOU M-
MLV Reverse Transcriptase (Promega). The thermal cycling conditions can
consist of
30 minutes at 48°C, 10 minutes at 95°C, followed by 40 cycles of
15 seconds at 95°C
and 1 minute at 60°C. Quantitation of mRNA levels is determined
relative to standards
generated from serially diluted total cellular RNA (300, 100, 33, 11 ng/rxn~
and
normalizing to 13-actin or GAPDH mRNA in parallel TAQMAN~ reactions (real-time
PCR monitoring of amplification). For each gene of interest an upper and lower
primer
and a fluorescently labeled probe are designed. Real time incorporation of
SYBR Green
I dye into a specific PCR product can be measured in glass capillary tubes
using a
lightcyler. A standard curve is generated for each primer pair using control
cI2NA.
Values are represented as relative expression to GAPDH in each sample.
Western blotting
Nuclear extracts can be prepared using a standard micro preparation technique
(see
for example Andrews and Fallen 1991, Nucleic Acids Research, 19, 2499).
Protein
extracts from supernatants are prepared, for example using TCA precipitation.
An equal
volume of 20% TCA is added to the cell supernatant, incubated on ice for 1
hour and
pelleted by centrifugation for 5 minutes. Pellets are washed in acetone, dried
and
resuspended in water. Cellular protein extracts are run on a 10% Bis-Tris
NuPage
(nuclear extracts) or 4-12% Tris-Glycine (supernatant extracts) polyacrylamide
gel and
transferred onto nitro-cellulose membranes. Non-specific binding can be
blocked by
incubation, for example, with 5% non-fat milk for 1 hour followed by primary
antibody
for 16 hour at 4°C. Following Washes, the secondary antibody is
applied, for example
(1:10,000 dilution) for 1 hour at room temperature and the signal detected
with
SuperSignal reagent (Pierce).
Example 8: Models useful to evaluate the down-regulation of gene exuression
Evaluating the efficacy of siNA molecules of the invention in animal models is
an
important prerequisite to human clinical trials. Various animal models of
cancer,
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proliferative, inflammatory, autoimmune, neurologic, ocular, respiratory,
metabolic, etc.
diseases, conditions, or disorders as are known in the art can be adapted for
use for pre-
clinical evaluation of the efficacy of nucleic acid compositions of the
invetention in
modulating target gene expression toward therapeutic, cosmetic, or research
use.
Example 9' RNAi mediated inhibition of target eg~Lne expression
siNA constructs (are tested for efficacy in reducing target RNA expression in
cells,
(e.g., HEKn/HEKa, HeLa, A549, A375 cells). Cells are plated approximately 24
hours
before transfection in 96-well plates at 5,000-7,500 cells/well, 100 ~.1/well,
such that at
the time of transfection cells are 70-90% confluent. For transfection,
annealed siNAs are
mixed with the transfection reagent (Lipofectamine 2000, Invitrogen) in a
volume of 50
~1/well and incubated for 20 minutes at room temperature. The siNA
transfection
mixtures are added to cells to give a final siNA concentration of 25 nM in a
volume of
150 ~.1. Each siNA transfection mixture is added to 3 wells for triplicate
siNA
treatments. Cells are incubated at 37° for 24 hours in the continued
presence of the siNA
transfection mixture. At 24 hours, RNA is prepared from each well of treated
cells. The
supernatants with the transfectiori mixtures are first removed and discarded,
then the
cells are lysed and RNA prepared from each well. Target gene expression
following
treatment is evaluated by RT-PCR for the target gene and for a control gene
(36B4, an
RNA polymerise subunit) for normalization. The triplicate data is averaged and
the
standard deviations determined for each treatment. Normalized data are graphed
and the
percent reduction of target mRNA by active siNAs in comparison to their
respective
inverted control siNAs is determined.
Example 10: Indications
Particular conditions and disease states that can be associated with gene
expression
modulation include, but are not limited to proliferative, inflammatory,
autoimmune,
neurologic, ocular, respiratory, metabolic etc. diseases, conditions, or
disorders as
described herein or otherwise known in the art, and any other diseases,
conditions or
disorders that are related to or will respond to the levels of a target (e.g.,
target protein or
target polynucleotide) in a cell or tissue, alone or in combination with other
therapies.
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Those skilled in the art will recognize that other drugs such as anti-cancer
compounds and therapies can be similarly be readily combined with the nucleic
acid
molecules of the instant invention (e.g. ribozymes and antisense molecules)
and are
hence within the scope of the instant invention. Such compounds and therapies
are well
known in the art. For combination therapy, the nucleic acids of the invention
are
prepared in one of two ways. First, the agents are physically combined in a
preparation
of nucleic acid and chemotherapeutic agent, such as a mixture of a nucleic
acid of the
invention encapsulated in liposomes and ifosfamide in a solution for
intravenous
administration, wherein both agents are present in a therapeutically effective
concentration (e.g., ifosfamide in solution to deliver 1000-1250 mg/m2/day and
liposome-associated nucleic acid of the invention in the same solution to
deliver 0.1-100
mg/kg/day). Alternatively, the agents are administered separately but
simultaneously in
their respective effective doses (e.g., 1000-1250 mg/m2/d ifosfamide and 0.1
to 100
mg/kg/day nucleic acid of the invention).
Example 1 l: Diagnostic uses
The siNA molecules of the invention can be used in a variety of diagnostic
applications, such as in the identification of molecular targets (e.g., RNA)
in a variety of
applications, for example, in clinical, industrial, environmental,
agricultural and/or
research settings. Such diagnostic use of siNA molecules involves utilizing
reconstituted
RNAi systems, for example, using cellular lysates or partially purifted
cellular lysates.
siNA molecules of this invention can be used as diagnostic tools to examine
genetic drift
and mutations within diseased cells or to detect the presence of endogenous or
exogenous, for example viral, RNA in a cell. The close relationship between
siNA
activity and the structure of the target RNA allows the detection of mutations
in any
region of the molecule, which alters the base-pairing and three-dimensional
structure of
the target RNA. By using multiple siNA molecules described in this invention,
one can
map nucleotide changes, which are important to RNA structure and function ih.
vitro, as
well as in cells and tissues. Cleavage of target RNAs with siNA molecules can
be used
to inhibit gene expression and define the role of specifted gene products in
the
progression of disease or infection. In this manner, other genetic targets can
be defined
as important mediators of the disease. These experiments will lead to better
treatment of
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the disease progression by affording the possibility of combination therapies
(e.g.,
multiple siNA molecules targeted to different genes, siNA molecules coupled
with
known small molecule inhibitors, or intermittent treatment with combinations
siNA
molecules and/or other chemical or biological molecules). Other ira vitro uses
of siNA
molecules of this invention are well known in the art, and include detection
of the
presence of mRNAs associated with a disease, infection, or related condition.
Such
RNA is detected by determining the presence of a cleavage product after
treatment yvith a
siNA using standard methodologies, for example, fluorescence resonance
emission
transfer (FRET).
In a specific example, siNA molecules that cleave only wild-type or mutant
forms
of the target RNA are used for the assay. The first siNA molecules (i.e.,
those that
cleave only wild-type forms of target RNA) are used to identify wild-type RNA
present
in the sample and the second siNA molecules (i.e., those that cleave only
mutant forms
of target RNA) are used to identify mutant RNA in the sample. As reaction
controls,
synthetic substrates of both wild-type and mutant RNA axe cleaved by both siNA
molecules to demonstrate the relative siNA efficiencies in the reactions and
the absence
of cleavage of the "non-targeted" RNA species. The cleavage products from the
synthetic substrates also serve to generate size markers for the analysis of
wild-type and
mutant RNAs in the sample population. Thus, each analysis requires two siNA
molecules, two substrates and one unknown sample, which is combined into six
reactions. The presence of cleavage products is determined using an RNase
protection
assay so that full-length and cleavage fragments of each RNA can be analyzed
1n one
lane of a polyacrylamide gel. It is not absolutely xequired to quantify the
results to gain
insight into the expression of mutant RNAs and putative risk of the desired
phenotypic
changes in target cells. The expression of mRNA whose protein product is
implicated in
the development of the phenotype (i.e., disease related or infection related)
is adequate to
establish risk. If probes of comparable speciftc activity are used for both
transcripts,
then a qualitative comparison of RNA levels is adequate and decreases the cost
of the
initial diagnosis. Higher mutant form to wild-type ratios are correlated with
higher risk
whether RNA levels are compared qualitatively or quantitatively.
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All patents and publications mentioned in the specification are indicative of
the
levels of skill of those skilled in the art to which the invention pertains.
AlI references
cited in this disclosure are incorporated by reference to the same extent as
if each
reference had been incorporated by reference in its entirety individually.
One skilled in the art would readily appreciate that the present invention is
well
adapted to carry out the objects and obtain the ends and advantages mentioned,
as well as
those inherent therein. The methods and compositions described herein as
presently
representative of preferred embodiments are exemplary and are not intended as
limitations on the scope of the invention. Changes therein and other uses will
occur to
those skilled in the art, which are encompassed within the spirit of the
invention, are
defined by the scope of the claims.
It will be readily apparent to one skilled in the art that varying
substitutions and
modifications can be made to the invention disclosed herein without departing
from the
scope and spirit of the invention. Thus, such additional embodiments are
within the
scope of the present invention and the following claims. The present invention
teaches
one skilled in the art to test various combinations andlor substitutions of
chemical
modifications described herein toward generating nucleic acid constructs with
improved
activity for mediating RNAi activity. Such improved activity can comprise
improved
stability, improved bioavailability, and/or improved activation of cellular
responses
mediating RNAi. Therefore, the specific embodiments described herein are not
limiting
and one skilled in the art can readily appreciate that specific combinations
of the
modifications described herein can be tested without undue experimentation
toward
identifying siNA molecules with improved RNAi activity.
The invention illustratively described herein suitably can be practiced in the
absence of any element or elements, limitation or limitations that are not
specifically
disclosed herein. Thus, for example, in each instance herein any of the terms
"comprising", "consisting essentially of', and "consisting of may be replaced
with either
of the other two terms. The terms and expressions which have been employed are
used
as terms of description and not of limitation, and there is no intention that
in the use of
such terms and expressions of excluding any equivalents of the features shown
and
described or portions thereof, but it is recognized that various modifications
are possible
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within the scope of the invention claimed. Thus, it should be understood that
although
the present invention has been specifically disclosed by preferred
embodiments, optional
features, modification and variation of the concepts herein disclosed may be
resorted to
by those skilled in the art, and that such modifications and variations are
considered to be
within the scope of this invention as defined by the description and the
appended claims.
In addition, where features or aspects of the invention are described in terms
of
Markush groups or other grouping of alternatives, those skilled in the art
will recognize
that the invention is also thereby described in terms of any individual member
or
subgroup of members of the Markush group or other group.
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NM_000536 Homo Sapiens recombination activating gene 2 (RAG2), mRNA
NM 000601 Homo sapiens hepatocyte growth factor (hepapoietin A; scatter
factor) (HGF;
NM_000940 Homo sapiens paraoxonase 3 (PON3), mRNA
NM_000941 Homo sapiens P450 (cytochrome) oxidoreductase (POR), mRNA
NM_000953 Homo sapiens prostaglandin D2 receptor (DP) (PTGDR), mRNA
NM_0010011. Homo sapiens intersectin 1 (SH3 domain protein) (ITSN1),
transcript variant
NM_0010011. Homo sapiens transient receptor potential cation channel,
subfamily M, mem
NM_0010012! Homo Sapiens solute carrier family 2 (facilitated glucose
transporter), membE
NM_0010013' Homo sapiens trypsin X3 (TRY1 ), mRNA
NM_0010013: Homo sapiens ATPase, Ca++ transporting, plasma membrane 1 (ATP2B1
), 1
NM 0010013: Homo sapiens similar to ubiquitin-specific protease 17-like
protein (LOC4014
NM_0010013: Homo Sapiens Kazal type serine protease inhibitor 5-like 2
(SPINK5L2), mRP
NM_0010013: Homo sapiens protein kinase C substrate 80K-H (PRKCSH), transcript
variar
NM_0010013: Homo sapiens chromosome 10 open reading frame 74 (C10orf74), mRNA
NM_0010013: Homo sapiens ATPase, Ca++ transporting, plasma membrane 2
(ATP2B2), 1
NM_0010013: Homo sapiens cytochrome b5 reductase b5R.2 (CYB5R2), transcript
variant
NM_0010013~ Homo Sapiens biogenesis of lysosome-related organelles complex-1,
subuni~
NM_0010013~ Homo sapiens MGC27121 gene (MGC27121), mRNA
NM_0010013~ Homo sapiens ATPase, Ca++ transporting, plasma membrane 3
(ATP2B3), t
NM_0010013~ Homo sapiens claudin 20 (CLDN20), mRNA
NM_0010013~ Homo sapiens NFKB inhibitor interacting Ras-like 2 (NKIRAS2),
transcript va
NM_0010013. Homo sapiens CD44 antigen (homing function and Indian blood group
syster
NM 0010013! Homo sapiens CD44 antigen (homing function and Indian blood group
syster
NM_0010013! Homo Sapiens CD44 antigen (homing function and Indian blood group
syster
NM_0010013! Homo sapiens CD44 antigen (homing function and Indian blood group
syster
NM_0010013! Homo sapiens HCG3 gene (HCG3), mRNA
NM_0010013! Homo Sapiens LIM domain only 3 (rhombotin-like 2) (LM03),
transcript variar
NM_0010013! Homo sapiens ATPase, Ca++ transporting, plasma membrane 4
(ATP2B4),1
NM_0010014' Homo sapiens hypothetical protein MGC24381 (MGC24381), mRNA
NM_0010014' Homo sapiens similar to Zinc finger protein 208 (LOC163223), mRNA
NM_0010014~ Homo sapiens family with sequence similarity 26,, member C
(FAM26C), mRl
NM_0010014' Homo Sapiens similar to F-box only protein 2 (LOC342897), mRNA
NM_0010014' Homo sapiens zinc finger protein 429 (ZNF429), mRNA
NM_0010014' Homo sapiens similar to TBC1 domain family, member 3, centromeric
(LOC4
NM_0010014' Homo sapiens similar to TBC1 domain family, member 3, telomeric
(MGC44E
NM_0010014' Homo Sapiens SMAD, mothers against DPP homolog 5 (Drosophila)
(SMAD;
NM 0010014: Homo sapiens SMAD, mothers against DPP homolog 5 (Drosophila)
(SMAD;
NM_0010014. Homo sapiens troponin T2, cardiac (TNNT2), transcript variant 2,
mRNA
NM_0010014: Homo Sapiens troponin T2, cardiac (TNNT2), transcript variant 3,
mRNA
NM_0010014: Homo sapiens troponin T2, cardiac (TNNT2), transcript variant 4,
mRNA
NM_0010014: Homo sapiens syntaxin 16 (STX16), transcript variant 1, mRNA
NM 0010014: Homo sapiens syntaxin 16 (STX16), transcript variant 3, mRNA
NM_0010014: Homo Sapiens chemokine (C-C motif) ligand 4-like (CCL4L), mRNA
NM_0010014: Homo sapiens similar to RIKEN cDNA 4921524J17 (LOC388272), mRNA
NM_0010014. Homo sapiens chemokine (C-C motif) ligand 3-like, centromeric
(MGC12815
NM_0010014: Homo sapiens lanosterol synthase (2,3-oxidosqualene-lanosterol
cyclase) (L
NM_0010014' Homo sapiens solute carrier family 35, member E4 (SLC35E4), mRNA
NM_00100141 Homo sapiens hypothetical protein FLJ11011 (FLJ11011), transcript
variant
NM 0010014. Homo sapiens hypothetical protein FLJ11011 (FLJ11011), transcript
variant
NM_00100147 Homo sapiens zinc finger, DHHC domain containing 13 (ZDHHC13),
transcri
NM 0010014. Homo sapiens phosphotriesterase related (PTER), transcript variant
1, mRN~
NM_0010014. Homo sapiens ATPase, Ca++ transporting, type 2C, member 1 (ATP2C1
), trs
NM_0010014. Homo sapiens ATPase, Ca++ transporting, type 2C, member 1 (ATP2C1
), tr;
NM 00100141 Homo sapiens ATPase, Ca++ transporting, type 2C, member 1 (ATP2C1
), try
NM_0010015~ Homo sapiens synuclein, beta (SNCB), transcript variant 1, mRNA
NM 00100151 Homo sapiens NADH dehydrogenase (ubiquinone) flavoprotein 3, 10kDa
(N1
NM 0010015: Homo sapiens hepatoma-derived growth factor-related protein 2
(HDGF2), tr
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NM 0010015: Homo Sapiens UDP-glucose pyrophosphorylase 2 (UGP2), transcript
variant
NM_0010015: Homo sapiens transgelin (TAGLN), transcript variant 1, mRNA
NM_0010015: Homo sapiens RAR-related orphan receptor C (RORC), transcript
variant 2, i
NM 0010015: Homo sapiens transmembrane 6 superfamily member 2 (TM6SF2),
transcript
NM_0010015~ Homo Sapiens CD36 antigen (collagen type I receptor,
thrombospondin recel
NM 0010015~ Homo sapiens CD36 antigen (collagen type I receptor,
thrombospondin recel
NM_0010015~ Homo sapiens growth factor receptor-bound protein 10 (GRB10),
transcript v
NM_0010015! Homo sapiens growth factor receptor-bound protein 10 (GRB10),
transcript v
NM_0010015! Homo Sapiens chromosome 9 open reading frame 103 (C9orf103), mRNA
NM 0010015! Homo sapiens LEM domain containing 1 (LEMD1), mRNA
NM_0010015! Homo Sapiens germ and embryonic stem cell enriched protein STELLA
(STE
NM_0010015! Homo sapiens growth factor receptor-bound protein 10 (GRB10),
transcript v
NM_0010015! Homo Sapiens galactokinase 2 (GALK2), transcript variant 2, mRNA
NM_0010015! Homo sapiens similar to growth differentiation factor 16
(LOC392255), mRN~
NM_00100151 Homo sapiens golgi associated, gamma adaptin ear containing, ARF
binding
NM_0010015~ Homo Sapiens golgi associated, gamma adaptin ear containing, ARF
binding
NM 0010015 Homo sapiens translocase of inner mitochondrial membrane 50 homolog
(ye
NM_00100151 Homo Sapiens phosphodiesterase 9A (PDE9A), transcript variant 2,
mRNA
NM_0010015~ Homo sapiens phosphodiesterase 9A (PDE9A), transcript variant 3,
mRNA
NM_0010015i Homo sapiens phosphodiesterase 9A (PDE9A), transcript variant 4,
mRNA
NM_0010015' Homo sapiens phosphodiesterase 9A (PDE9A), transcript variant 5,
mRNA
NM_0010015' Homo sapiens phosphodiesterase 9A (PDE9A), transcript variant 6,
mRNA
NM_0010015' Homo Sapiens phosphodiesterase 9A (PDE9A), transcript variant 7,
mRNA
NM_0010015' Homo sapiens phosphodiesterase 9A (PDE9A), transcript variant 8,
mRNA
NM_0010015' Homo sapiens phosphodiesterase 9A (PDE9A), transcript variant 9,
mRNA
NM_0010015' Homo sapiens phosphodiesterase 9A (PDE9A), transcript variant 10,
mRNA
NM_0010015' Homo sapiens phosphodiesterase 9A (PDE9A), transcript variant 11,
mRNA
NM 0010015' Homo sapiens phosphodiesterase 9A (PDE9A), transcript variant 12,
mRNA
NM_0010015' Homo sapiens phosphodiesterase 9A (PDE9A), transcript variant 13,
mRNA
NM_0010015' Homo sapiens phosphodiesterase 9A (PDE9A), transcript variant 14,
mRNA
NM_0010015. Homo sapiens phosphodiesterase 9A (PDE9A), transcript variant 15,
mRNA
NM_0010015~ Homo sapiens phosphodiesterase 9A (PDE9A), transcript variant 16,
mRNA
NM_0010015. Homo sapiens phosphodiesterase 9A (PDE9A), transcript variant 17,
mRNA
NM_0010015. Homo sapiens phosphodiesterase 9A (PDE9A), transcript variant 18,
mRNA
NM_0010015. Homo sapiens phosphodiesterase 9A (PDE9A), transcript variant 19,
mRNA
NM_00100151 Homo Sapiens phosphodiesterase 9A (PDE9A), transcript variant 20,
mRNA
NM 0010015. Homo sapiens ATPase, Na+/K+ transporting, alpha 1 polypeptide
(ATP1A1 ),
NM_0010016! Homo sapiens mediator of RNA polymerase II transcription, subunit
8 homoh
NM 0010016! Homo sapiens mediator of RNA polymerase II transcription, subunit
8 homoh
NM_0010016! Homo sapiens mediator of RNA polymerase II transcription, subunit
8 homoh
NM_0010016! Homo sapiens similar to hypothetical protein 9530023602
(MGC90512), mR
NM_0010016! Homo sapiens olfactory receptor, family 9, subfamily A, member 4
(OR9A4),
NM_0010016! Homo sapiens olfactory receptor, family 9, subfamily A, member 2
(OR9A2),
NM 0010016! Homo Sapiens olfactory receptor, family 2, subfamily A, member 14
(OR2A1 ~
NM_0010016~ Homo sapiens hypothetical protein LOC144363 (LOC144363), mRNA
NM_0010016~ Homo Sapiens hypothetical protein LOC155054 (LOC155054), mRNA
NM_0010016~ Homo sapiens FLJ16636 protein (FLJ16636), mRNA
NM_0010016~ Homo sapiens hypothetical LOC255349 (bA9F11.1), mRNA
NM 0010016 Homo sapiens hypothetical protein LOC339745 (LOC339745), mRNA
NM_00100161 Homo Sapiens FLJ16008 protein (FLJ16008), mRNA
NM 0010016 Homo sapiens prostate cancer associated protein 5 (PCANAPS),
transcript v
NM_0010016~ Homo sapiens olfactory receptor, family 6, subfamily V, member 1
(OR6V1),
NM 0010016 Homo Sapiens FLJ26175 protein (FLJ26175), mRNA
NM_0010016~ Homo sapiens FLJ41603 protein (FLJ41603), mRNA
NM_0010016' Homo sapiens FLJ46321 protein (FLJ46321), mRNA
NM 0010016' Homo sapiens FLJ16518 protein (FLJ16518), mRNA
NM 0010016' Homo sapiens ribonuclease-like protein 9 (h461), mRNA
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NM_0010016' Homo sapiens FLJ46385 protein (FLJ46385), mRNA
NM_0010016' Homo sapiens lipocalin 9 (LCN9), mRNA
NM 0010016' Homo sapiens FLJ46300 protein (FLJ46300), mRNA
NM_0010016' Homo Sapiens FLJ44653 protein (FLJ44653), mRNA
NM_0010016' Homo sapiens FLJ41423 protein (FLJ41423), mRNA
NM_0010016. Homo Sapiens FLJ42102 protein (FLJ42102), mRNA
NM_0010016. Homo sapiens FLJ45300 protein (FLJ45300), mRNA
NM 0010016. Homo sapiens FLJ45530 protein (FLJ45530), mRNA
NM 00100161 Homo sapiens similar to HSPC296 (MGC88387), mRNA
NM_0010016. Homo sapiens FLJ45831 protein (FLJ45831 ), mRNA
NM_0010016i Homo Sapiens FLJ45079 protein (FLJ45079), mRNA
NM_0010016. Homo sapiens FLJ43870 protein (FLJ43870), mRNA
NM 0010016. Homo sapiens FLJ26850 protein (FLJ26850), mRNA
NM 0010016. Homo sapiens FLJ35409 protein (FLJ35409), mRNA
NM 0010016. Homo sapiens FLJ44005 protein (FLJ44005), mRNA
NM_0010016! Homo Sapiens hypothetical FLJ42133 (FLJ42133), mRNA
NM_0010016! Homo sapiens FLJ44790 protein (FLJ44790), mRNA
NM_0010016! Homo sapiens FLJ45139 protein (FLJ45139), mRNA
NM_0010016! Homo sapiens FLJ46257 protein (FLJ46257), mRNA
NM_0010016! Homo Sapiens FLJ41993 protein (FLJ41993), mRNA
NM_0010016! Homo sapiens FLJ42418 protein (FLJ42418), mRNA
NM_0010016! Homo sapiens FLJ44006 protein (FLJ44006), mRNA
NM_0010016! Homo sapiens FLJ41821 protein (FLJ41821 ), mRNA
NM_0010016! Homo sapiens FLJ43879 protein (FLJ43879), mRNA
NM_0010016! Homo sapiens FLJ25996 protein (FLJ25996), mRNA
NM_00100171 Homo sapiens FLJ45966 protein (FLJ45966), mRNA
NM_00100171 Homo sapiens HCV F-transactivated protein 1 (LOC401152), mRNA
NM_00100171 Homo sapiens FLJ33360 protein (FLJ33360), mRNA
NM_00100171 Homo sapiens FLJ46010 protein (FLJ46010), mRNA
NM_00100171 Homo sapiens FLJ44796 protein (FLJ44796), mRNA
NM_00100171 Homo sapiens FLJ41649 protein (FLJ41649), mRNA
NM 0010017! Homo sapiens FLJ42177 protein (FLJ42177), mRNA
NM 00100171 Homo Sapiens FLJ45974 protein (FLJ45974), mRNA
NM_00100171 Homo sapiens FLJ45537 protein (FLJ45537), mRNA
NM_0010017' Homo sapiens similar to 4931415M17 protein (LOC401565), mRNA
NM_001001T Homo sapiens DNA-damage inducible protein 1 (DD11), mRNA
NM_001001T Homo sapiens lipocalin 10 (LCN10), mRNA
NM 0010017' Homo sapiens SH3 domain binding glutamic acid-rich protein
(SH3BGR), tra
NM_001001T Homo sapiens FERM, RhoGEF (ARHGEF) and pleckstrin domain protein 1
(~
NM_0010017' Homo sapiens nuclear factor of kappa light polypeptide gene
enhancer in B-c
NM_0010017: Homo Sapiens chromodomain protein, Y chromosome, 2 related (CDY),
mR~
NM_0010017: Homo sapiens transmembrane protein 1 (TMEM1 ), transcript variant
2, mRN
NM_0010017: Homo sapiens Mahlavu hepatocellular carcinoma (HHCM), mRNA
NM_0010017: Homo sapiens chromosome 10 open reading frame 130 (C10orf130),
mRNA
NM_0010017: Homo sapiens ATPase, Na+/K+ transporting, alpha 4 polypeptide
(ATP1 A4),
NM 0010017 Homo Sapiens constitutive photomorphogenic protein (COP1 ),
transcript vari.
NM_0010017I Homo sapiens BRCC2 mRNA (BRCC2), mRNA
NM_0010017I Homo Sapiens ATPase, Na+/K+ transporting, beta 1 polypeptide (ATP1
B1 ), t
NM 00100171 Homo sapiens chromosome 21 open reading frame 24 (C21orf24), mRNA
NM_0010017! Homo Sapiens chromosome 9 open reading frame 105 (C9orF105), mRNA
NM_0010017! Homo sapiens chromosome 10 open reading frame 55 (C10orf55), mRNA
NM 0010017! Homo sapiens similar to RIKEN cDNA 1700027J05 gene (MGC33692), mRN
NM_0010017! Homo Sapiens similar to RIKEN cDNA C030006K11 gene (MGC70857), mRl
NM_0010018r Homo sapiens olfactory receptor, family 2, subfamily A, member 42
(OR2A4:
NM_0010018: Homo sapiens olfactory receptor, family 2, subfamily T, member 34
(OR2T34
NM 0010018: Homo Sapiens olfactory receptor, family 2, subfamily T, member 27
(OR2T27
NM 0010018: Homo sapiens olfactory receptor, family 2, subfamily T, member 35
(OR2T3~
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NM_0010018! Homo sapiens similar to RIKEN cDNA At)30009B12 gene (MGC21382),
mRP
NM_0010018! Homo sapiens inter-alpha (globulin) inhibitor H5 (ITIHS),
transcript variant 3,
NM 0010018! Homo sapiens serine/threonine-protein kinase pim-3 (PIM3), mRNA
NM 0010018' Homo sapiens hypothetical protein MGC14376 (MGC14376), transcript
varia
NM_0010018' Homo sapiens heat shock transcription factor, Y-linked 1 (HSFY1 ),
transcript
NM_0010018' Homo sapiens chromosome 14 open reading frame 37 (C14orf37), mRNA
NM_0010018' Homo sapiens hypothetical protein LOC283174 (LOC283174), mRNA
NM_0010018' Homo sapiens protein kinase NYD-SP25 (NYD-SP25), transcript
variant 2, m
NM 0010018' Homo sapiens protein kinase NYD-SP25 (NYD-SP25), transcript
variant 3, rr
NM_0010018' Homo sapiens heat shock transcription factor, Y linked 2 (HSFY2),
transcript
NM_0010018' Homo sapiens heat shock transcription factor, Y linked 2 (HSFY2),
transcript
NM_0010018. Homo sapiens interferon-induced protein with tetratricopeptide
repeats 1 (1F1'
NM_0010018! Homo sapiens variably charged X-C (VCX-C), mRNA
NM_0010018! Homo sapiens runt-related transcription factor 1 (acute myeloid
leukemia 1;
NM_0010018! Homo sapiens prostate cancer associated protein 5 (PCANAPS),
transcript v
NM_0010018! Homo sapiens tetratricopeptide repeat domain 3 (TTC3), transcript
variant 2,
NM_0010018! Homo sapiens ubiquitin associated and SH3 domain containing, A
(UBASH3
NM_0010019' Homo Sapiens olfactory receptor, family 4, subfamily E, member 2
(OR4E2),
NM_0010019' Homo sapiens olfactory receptor, family 52, subfamily N, member 1
(OR52N'
NM_0010019~ Homo sapiens olfactory receptor, family 2, subfamily G, member 3
(OR2G3),
NM_0010019' Homo sapiens olfactory receptor, family 2, subfamily G, member 2
(OR2G2),
NM_0010019' Homo sapiens olfactory receptor, family 52, subfamily J, member 3
(OR52J3
NM_0010019' Homo sapiens olfactory receptor, family 56, subfamily A, member 1
(OR56A'
NM_0010019~ Homo sapiens olfactory receptor, family 5, subfamily BF, member 1
(ORSBF~
NM_0010019: Homo Sapiens olfactory receptor, family 5, subfamily AS, member 1
(ORSAS
NM_0010019: Homo sapiens olfactory receptor OR11-62 (0R11-62), mRNA
NM_0010019: Homo Sapiens mitochondria) tumor suppressor 1 (MTUS1 ), transcript
variant
NM 0010019: Homo sapiens mitochondria) tumor suppressor 1 (MTUS1 ), transcript
variant
NM 0010019: Homo sapiens mitochondria) tumor suppressor 1 (MTUS1 ), transcript
variant
NM_0010019: Homo sapiens peroxisome proliferative activated receptor, alpha
(PPARA), tr
NM_0010019: Homo sapiens peroxisome proliferative activated receptor, alpha
(PPARA), tr
NM_0010019: Homo sapiens peroxisome proliferative activated receptor, alpha
(PPARA), tr
NM_0010019: Homo sapiens mitochondria) tumor suppressor 1 (MTUS1 ), transcript
variant
NM_0010019: Homo sapiens LIM homeobox 8 (LHXB), mRNA
NM_0010019: Homo Sapiens ATP synthase, H+ transporting, mitochondria) F1
complex, alb
NM 0010019: Homo sapiens KIAA1914 (KIAA1914), transcript variant 1, mRNA
NM 0010019: Homo Sapiens ATP synthase, H+ transporting, mitochondria) F1
complex, aIK
NM_0010019. Homo sapiens chromosome 9 open reading frame 47 (C9orf47), mRNA
NM_0010019: Homo sapiens 6-pyruvoyl-tetrahydropterin synthase/dimerization
cofactor of I
NM_0010019! Homo Sapiens olfactory receptor, family 10, subfamily G, member 9
(OR10G
NM_0010019! Homo sapiens olfactory receptor, family 5, subfamily A, member 2
(OR5A2),
NM 0010019! Homo sapiens olfactory receptor, family 13, subfamily C, member 9
(OR13C!
NM_0010019! Homo sapiens olfactory receptor, family 2, subfamily W, member 3
(OR2W3'
NM_0010019! Homo sapiens olfactory receptor, family 7, subfamily G, member 3
(OR7G3),
NM 0010019! Homo sapiens olfactory receptor, family 11, subfamily L, member 1
(OR11L1
NM_0010019~ Homo sapiens olfactory receptor, family 5, subfamily W, member 2
(OR5W2'
NM_0010019i Homo sapiens olfactory receptor, family 13, subfamily C, member 3
(OR13C:
NM_0010019~ Homo sapiens olfactory receptor, family 6, subfamily B, member 2
pseudoge
NM 00100191 Homo Sapiens olfactory receptor, family 2, subfamily L, member 8
(OR2L8), i
NM_0010019~ Homo sapiens olfactory receptor, family 2, subfamily T, member 11
(OR2T11
NM_0010019~ Homo sapiens olfactory receptor, family 4, subfamily D, member 5
(OR4D5),
NM_00100191 Homo sapiens olfactory receptor, family 5, subfamily AT, member 1
(ORSAT~
NM_00100191 Homo sapiens olfactory receptor, family 5, subfamily D, member 13
(OR5D1:
NM_0010019~ Homo sapiens olfactory receptor, family 6, subfamily S, member 1
(OR6S1 ),
NM_0010019' Homo sapiens family with sequence similarity 13, member C1
(FAM13C1 ), tr
NM 0010019' Homo sapiens ATP synthase, H+ transporting, mitochondria) F1
complex, ga
NM 0010019' Homo sapiens pleckstrin homology domain containing, family A
(phosphoino
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NM_0010019' Homo sapiens ATP synthase, H+ transporting, mitochondria) F1
complex, de
NM_0010019' Homo sapiens arginyltransferase 1 (ATE1), transcript variant 1,
mRNA
NM_0010019' Homo sapiens ATP synthase, H+ transporting, mitochondria) F1
complex, ep
NM_0010019! Homo sapiens regeneration associated muscle protease
(DKFZP586H2123)
NM_0010019! Homo sapiens ubiquitin specific protease 16 (USP16), transcript
variant 2, m
NM_0010019! Homo sapiens glycoprotein M6B (GPM6B), transcript variant 4, mRNA
NM_0010019! Homo sapiens glycoprotein M6B (GPM6B), transcript variant 1, mRNA
NM_0010019! Homo Sapiens glycoprotein M6B (GPM6B), transcript variant 2, mRNA
NM_0010019! Homo sapiens exosome component 10 (EXOSC10), transcript variant 1,
mRl
NM_00100201 Homo sapiens guanosine monophosphate reductase 2 (GMPR2),
transcript ~
NM_0010020i Homo sapiens guanosine monophosphate reductase 2 (GMPR2),
transcript ~
NM_00100201 Homo Sapiens guanosine monophosphate reductase 2 (GMPR2),
transcript ~
NM_00100201 Homo sapiens 5'-nucleotidase, cytosolic IB (NT5C1B), transcript
variant 1, m
NM 0010020' Homo Sapiens ATP synthase, H+ transporting, mitochondria) FO
complex, su
NM 0010020' Homo sapiens ATP synthase, H+ transporting, mitochondria) FO
complex, su
NM 0010020' Homo Sapiens host cell factor C1 regulator 1 (XP01 dependant)
(HCFC1 R1 )
NM_0010020' Homo sapiens host cell factor C1 regulator 1 (XP01 dependant)
(HCFC1 R1 )
NM_0010020: Homo sapiens phosphofructokinase, liver (PFKL), transcript variant
1, mRNA
NM_0010020: Homo sapiens claudin 18 (CLDN18), transcript variant 2, mRNA
NM_0010020: Homo sapiens ATP synthase, H+ transporting, mitochondria) FO
complex, su
NM_0010020: Homo sapiens complement component 4B, centromeric (C4B), mRNA
NM_0010020: Homo sapiens ATP synthase, H+ transporting, mitochondria) FO
complex, su
NM_0010020: Homo Sapiens hematological and neurological expressed 1 (HN1),
transcript
NM_0010020: Homo sapiens hematological and neurological expressed 1 (HN1),
transcript
NM_0010020: Homo sapiens defensin, beta 108 (DEFB108), mRNA
NM 0010020: Homo sapiens astacin-like metalloendopeptidase (M12 family)
(ASTL), mRN,
NM 0010022: Homo sapiens kallikrein 2, prostatic (KLK2), transcript variant 2,
mRNA
NM 0010022: Homo sapiens kallikrein 2, prostatic (KLK2), transcript variant 3,
mRNA
NM_0010022: Homo sapiens RAB11 family interacting protein 1 (class I)
(RAB11FIP1), tray
NM_0010022. Homo Sapiens sodium channel modifier 1 (SCNM1), transcript variant
2, mRl
NM_0010022: Homo sapiens serine (or cysteine) proteinase inhibitor, Glade A
(alpha-1 anti)
NM_0010022. Homo sapiens serine (or cysteine) proteinase inhibitor, Glade A
(alpha-1 anti)
NM_0010022~ Homo Sapiens aftiphilin protein (AFTIPHILIN), transcript variant
3, mRNA
NM_0010022~ Homo sapiens APC11 anaphase promoting complex subunit 11 homolog
(ye
NM_0010022~ Homo Sapiens APC11 anaphase promoting complex subunit 11 homolog
(ye
NM_0010022~ Homo Sapiens APC11 anaphase promoting complex subunit 11 homolog
(ye
NM_0010022~ Homo sapiens APC11 anaphase promoting complex subunit 11 homolog
(ye
NM_0010022~ Homo Sapiens APC11 anaphase promoting complex subunit 11 homolog
(ye
NM_0010022~ Homo sapiens APC11 anaphase promoting complex subunit 11 homolog
(ye
NM_0010022! Homo Sapiens ADP-ribosylation-like factor 6 interacting protein 4
(ARL61P4),
NM_0010022! Homo sapiens ADP-ribosylation-like factor 6 interacting protein 4
(ARL61P4),
NM_0010022! Homo Sapiens SMT3 suppressor of mif two 3 homolog 4 (yeast)
(SUM04), rr
NM_0010022! Homo sapiens ATP synthase, H+ transporting, mitochondria) FO
complex, su
NM_0010022! Homo sapiens acyl-CoA:lysocardiolipin acyltransferase 1 (ALCAT1),
transcril
NM_0010022! Homo Sapiens ATP synthase, H+ transporting, mitochondria) FO
complex, su
NM_0010022! Homo sapiens C1q domain containing 1 (C1QDC1), transcript variant
1, mR~
NM_0010022i Homo sapiens chromosome 9 open reading frame 58 (C9orf58),
transcript v~
NM_0010022~ Homo Sapiens zinc finger, FYVE domain containing 27 (ZFYVE27),
transcrip
NM_0010022~ Homo sapiens zinc finger, FYVE domain containing 27 (ZFYVE27),
transcript
NM_00100221 Homo sapiens epithelial stromal interaction 1 (breast) (EPSTI1 ),
mRNA
NM_0010022~ Homo sapiens c-mir, cellular modulator of immune recognition
(MIR), transcr
NM_00100221 Homo sapiens c-mir, cellular modulator of immune recognition
(MIR), transcr
NM 00100221 Homo sapiens exosome component 3 (EXOSC3), transcript variant 2,
mRNP
NM 0010022' Homo sapiens Fc fragment of IgG, low affinity I Ib, receptor for
(CD32) (FCGF
NM 0010022' Homo Sapiens Fc fragment of IgG, low affinity Ilb, receptor for
(CD32) (FCGF
NM 0010022' Homo sapiens Fc fragment of IgG, low affinity Ilb, receptor for
(CD32) (FCGF
NM 0010022! Homo sapiens putative NFkB activating protein 373 (FLJ23091 ),
transcript va
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NM_0010022! Homo sapiens flavin containing monooxygenase 3 (FM03), transcript
variant
NM_0010022! Homo sapiens GATA binding protein 3 (GATA3), transcript variant 1,
mRNA
NM_0010022! Homo sapiens golgi autoantigen, golgin subfamily a, 7 (GOLGA7),
transcript
NM 0010027! Homo sapiens HIRA interacting protein 5 (HIRIPS), transcript
variant 2, mRN
NM 0010027! Homo Sapiens HIRA interacting protein 5 (HIRIPS), transcript
variant 3, mRN
NM_0010027! Homo sapiens HIRA interacting protein 5 (HIRIPS), transcript
variant 4, mRN
NM_0010027! Homo sapiens PTPN13-like, Y-linked, centromeric (PRY), mRNA
NM_0010027! Homo sapiens chromosome 10 open reading frame 78 (C10orf78),
transcript
NM_0010027~ Homo sapiens basic charge, Y-linked, 2 (BPY2), mRNA
NM_0010027i Homo sapiens basic charge, Y-linked, 2 (BPY2), mRNA
NM_0010027~ Homo sapiens DnaJ (Hsp40) homolog, subfamily B, member 12
(DNAJB12),
NM_0010027! Homo Sapiens multiple C2-domains with two transmembrane regions 1
(MCl
NM_0010027! Homo sapiens SMC4 structural maintenance of chromosomes 4-like 1
(yeast
NM_0010028~ Homo sapiens SMC4 structural maintenance of chromosomes 4-like 1
(yeast
NM 0010028' Homo sapiens phosphodiesterase 4D interacting protein (myomegalin)
(PDE
NM 0010028 Homo sapiens phosphodiesterase 4D interacting protein (myomegalin)
(PDE
NM_0010028' Homo sapiens phosphodiesterase 4D interacting protein (myomegalin)
(PDE
NM_0010028' Homo sapiens RAB11 family interacting protein 1 (class I) (RAB11
FIP1 ), trar
NM_0010028: Homo sapiens hypothetical protein LOC126208 (LOC126208), mRNA
NM_0010028. Homo sapiens phosphatidylinositol (4,5) bisphosphate 5-
phosphatase, A (P11
NM 0010028: Homo Sapiens protein kinase, lysine deficient 3 (PRKWNK3),
transcript varia
NM_0010028~ Homo sapiens DKFZp434A0131 protein (DKFZP434A0131 ), transcript
variar
NM_0010028~ Homo sapiens myosin, light polypeptide 4, alkali; atrial,
embryonic (MYL4), tr
NM_0010028~ Homo sapiens suppressor of hairy wing homolog 4 (Drosophila)
(SUHW4), tr
NM_0010028~ Homo sapiens suppressor of hairy wing homolog 4 (Drosophila)
(SUHW4), tr
NM_0010028~ Homo sapiens suppressor of hairy wing homolog 4 (Drosophila)
(SUHW4), tr
NM_0010028~ Homo sapiens CTFB, chromosome transmission fidelity factor 8
homolog (S.
NM_0010028~ Homo sapiens lymphocyte antigen 6 complex, locus G5C (LY6G5C),
transcri
NM_0010028~ Homo Sapiens lymphocyte antigen 6 complex, locus G5C (LY6G5C),
transcri
NM_0010028! Homo sapiens annexin A2 (ANXA2), transcript variant 2, mRNA
NM_0010028! Homo sapiens annexin A2 (ANXA2), transcript variant 1, mRNA
NM_0010028i Homo sapiens BTB (POZ) domain containing 7 (BTBD7), transcript
variant 1.
NM_00100281 Homo sapiens Rho guanine nucleotide exchange factor (GEF) 5
(ARHGEFS;
NM_00100281 Homo sapiens chromosome 22 open reading frame 14 (C22orf14),
transcript
NM_0010028' Homo sapiens chromosome 22 open reading frame 18 (C22orf18),
transcript
NM_0010028' Homo sapiens chromosome 22 open reading frame 19 (C22ort19),
transcript
NM_0010028' Homo Sapiens chromosome 22 open reading frame 19 (C22orf19),
transcript
NM_0010028' Homo sapiens chromosome 22 open reading frame 19 (C22orf19),
transcript
NM_0010028. Homo Sapiens chromosome 22 open reading frame 2 (C22orf2),
transcript v~
NM_00100281 Homo sapiens phosphatidylinositol-3-phosphate/phosphatidylinositol
5-kinas
NM_0010029~ Homo sapiens hypothetical protein FLJ31052 (FLJ31052), mRNA
NM_0010029i Homo sapiens olfactory receptor, family 8, subfamily G, member 1
(OR8G1 P
NM_00100291 Homo sapiens X Kell blood group precursor-related, Y-linked 2
(XKRY2), mR
NM_00100291 Homo sapiens olfactory receptor, family 8, subfamily K, member 1
(OR8K1),
NM_00100291 Homo sapiens KIAA0553 protein (KIAA0553), mRNA
NM_0010029' Homo sapiens cytochrome P450, family 2, subfamily D, polypeptide 7
pseudo
NM_0010029' Homo sapiens G protein-coupled receptor 139 (GPR139), mRNA
NM_0010029' Homo sapiens chromosome 9 open reading frame 115 (C9orf115), mRNA
NM_0010029' Homo sapiens potassium channel tetramerisation domain containing
11 (KC'
NM_0010029' Homo Sapiens insulin growth factor-like family member 2 (IGFL2),
mRNA
NM_0010029' Homo Sapiens H2B histone family, member W, testis-specific
(H2BFWT), mF
NM_0010029' Homo Sapiens olfactory receptor, family 8, subfamily D, member 1
(OR8D1),
NM_0010029' Homo Sapiens olfactory receptor, family 8, subfamily D, member 2
(OR8D2),
NM_0010029' Homo sapiens hypothetical protein LOC285016 (LOC285016), mRNA
NM 0010029: Homo sapiens protein expressed in prostate, ovary, testis, and
placenta 8 (P
NM 0010029; Homo sapiens adenylate kinase 3-like 2 (AK3L2), mRNA
NM 0010029; Homo sapiens similar to PM5 (FLJ43542), mRNA
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NM_0010029; Homo sapiens insulin growth factor-like family member 4 (IGFL4),
mRNA
NM 0010029; Homo Sapiens adaptor-related protein complex 3, sigma 1 subunit
(AP3S1 ), '
NM 0010029; Homo sapiens olfactory receptor, family 5, subfamily AP, member 2
(ORSAP
NM 0010029; Homo sapiens TWIST neighbor (TWISTNB), mRNA
NM 0010033! Homo sapiens Bicaudal D homolog 1 (Drosophila) (BICD1 ),
transcript variant
NM 0010033! Homo sapiens DKFZp451A211 protein (DKFZp451A211), mRNA
NM 00100341 Homo sapiens calcium channel, voltage-dependent, alpha 1 I subunit
(CACN,
NM 0010034~ Homo sapiens olfactory receptor, family 56, subfamily A, member 3
{OR56A;
NM_0010036! Homo sapiens protein phosphatase 2, regulatory subunit B, delta
isoform (PF
NM 00100361 Homo sapiens similar to hypothetical protein Y97E10AL.1 (DKFZp761
P211 ),
NM 0010036' Homo sapiens chromosome 18 open reading frame 1 (C18orf1),
transcript v~
NM 0010036' Homo sapiens chromosome 18 open reading frame 1 (C18orf1),
transcript v~
NM_0010036' Homo sapiens leptin receptor (LEPR), transcript variant 2, mRNA
NM_0010036. Homo sapiens leptin receptor (LEPR), transcript variant 3, mRNA
NM 001079 Homo Sapiens zeta-chain (TCR) associated protein kinase 70kDa
(ZAP70), t
NM 001132 Homo sapiens AFG3 ATPase family gene 3-like 1 (yeast) (AFG3L1 ),
mRNA
NM 001222 Nomo sapiens calcium/calmodulin-dependent protein kinase (CaM
kinase) II
NM 001369 Homo sapiens dynein, axonemal, heavy polypeptide 5 (DNAH5), mRNA
NM 001376 Homo sapiens dynein, cytoplasmic, heavy polypeptide 1 (DNCH1), mRNA
NM 001378 Homo sapiens dynein, cytoplasmic, intermediate polypeptide 2
(DNCI2), mRl
NM 001410 Homo sapiens EGF-like-domain, multiple 4 (EGFL4), mRNA
NM 001547 Homo Sapiens interferon-induced protein with tetratricopeptide
repeats 2 (1F1
NM 001556 Nomo sapiens inhibitor of kappa light polypeptide gene enhancer in B-
cells, I
NM 001636 Homo sapiens solute carrier family 25 {mitochondria) carrier;
adenine nucleon
NM 001763 Homo sapiens CD1A antigen, a polypeptide (CD1A), mRNA
NM 001810 Homo sapiens centromere protein B, 80kDa (CENPB), mRNA
NM_001931 Homo sapiens dihydrolipoamide S-acetyltransferase (E2 component of
pyru~
NM_001947 Homo Sapiens dual specificity phosphatase 7 (DUSP7), mRNA
NM_001984 Homo sapiens esterase D/formylglutathione hydrolase {ESD), mRNA
NM 001986 Homo sapiens ets variant gene 4 (E1A enhancer binding protein, E1AF)
(E'P
NM_002154 Homo sapiens heat shock 70kDa protein 4 (HSPA4), transcript variant
1, mR
NM_002242 Homo sapiens potassium inwardly-rectifying channel, subfamily J,
member 1
NM_002348 Homo sapiens lymphocyte antigen 9 (LY9), mRNA
NM_002399 Homo sapiens Meis1, myeloid ecotropic viral integration site 1
homolog 2 (m~
NM_002404 Homo sapiens microfibrillar-associated protein 4 (MFAP4), mRNA
NM_002471 Homo sapiens myosin, heavy polypeptide 6, cardiac muscle, alpha
(cardiom~
NM 002498 Homo sapiens NIMA (never in mitosis gene a)-related kinase 3 (NEK3),
tran.
NM_002523 Homo sapiens neuronal pentraxin II (NPT7f2), mRNA
NM_002596 Homo sapiens PCTAIRE protein kinase 3 (PCTK3), transcript variant 3,
mR~
NM_002603 Homo sapiens phosphodiesterase 7A (PDE7A), transcript variant 1,
mRNA
NM 002604 Homo sapiens phosphodiesterase 7A (PDE7A), transcript variant 2,
mRNA
NM 002605 Homo sapiens phosphodiesterase 8A (PDE8A), transcript variant 1,
mRNA
NM_002679 Homo Sapiens postmeiotic segregation increased 2-like 2 (PMS2L2),
mRNA
NM 002735 Homo sapiens protein kinase, CAMP-dependent, regulatory, type I,
beta (PRI
NM 002746 Homo sapiens mitogen-activated protein kinase 3 (MAPK3), mRNA
NM_002791 Homo Sapiens proteasome {prosome, macropain) subunit, alpha type, 6
(PSI
NM 002798 Homo sapiens proteasome (prosome, macropain) subunit, beta type, 6
(PSN
NM_002972 Homo sapiens SET binding factor 1 (SBF1 ), transcript variant 1,
mRNA
NM 002974 Homo sapiens serine (or cysteine) proteinase inhibitor, Glade B
(ovalbumin),
NM_002998 Homo sapiens syndecan 2 {heparan sulfate proteoglycan 1, cell
surface-asst
NM_003013 Homo Sapiens secreted frizzled-related protein 2 (SFRP2), mRNA
NM 003047 Homo sapiens solute carrier family 9 (sodium/hydrogen exchanger),
isoform
NM_003106 Homo sapiens SRY (sex determining region Y)-box 2 (SOX2), mRNA
NM 003111 Homo Sapiens Sp3 transcription factor (SP3), mRNA
NM 003179 Homo sapiens synaptophysin (SYP), mRNA
NM_003196 Homo sapiens transcription elongation factor A (S11), 3 (TCEA3),
mRNA
NM~003200 Homo Sapiens transcription factor 3 (E2A immunoglobulin enhancer
binding
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NM_003302 Homo sapiens thyroid hormone receptor interactor 6 (TRIPE), mRNA
NM_003415 Homo Sapiens zinc finger protein 268 (ZNF268), mRNA
NM_003444 Homo sapiens zinc finger protein 154 (pHZ-92) (ZNF154), mRNA
NM_003502 Homo sapiens axin 1 (AXIN1), transcript variant 1, mRNA
NM_003517 Homo sapiens histone 2, H2ac (HIST2H2AC), mRNA
NM_003575 Homo Sapiens zinc finger protein 282 (ZNF282), mRNA
NM_003598 Homo sapiens TEA domain family member 2 (TEAD2), mRNA
NM_003638 Homo sapiens integrin, alpha 8 (ITGA8), mRNA
NM_003660 Homo sapiens protein tyrosine phosphatase, receptor type, f
polypeptide (P1
NM 003677 Homo Sapiens density-regulated protein (DENR), mRNA
NM 003700 Homo sapiens olfactory receptor, family 2, subfamily D, member 2
(OR2D2),
NM 003719 Homo sapiens phosphodiesterase 8B (PDE8B), mRNA
NM_003724 Homo Sapiens jerky homolog (mouse) (JRK), mRNA
NM_003741 Homo sapiens chordin (CHRD), transcript variant 1, mRNA
NM_003817 Homo sapiens a disintegrin and metalloproteinase domain 7 (ADAM7),
mRN,
NM_003818 Homo Sapiens CDP-diacylglycerol synthase (phosphatidate
cytidylyltransfer2
NM_003828 Homo sapiens myotubularin related protein 1 (MTMR1), transcript
variant 1, i
NM_003845 Homo sapiens dual-specificity tyrosine-(Y)-phosphorylation regulated
kinase
NM_003848 Homo sapiens succinate-CoA ligase, GDP-forming, beta subunit
(SUCLG2),
NM_003858 Homo sapiens cyclin K (CCNK), mRNA
NM_003898 Homo sapiens synaptojanin 2 (SYNJ2), mRNA
NM_003907 Homo sapiens eukaryotic translation initiation factor 2B, subunit 5
epsilon, 8~
NM_003957 Homo Sapiens serine/threonine kinase 29 (STK29), mRNA
NM_003959 Homo sapiens huntingtin interacting protein-1-related (HIP1R), mRNA
NM_003972 Homo sapiens BTAF1 RNA polymerase II, B-TFIID transcription factor-
assoc
NM_004080 Homo sapiens diacylglycerol kinase, beta 90kDa (DGKB), transcript
variant 1
NM_004097 Homo sapiens empty spiracles homolog 1 (Drosophila) (EMX1), mRNA
NM 004118 Homo sapiens forkhead-like 18 (Drosophila) (FKHL18), mRNA
NM 004136 Homo sapiens iron-responsive element binding protein 2 (IREB2), mRNA
NM_004200 Homo sapiens synaptotagmin VII (SYT7), mRNA
NM 004220 Homo sapiens zinc finger protein 213 (ZNF213), mRNA
NM 004241 Homo sapiensjumonji domain containing 1C (JMJD1C), mRNA
NM_004242 Homo sapiens high mobility group nucleosomal binding domain 3
(HMGN3),
NM_004319 Homo sapiens astrotactin (ASTN), transcript variant 1, mRNA
NM_004439 Homo sapiens EphA5 (EPHAS), transcript variant 1, mRNA
NM_004498 Homo sapiens one cut domain, family member 1 (ONECUT1 ), mRNA
NM_004650 Homo sapiens GS2 gene (DXS1283E), mRNA
NM_004685 Homo sapiens myotubularin related protein 6 (MTMR6), mRNA
NM_004691 Homo sapiens ATPase, H+ transporting, lysosomal 38kDa, VO subunit d
isof~
NM_004764 Homo sapiens piwi-like 1 (Drosophila) (PIWIL1), mRNA
NM_004773 Homo sapiens thyroid hormone receptor interactor 3 (TRIP3), mRNA
NM_004816 Homo sapiens chromosome 9 open reading frame 61 (C9orf61), mRNA
NM_004840 Homo Sapiens Rac/Cdc42 guanine nucleotide exchange factor (GEF) 6
(ARE-
NM_004884 Homo sapiens putative neuronal cell adhesion molecule (PUNC), mRNA
NM_004946 Homo sapiens dedicator of cytokinesis 2 (DOCK2), mRNA
NM_004947 Homo Sapiens dedicator of cytokinesis 3 (DOCK3), mRNA
NM_005054 Homo sapiens RAN binding protein 2-like 1 (RANBP2L1), transcript
variant 1
NM_005105 Homo sapiens RNA binding motif protein 8A (RBMBA), mRNA
NM_005126 Homo Sapiens nuclear receptor subfamily 1, group D, member 2 (NR1
D2), rr
NM_005140 Homo sapiens cyclic nucleotide gated channel alpha 2 (CNGA2), mRNA
NM_005144 Homo sapiens hairless homolog (mouse) (HR), transcript variant 1,
mRNA
NM_005153 Homo sapiens ubiquitin specific protease 10 (USP10), mRNA
NM_005202 Homo sapiens collagen, type VIII, alpha 2 (COL8A2), mRNA
NM_005240 Homo sapiens ets variant gene 3 (ETV3), mRNA
NM_005241 Homo sapiens ecotropic viral integration site 1 (EVI1), mRNA
NM 005250 Homo sapiens forkhead box L1 (FOXL1), mRNA
NM 005272 Homo sapiens guanine nucleotide binding protein (G protein), alpha
transduc
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NM 005278 Homo Sapiens glycoprotein M6B (GPM6B), transcript variant 3, mRNA
NM 005349 Homo sapiens recombining binding protein suppressor of hairless
(Drosophil
NM_005376 Homo sapiens v-myc myelocytomatosis viral oncogene homolog 1, lung
carc
NM_005407 Homo sapiens sal-like 2 (Drosophila) (SALL2), mRNA
NM_005482 Homo sapiens phosphatidylinositol glycan, class K (PIGK), mRNA
NM_005487 Homo sapiens high-mobility group protein 2-like 1 (HMG2L1), mRNA
NM 005533 Homo sapiens interferon-induced protein 35 (1F135), mRNA
NM 005559 Homo Sapiens laminin, alpha 1 (LAMA1 ), mRNA
NM 005595 Homo sapiens nuclear factor I/A (NFIA), mRNA
NM 005650 Homo sapiens transcription factor 20 (AR1 ) (TCF20), transcript
variant 1, mF
NM 005669 Homo sapiens chromosome 5 open reading frame 18 (C5orf18), mRNA
NM_005680 Homo sapiens TATA box binding protein (TBP)-associated factor, RNA
polyn
NM 005702 Homo sapiens Era G-protein-like 1 (E. colt) (ERAL1), mRNA
NM_005707 Homo sapiens programmed cell death 7 (PDCD7), mRNA
NM_005779 Homo sapiens lipoma HMGIC fusion partner-like 2 (LHFPL2), mRNA
NM_005788 Homo sapiens HMT1 hnRNP methyltransferase-like 3 (S. cerevisiae)
(HRMT
NM_005791 Homo sapiens M-phase phosphoprotein 10 (U3 small nucleolar
ribonucleopn
NM_005840 Homo sapiens sprouty homolog 3 (Drosophila) (SPRY3), mRNA
NM_005841 Homo sapiens sprouty homolog 1, antagonist of FGF signaling
(Drosophila) a
NM_005848 Homo sapiens c-myc promoter binding protein (MYCPBP), mRNA
NM_005914 Homo Sapiens MCM4 minichromosome maintenance deficient 4 (S.
cerevisi~
NM_005942 Homo sapiens molybdenum cofactor synthesis 1 (MOCS1 ), transcript
variant
NM_005943 Homo sapiens molybdenum cofactor synthesis 1 (MOCS1), transcript
variant
NM_005946 Homo sapiens metallothionein 1A (functional) (MT1A), mRNA
NM_005947 Homo sapiens metallothionein 1 B (functional) (MT1 B), mRNA
NM_005949 Homo sapiens metallothionein 1 F (functional) (MT1 F), mRNA
NM_005964 Homo Sapiens myosin, heavy polypeptide 10, non-muscle (MYH10), mRNA
NM_005984 Homo sapiens solute carrier family 25 (mitochondria) carrier;
citrate transport
NM_005995 Homo sapiens T-box 10 (TBX10), mRNA
NM_006036 Homo sapiens putative prolyl oligopeptidase (KIAA0436), mRNA
NM_006040 Homo sapiens heparin sulfate (glucosamine) 3-O-sulfotransferase 4
(HS3Sl
NM_006062 Homo sapiens SMYD family member 5 (SMYDS), mRNA
NM_006091 Homo sapiens coronin, actin binding protein, 2B (COR02B), mRNA
NM_006108 Homo sapiens spondin 1, extracellular matrix protein (SPON1), mRNA
NM_006133 Homo sapiens chromosome 11 open reading frame 11 (C11orf11), mRNA
NM_006151 Homo sapiens lactoperoxidase (LPO), mRNA
NM_006154 Homo Sapiens neural precursor cell expressed, developmentally down-
reguh
NM_006172 Homo sapiens natriuretic peptide precursor A (NPPA), mRNA
NM_006175 Homo Sapiens nebulin-related anchoring protein (NRAP), transcript
variant 1
NM_006210 Homo sapiens paternally expressed 3 (PEG3), mRNA
NM_006216 Homo sapiens serine (or cysteine) proteinase inhibitor, Glade E
(nexin, plasn-
NM_006266 Homo sapiens rat guanine nucleotide dissociation stimulator
(RALGDS), mRl
NM_006277 Homo sapiens intersectin 2 (ITSN2), transcript variant 1, mRNA
NM_006452 Homo sapiens phosphoribosylaminoimidazole carboxylase,
phosphoribosyla
NM 006524 Homo sapiens zinc finger protein 138 (clone pHZ-32) (ZNF138), mRNA
NM 006591 Homo sapiens polymerise (DNA-directed), delta 3, accessory subunit
(POLC
NM 006617 Homo sapiens nestin (NES), mRNA
NM_006630 Homo sapiens zinc finger protein 234 (ZNF234), mRNA
NM_006631 Homo sapiens zinc finger protein 266 (ZNF266), mRNA
NM_006635 Homo sapiens zinc finger protein 272 (ZNF272), mRNA
NM_006642 Homo sapiens serologically defined colon cancer antigen 8 (SDCCAG8),
mR
NM_006647 Homo sapiens NADPH oxidise activator 1 (NOXA1), mRNA
NM_006673 Homo Sapiens AT rich interactive domain 5A (MRF1-like) (ARIDSA),
transcriC
NM_006714 Homo sapiens sphingomyelin phosphodiesterase, acid-like 3A
(SMPDL3A), t
NM_006722 Homo sapiens microphthalmia-associated transcription factor (MITF),
transcr
NM_006742 Homo sapiens protein serine kinase H1 (PSKH1), mRNA
NM_006775 Homo sapiens quaking homolog, KH domain RNA binding (mouse) (QKI),
try
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NM_006828 Homo sapiens activating signal cointegrator 1 complex subunit 3
(ASCC3), n
NM_006832 Homo sapiens pleckstrin homology domain containing, family C (with
FERM
NM_006857 Homo sapiens putative nucleic acid binding protein RY-1 (RY1), mRNA
NM_006859 Homo sapiens lipoic acid synthetase (LIAS), nuclear gene encoding
mitocho
NM_006897 Homo Sapiens homeo box C9 (HOXC9), mRNA
NM_006909 Homo sapiens Ras protein-specific guanine nucleotide-releasing
factor 2 (Rf
NM_006916 Homo sapiens ribulose-5-phosphate-3-epimerase (RPE), transcript
variant 2.
NM_006920 Homo sapiens sodium channel, voltage-gated, type I, alpha (SCN1A),
mRNP
NM_006939 Homo sapiens son of sevenless homolog 2 (Drosophila) (SOS2), mRNA
NM_006955 Homo sapiens zinc finger protein 11 b (KOX 2) (ZNF11 B), mRNA
NM_006956 Homo sapiens zinc finger protein 12 (KOX 3) (ZNF12), mRNA
NM_006959 Homo sapiens zinc finger protein 17 (HPF3, KOX 10) (ZNF17), mRNA
NM_006961 Homo sapiens zinc finger protein 19 (KOX 12) (ZNF19), mRNA
NM_006969 Homo sapiens zinc finger protein 28 (KOX 24) (ZNF28), mRNA
NM_006973 Homo sapiens zinc finger protein 32 (KOX 30) (ZNF32), mRNA
NM_006974 Homo sapiens zinc finger protein 33a (KOX 31 ) (ZNF33A), mRNA
NM_006996 Homo sapiens solute carrier family 19 (thiamine transporter), member
2 (SLC
NM_007001 Homo sapiens solute carrier family 35, member D2 (SLC35D2), mRNA
NM_007010 Homo sapiens DEAD (Asp-Glu-Ala-Asp) box polypeptide 52 (DDX52),
transc
NM_007041 Homo sapiens arginyltransferase 1 (ATE1), transcript variant 2, mRNA
NM_007078 Homo sapiens LIM domain binding 3 (LDB3), mRNA
NM_007130 Homo sapiens zinc finger protein 41 (ZNF41), transcript variant 1,
mRNA
NM_007131 Homo sapiens zinc finger protein 75 (D8C6) (ZNF75), mRNA
NM_007135 Homo sapiens zinc finger protein 79 (pT7) (ZNF79), mRNA
NM_007137 Homo sapiens zinc finger protein 81 (HFZ20) (ZNF81 ), mRNA
NM_007139 Homo sapiens zinc finger protein 92 (HTF12) (ZNF92), mRNA
NM_007149 Homo sapiens zinc finger protein 184 (Kruppel-like) (ZNF184), mRNA
NM_007156 Homo Sapiens zinc finger, X-linked, duplicated A (ZXDA), mRNA
NM_007157 Homo sapiens zinc finger, X-linked, duplicated B (ZXDB), mRNA
NM_007162 Homo sapiens transcription factor EB (TFEB), mRNA
NM_007174 Homo Sapiens citron (rho-interacting, serine/threonine kinase 21)
(CIT), mRf~
NM_007189 Homo sapiens ATP-binding cassette, sub-family F (GCN20), member 2
(ABC
NM_007224 Homo Sapiens neurexophilin 4 (NXPH4), mRNA
NM_007225 Homo sapiens neurexophilin 3 (NXPH3), mRNA
NM_007243 Homo sapiens nurim (nuclear envelope membrane protein) (NRM), mRNA
NM_007261 Homo Sapiens leukocyte membrane antigen (CMRF-35H), mRNA
NM_007270 Homo sapiens FK506 binding protein 9, 63 kDa (FKBP9), mRNA
NM_007277 Homo Sapiens SEC6-like 1 (S. cerevisiae) (SEC6L1), mRNA
NM_007280 Homo sapiens Opa-interacting protein 5 (DIPS), mRNA
NM_007349 Homo sapiens PAX transcription activation domain interacting protein
1 like
NM_007356 Homo sapiens laminin, beta 4 (LAMB4), mRNA
NM_012073 Homo sapiens chaperonin containing TCP1, subunit 5 (epsilon) (CCTS),
mRl
NM_012154 Homo sapiens eukaryotic translation initiation factor 2C, 2
(EIF2C2), mRNA
NM_012156 Homo sapiens erythrocyte membrane protein band 4.1-like 1 (EPB41L1),
trai
NM_012167 Homo sapiens F-box protein 11 (FBX011 ), transcript variant 3, mRNA
NM_012174 Homo sapiens F-box and WD-40 domain protein 8 (FBXWB), transcript
varia
NM_012184 Homo Sapiens forkhead box D4 like 1 (FOXD4L1), mRNA
NM_012212 Homo sapiens leukotriene B4 12-hydroxydehydrogenase (LTB4DH), mRNA
NM_012224 Homo sapiens NIMA (never in mitosis gene a)-related kinase 1 (NEK1
), mR~
NM_012232 Homo Sapiens polymerase I and transcript release factor (PTRF), mRNA
NM_012235 Homo sapiens SREBP CLEAVAGE-ACTIVATING PROTEIN (SCAP), mRNA
NM_012271 Homo sapiens huntingtin interacting protein B (HYPE), transcript
variant 2, rr
NM_012272 Homo sapiens Huntingtin interacting protein C (HYPC), mRNA
NM_012284 Homo sapiens potassium voltage-gated channel, subfamily H (eag-
related), i
NM_012292 Homo sapiens minor histocompatibility antigen HA-1 (HA-1), mRNA
NM 012305 Homo sapiens adaptor-related protein complex 2, alpha 2 subunit
(AP2A2), r
NM 012309 Homo sapiens SH3 and multiple ankyrin repeat domains 2 (SHANK2),
transc
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NM_012315 Homo sapiens kallikrein 9 (KLK9), mRNA
NM_012335 Homo sapiens myosin IF (MY01 F), mRNA
NM_012363 Homo sapiens olfactory receptor, family 1, subfamily N, member 1
(OR1N1),
NM 012364 Homo Sapiens olfactory receptor, family 1, subfamily Q, member 1
(OR1Q1),
NM_012367 Homo sapiens olfactory receptor, family 2, subfamily B, member 6
(OR2B6),
NM_012374 Homo sapiens olfactory receptor, family 4, subfamily D, member 1
(OR4D1 ),
NM_012378 Homo sapiens olfactory receptor, family 8, subfamily B, member 8
(OR8B8),
NM 012393 Homo sapiens phosphoribosylformylglycinamidine synthase (FGAR
amidotr2
NM_012398 Homo sapiens phosphatidylinositol-4-phosphate 5-kinase, type I,
gamma (PI
NM_012416 Homo sapiens RAN binding protein 6 (RANBP6), mRNA
NM_012477 Homo sapiens WW domain binding protein 1 (WBP1), mRNA
NM 012478 Homo sapiens WW domain binding protein 2 (WBP2), mRNA
NM_013304 Homo Sapiens zinc finger, DHHC domain containing 1 (ZDHHC1 ), mRNA
NM_013321 Homo sapiens sorting nexin 8 (SNXB), mRNA
NM_013373 Homo sapiens zinc finger, DHHC domain containing 8 (ZDHHCB), mRNA
NM_014010 Homo sapiens astrotactin 2 (ASTN2), transcript variant 1, mRNA
NM 014014 Homo sapiens U5 snRNP-specific protein, 200-KD (U5-200KD), mRNA
NM_014089 Homo sapiens nucleoporin like 1 (NUPL1), mRNA
NM_014098 Homo sapiens peroxiredoxin 3 (PRDX3), nuclear gene encoding
mitochondri
NM_014215 Homo sapiens insulin receptor-related receptor (INSRR), mRNA
NM_014220 Homo sapiens transmembrane 4 superfamily member 1 (TM4SF1 ), mRNA
NM_014224 Homo sapiens pepsinogen 5, group I (pepsinogen A) (PGA5), mRNA
NM_014243 Homo sapiens a disintegrin-like and metalloprotease (reprolysin
type) with th
NM_014261 Homo Sapiens TIR domain containing adaptor inducing interferon-beta
(TRIF
NM_014282 Homo sapiens hyaluronan binding protein 4 (HABP4), mRNA
NM_014284 Homo sapiens neurochondrin (NCDN), mRNA
NM_014290 Homo sapiens tudor domain containing 7 (TDRD7), mRNA
NM_014301 Homo sapiens iron-sulfur cluster assembly enzyme (ISCU), mRNA
NM_014346 Homo Sapiens chromosome 22 open reading frame 4 (C22orf4), mRNA
NM_014376 Homo sapiens cytoplasmic FMR1 interacting protein 2 (CYFIP2), mRNA
NM_014381 Homo sapiens mutt homolog 3 (E. coli) (MLH3), mRNA
NM_014389 Homo sapiens proline-, glutamic acid-, leucine-rich protein 1
(PELP1), mRN~
NM_014422 Homo sapiens phosphatidylinositol (4,5) bisphosphate 5-phosphatase,
A (P11
NM 014435 Homo sapiens N-acylsphingosine amidohydrolase (acid ceramidase)-like
(A;
NM_014441 Homo sapiens sialic acid binding Ig-like lectin 9 (SIGLEC9), mRNA
NM_014455 Homo sapiens zinc finger protein 364 (ZNF364), mRNA
NM_014460 Homo Sapiens RNA-binding protein pippin (PIPPIN), mRNA
NM_014472 Homo sapiens chromosome 10 open reading frame 28 (C10orf28), mRNA
NM_014494 Homo sapiens trinucleotide repeat containing 6 (TNRC6), mRNA
NM_014507 Homo sapiens malonyl-CoA:acyl carrier protein transacylase
(malonyltransfe
NM 014508 Homo sapiens apolipoprotein B mRNA editing enzyme, catalytic
polypeptide-
NM_014510 Homo sapiens piccolo (presynaptic cytomatrix protein) (PCLO),
transcript var
NM_014562 Homo Sapiens orthodenticle homolog 1 (Drosophila) (OTX1), mRNA
NM_014568 Homo sapiens UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-
acetylga
NM 014572 Homo sapiens LATS, large tumor suppressor, homolog 2 (Drosophila)
(LAT.
NM_014573 Homo sapiens hypothetical protein MAC30 (MAC30), mRNA
NM_014594 Homo sapiens zinc finger protein 354C (ZNF354C), mRNA
NM 014602 Homo sapiens phosphoinositide-3-kinase, regulatory subunit 4, p150
(PIK3R
NM_014603 Homo sapiens paraneoplastic antigen (HUMPPA), mRNA
NM_014607 Homo sapiens UBX domain containing 2 (UBXD2), mRNA
NM 014608 Homo Sapiens cytoplasmic FMR1 interacting protein 1 (CYFIP1 ), mRNA
NM_014611 Homo Sapiens MDN1, midasin homolog (yeast) (MDN1), mRNA
NM_014613 Homo Sapiens expressed in T-cells and eosinophils in atopic
dermatitis (ETE
NM 014614 Homo sapiens proteasome (prosome, macropain) activator subunit 4
(PSME
NM_014615 Homo sapiens KIAA0182 protein (KIAA0182), mRNA
NM_014647 Homo Sapiens limkain b1 (LKAP), transcript variant 1, mRNA
NM 014655 Homo Sapiens KIAA0446 gene product (KIAA0446), mRNA
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NM_014657 Homo sapiens KIAA0406 gene product (KIAA0406), mRNA
NM_014667 Homo sapiens vestigial like 4 (Drosophila) (VGLL4), mRNA
NM_014691 Homo sapiens aquarius homolog (mouse) (AQR), mRNA
NM 014697 Homo sapiens C-terminal PDZ domain ligand of neuronal nitric oxide
synths:
NM 014701 Homo sapiens KIAA0256 gene product (KIAA0256), mRNA
NM_014756 Homo sapiens KIAA0097 gene product (ch-TOG), mRNA
NM_014798 Homo sapiens pleckstrin homology domain containing, family M (with
RUN d
NM_014802 Homo sapiens KIAA0528 gene product (KIAA0528), mRNA
NM_014836 Homo sapiens Rho-related BTB domain containing 1 (RHOBTB1),
transcript
NM_014839 Homo sapiens plasticity related gene 1 (LPPR4), mRNA
NM_014850 Homo Sapiens SLIT-ROBO Rho GTPase activating protein 2 (SRGAP2), mR
NM_014854 Homo sapiens solute carrier family 35, member E2 (SLC35E2), mRNA
NM_014858 Homo sapiens cerebral protein 11 (HUCEP11), mRNA
NM_014881 Homo sapiens DNA cross-link repair 1A (PS02 homolog, S. cerevisiae)
(DCl
NM 014884 Homo sapiens splicing factor, arginine/serine-rich 14 (SFRS14), mRNA
NM_014919 Homo sapiens Wolf Hirschhorn syndrome candidate 1 (WHSC1),
transcript ~
NM_014955 Homo sapiens CGI-01 protein (CGI-01 ), transcript variant 2, mRNA
NM_014957 Homo sapiens KIAA0870 protein (KIAA0870), mRNA
NM 014974 Homo sapiens KIAA0934 (KIAA0934), mRNA
NM 014975 Homo sapiens microtubule associated serine/threonine kinase 1
(MAST1), rr
NM_014982 Homo sapiens pecanex homolog (Drosophila) (PCNX), mRNA
NM_014989 Homo Sapiens regulating synaptic membrane exocytosis 1 (RIMS1),
transcril
NM_014991 Homo sapiens WD repeat and FYVE domain containing 3 (WDFY3),
transcri
NM_014992 Homo sapiens dishevelled associated activator of morphogenesis 1
(DAAM1
NM_014997 Homo sapiens KIAA0265 protein (KIAA0265), mRNA
NM_015000 Homo sapiens serine/threonine kinase 38 like (STK38L), mRNA
NM_015004 Homo sapiens exosome component 7 (EXOSC7), mRNA
NM_015008 Homo sapiens KIAA0779 protein (KIAA0779), mRNA
NM_015013 Homo sapiens amine oxidase (flavin containing) domain 2 (AOF2), mRNA
NM_015014 Homo sapiens KIAA0117 protein (KIAA0117), mRNA
NM_015015 Homo sapiens jumonji domain containing 2B (JMJD2B), mRNA
NM_015017 Homo sapiens ubiquitin specific protease 33 (USP33), transcript
variant 1, m
NM_015018 Homo sapiens KIAA1117 (KIAA1117), mRNA
NM_015022 Homo sapiens PDZ domain containing 3 (PDZK3), transcript variant 2,
mRNi
NM_015027 Homo sapiens KIAA0251 protein (KIAA0251), mRNA
NM_015029 Homo sapiens processing of precursor 1, ribonuclease P/MRP subunit
(S. ce
NM_015033 Homo sapiens formin binding protein 1 (FNBP1), mRNA
NM_015035 Homo sapiens zinc fingers and homeoboxes 3 (ZHX3), mRNA
NM_015037 Homo sapiens KIAA0913 (KIAA0913), mRNA
NM_015039 Homo sapiens nicotinamide nucleotide adenylyltransferase 2 (NMNAT2),
trar
NM_015040 Homo Sapiens phosphatidylinositol-3-phosphate/phosphatidylinositol 5-
kings
NM_015045 Homo sapiens KIAA0261 (KIAA0261), mRNA
NM_015047 Homo Sapiens KIAA0090 protein (KIAA0090), mRNA
NM_015050 Homo sapiens KIAA0082 (KIAA0082), mRNA
NM_015052 Homo sapiens HECT type E3 ubiquitin ligase (NEDL1 ), mRNA
NM_015055 Homo sapiens SWAP-70 protein (SWAP70), mRNA
NM_015059 Homo sapiens talin 2 (TLN2), mRNA
NM_015061 Homo sapiens jumonji domain containing 2C (JMJD2C), mRNA
NM_015065 Homo sapiens SLAC2-B (SLAC2-B), mRNA
NM 015066 Homo sapiens tripartite motif-containing 35 (TRIM35), transcript
variant 1, ml
NM 015069 Homo Sapiens zinc finger protein 423 (ZNF423), mRNA
NM_015076 Homo Sapiens cyclin-dependent kinase (CDC2-like) 11 (CDK11), mRNA
NM_015078 Homo Sapiens Rho family guanine-nucleotide exchange factor (KIAA0861
), r
NM_015079 Homo sapiens KIAA1055 protein (KIAA1055), mRNA
NM_015085 Homo sapiens GTPase activating RANGAP domain-like 4 (GARNL4), mRNA
NM_015087 Homo sapiens spastic paraplegia 20, spartin (Troyer syndrome)
(SPG20), ml
NM_015089 Homo sapiens p53-associated parkin-like cytoplasmic protein (PARC),
mRN~
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NM_015091 Homo Sapiens KIAA0423 (KIAA0423), mRNA
NM 015094 Homo sapiens hypermethylated in cancer 2 (HIC2), mRNA
NM 015099 Homo sapiens calmodulin binding transcription activator 2 (CAMTA2),
mRNP
NM_015100 Homo sapiens pogo transposable element with ZNF domain (POGZ),
transcr
NM_015102 Homo sapiens nephronophthisis 4 (NPHP4), mRNA
NM_015103 Homo Sapiens plexin D1 (PLXND1), mRNA
NM_015106 Homo sapiens KIAA0809 protein (SRISNF2L), mRNA
NM_015107 Homo sapiens PHD finger protein 8 (PHFB), mRNA
NM_015110 Homo Sapiens SMC5 structural maintenance of chromosomes 5-like 1
(yeast
NM_015115 Homo sapiens KIAA0276 protein (KIAA0276), mRNA
NM_015116 Homo sapiens leucine-rich repeats and calponin homology (CH) domain
con'
NM_015117 Homo sapiens zinc finger CCCH type domain containing 3 (ZC3HDC3),
mR~
NM_015120 Homo sapiens Alstrom syndrome 1 (ALMS1), mRNA
NM_015122 Homo sapiens FCH domain only 1 (FCH01), mRNA
NM_015134 Homo sapiens myosin phosphatase-Rho interacting protein (M-RIP),
mRNA
NM_015138 Homo sapiens KIAA0252 (KIAA0252), mRNA
NM_015141 Homo sapiens glycerol-3-phosphate dehydrogenase 1-like (GPD1 L),
mRNA
NM_015143 Homo sapiens methionyl aminopeptidase 1 (METAP1), mRNA
NM_015144 Homo sapiens zinc finger, CCHC domain containing 14 (ZCCHC14), mRNA
NM_015150 Homo sapiens raft-linking protein (RAFTLIN), mRNA
NM_015151 Homo sapiens chromosome 21 open reading frame 106 (C21orf106),
transcr
NM_015157 Homo Sapiens pleckstrin homology-like domain, family B, member 1
(PHLDE
NM_015158 Homo sapiens ankyrin repeat domain 15 (ANKRD15), transcript variant
1, ml
NM_015160 Homo sapiens peptidase (mitochondria) processing) alpha (PMPCA),
nuclear
NM_015161 Homo sapiens ADP-ribosylation factor-like 6 interacting protein
(ARL61P), mf
NM_015167 Homo Sapiens phosphatidylserine receptor (PTDSR), mRNA
NM_015170 Homo sapiens sulfatase 1 (SULF1 ), mRNA
NM_015171 Homo Sapiens exportin 6 (XP06), mRNA
NM_015172 Homo sapiens HBxAg transactivated protein 2 (XTP2), mRNA
NM_015173 Homo sapiens TBC1 (tre-2/USP6, BUB2, cdc16) domain family, member 1
(1
NM_015184 Homo Sapiens phospholipase C-like 2 (PLCL2), mRNA
NM_015187 Homo Sapiens KIAA0746 protein (KIAA0746), mRNA
NM_015190 Homo sapiens DnaJ (Hsp40) homolog, subfamily C, member 9 (DNAJC9), m
NM 015191 Homo sapiens salt-inducible serinelthreonine kinase 2 (SIK2), mRNA
NM 015198 Homo sapiens cordon-bleu homolog (mouse) (COBL), mRNA
NM_015199 Homo sapiens ankyrin repeat domain 28 (ANKRD28), mRNA
NM_015200 Homo sapiens KIAA0648 protein (KIAA0648), mRNA
NM 015201 Homo sapiens block of proliferation 1 (BOP1), mRNA
NM_015203 Homo sapiens KIAA0460 protein (KIAA0460), mRNA
NM_015210 Homo sapiens KIAA0802 (KIAA0802), mRNA
NM_015213 Homo sapiens RAB6 interacting protein 1 (RAB61P1), mRNA
NM_015219 Homo sapiens exocyst complex component 7 (EXOC7), mRNA
NM_015221 Homo sapiens dynamin binding protein (DNMBP), mRNA
NM_015229 Homo sapiens KIAA0664 protein (KIAA0664), mRNA
NM_015234 Homo Sapiens G protein-coupled receptor 116 (GPR116), mRNA
NM_015238 Homo sapiens KIBRA protein (KIBRA), mRNA
NM_015243 Homo sapiens Cohen syndrome 1 (COH1), transcript variant 3, mRNA
NM_015245 Homo sapiens ankyrin repeat and sterile alpha motif domain
containing 1 (A~
NM_015246 Homo sapiens mahogunin, ring finger 1 (MGRN1), mRNA
NM_015250 Homo sapiens bicaudal D homolog 2 (Drosophila) (BICD2), mRNA
NM_015252 Homo sapiens NPF/calponin-like protein (NACSIN), mRNA
NM 015255 Homo sapiens chromosome 6 open reading frame 133 (C6orf133), mRNA
NM_015259 Homo Sapiens inducible T-cell co-stimulator ligand (ICOSL), mRNA
NM_015261 Homo sapiens KIAA0056 protein (KIAA0056), mRNA
NM_015263 Homo sapiens rabconnectin-3 (RC3), mRNA
NM_015265 Homo sapiens SATB family member 2 (SATB2), mRNA
NM 015266 Homo sapiens solute carrier family 9 (sodium/hydrogen exchanger),
isoform
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NM 015268 Homo sapiens DnaJ (Hsp40) homolog, subfamily C, member 13 (DNAJC13);
NM 015274 Homo Sapiens mannosidase, alpha, class 2B, member 2 (MAN2B2), mRNA
NM 015275 Homo Sapiens KIAA1033 protein (KIAA1033), mRNA
NM_015278 Homo sapiens SAM and SH3 domain containing 1 (SASH1), mRNA
NM_015281 Homo sapiens KIAA1043 protein (KIAA1043), mRNA
NM_015282 Homo sapiens cytoplasmic linker associated protein 1 (CLASP1 ), mRNA
NM_015284 Homo sapiens KIAA0467 protein (KIAA0467), mRNA
NM_015286 Homo sapiens desmuslin (DMN), transcript variant B, mRNA
NM_015289 Homo sapiens vacuolar protein sorting 39 (yeast) (VPS39), mRNA
NM_015293 Homo sapiens spectrin repeat containing, nuclear envelope 1 (SYNE1
), tran;
NM_015296 Homo sapiens dedicator of cytokinesis 9 (DOCKS), mRNA
NM 015305 Homo sapiens KIAA0759 (KIAA0759), mRNA
NM_015308 Homo sapiens formin binding protein 4 (FNBP4), mRNA
NM 015315 Homo sapiens likely ortholog of mouse la related protein (LARP),
mRNA
NM_015316 Homo sapiens protein phosphatase 1, regulatory (inhibitor) subunit
13B (PPF
NM 015319 Homo sapiens tensin like C1 domain containing phosphatase (TENC1),
tran:
NM_015321 Homo sapiens mucoepidermoid carcinoma translocated 1 (MECT1 ), mRNA
NM_015323 Homo sapiens KIAA0776 (KIAA0776), mRNA
NM_015327 Homo Sapiens Est1p-like protein B (EST1B), mRNA
NM_015328 Homo sapiens KIAA0828 protein (KIAA0828), mRNA
NM 015329 Homo sapiens KIAA0892 (KIAA0892), mRNA
NM_015330 Homo Sapiens KIAA0376 protein (KIAA0376), mRNA
NM 015331 Homo sapiens nicastrin (NCSTN), mRNA
NM_015335 Homo sapiens thyroid hormone receptor associated protein 2 (THRAP2),
mF
NM_015336 Homo sapiens zinc finger, DHHC domain containing 17 (ZDHHC17), mRNA
NM 015338 Homo sapiens additional sex combs like 1 (Drosophila) (ASXL1 ), mRNA
NM_015341 Homo sapiens barren homolog (Drosophila) (BRRN1), mRNA
NM 015342 Homo sapiens KIAA0073 protein (KIAA0073), mRNA
NM_015345 Homo sapiens dishevelled associated activator of morphogenesis 2
(DAAM2
NM_015346 Homo sapiens zinc finger, FYVE domain containing 26 (ZFYVE26), mRNA
NM_015347 Homo Sapiens RIM binding protein 2 (KIAA0318), mRNA
NM_015350 Homo sapiens T-cell activation leucine repeat-rich protein (TA-
LRRP), mRN,~
NM_015352 Homo sapiens protein O-fucosyltransferase 1 (POFUT1), transcript
variant 1,
NM_015358 Homo Sapiens zinc finger, CW-type with coiled-coil domain 3
(ZCWCC3), mF
NM_015359 Homo Sapiens solute carrier family 39 (zinc transporter), member 14
(SLC39
NM_015360 Homo sapiens KIAA0052 (KIAA0052), mRNA
NM_015374 Homo sapiens unc-84 homolog B (C. elegans) (UNC84B), mRNA
NM 015375 Homo sapiens receptor interacting protein kinase 5 (RIPKS),
transcript variar
NM_015378 Homo sapiens vacuolar protein sorting 13D (yeast) (VPS13D), mRNA
NM_015381 Homo Sapiens TAFA protein 5 (TAFAS), mRNA
NM 015382 Homo sapiens HECT domain containing 1 (HECTD1), mRNA
NM_015386 Homo sapiens component of oligomeric golgi complex 4 (COG4), mRNA
NM 015391 Homo Sapiens anaphase promoting complex subunit 13 (ANAPC13), mRNA
NM_015395 Homo sapiens DKFZP434B0335 protein (DKFZP434B0335), mRNA
NM 015397 Homo Sapiens WD repeat domain 40A (WDR40A), mRNA
NM_015404 Homo Sapiens deafness, autosomal recessive 31 (DFNB31), mRNA
NM_015411 Homo sapiens sulfatase modifying factor 2 (SUMF2), mRNA
NM 015412 Homo sapiens DKFZP434F2021 protein (DKFZP434F2021), mRNA
NM_015430 Homo sapiens regeneration associated muscle protease (DKFZP586H2123)
NM 015431 Homo sapiens BIA2 (BIA2), mRNA
NM_015433 Homo sapiens hepatocellularcarcinoma-associated antigen HCA557a
(DKFz
NM_015436 Homo Sapiens ring finger and CHY zinc finger domain containing 1
(RCHY1 )
NM_015439 Homo sapiens chromosome 6 open reading frame 80 (Ctiorf80), mRNA
NM_015440 Homo sapiens formyltetrahydrofolate synthetase domain containing 1
(FTHF
NM_015441 Homo sapiens olfactomedin-like 2B (OLFML2B), mRNA
NM_015443 Homo sapiens hypothetical protein LOC284058 (LOC284058), mRNA
NM 015444 Homo sapiens Ras-induced senescence 1 (RIS1), mRNA
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NM 015446 Homo sapiens ELYS transcription factor-like protein TMBS62 (ELYS),
mRNA
NM_015447 Homo sapiens calmodulin regulated spectrin-associated protein 1
(CAMSAP
NM_015448 Homo sapiens deleted in a mouse model of primary ciliary dyskinesia
(DPCC
NM_015457 Homo sapiens zinc finger, DHHC domain containing 5 (ZDHHCS), mRNA
NM_015459 Homo sapiens DKFZP564J0863 protein (DKFZP564J0863), mRNA
NM_015460 Homo sapiens myosin VIIA and Rab interacting protein (MYRIP), mRNA
NM_015461 Homo sapiens zinc finger protein 521 (ZNF521 ), mRNA
NM_015463 Homo sapiens chromosome 2 open reading frame 32 (C2orf32), mRNA
NM_015464 Homo sapiens sclerostin domain containing 1 (SOSTDC1), mRNA
NM 015465 Homo sapiens gem (nuclear organelle) associated protein 5 (GEMINS),
mR~
NM 015466 Homo sapiens protein tyrosine phosphatase, non-receptor type 23
(PTPN23;
NM_015469 Homo sapiens nipsnap homolog 3A (C, elegans) (NIPSNAP3A), mRNA
NM_015470 Homo sapiens RAB11 family interacting protein 5 (class I)
(RAB11FIP5), mR
NM_015475 Homo sapiens DKFZP564F0522 protein (DKFZP564F0522), mRNA
NM_015476 Homo sapiens chromosome 18 open reading frame 10 (C18orF10), mRNA
NM 015477 Homo sapiens SIN3 homolog A, transcriptional regulator (yeast)
(SIN3A), mF
NM 015481 Homo sapiens zinc finger protein 385 (ZNF385), mRNA
NM 015483 Homo Sapiens ketch repeat and BTB (POZ) domain containing 2
(KBTBD2),
NM_015488 Homo sapiens myofibrillogenesis regulator 1 (MR-1), mRNA
NM_015503 Homo sapiens SH2-B homolog (SH2B), mRNA
NM_015508 Homo sapiens TCDD-inducible poly(ADP-ribose) polymerase (TIPARP),
mRl
NM_015518 Homo sapiens DKFZP434C131 protein (DKFZP434C131), mRNA
NM_015522 Homo sapiens dynein 2 light intermediate chain (D2LIC), transcript
variant 2,
NM_015529 Homo sapiens monooxygenase, DBH-like 1 (MOXD1), mRNA
NM_015531 Homo sapiens DKFZP586P0123 protein (DKFZP586P0123), mRNA
NM_015532 Homo sapiens glutamate receptor, ionotropic, N-methyl D-aspartate-
like 1A
NM_015534 Homo Sapiens zinc finger, ZZ domain containing 3 (ZZZ3), mRNA
NM 015541 Homo sapiens leucine-rich repeats and immunoglobulin-like domains 1
(LRI(
NM 015547 Homo sapiens thioesterase, adipose associated (THEA), transcript
variant 1,
NM_015548 Homo sapiens dystonin (DST), transcript variant 1eA, mRNA
NM_015553 Homo sapiens phosphoinositide-binding protein PIP3-E (PIP3-E), mRNA
NM_015555 Homo sapiens zinc finger protein 451 (ZNF451 ), mRNA
NM_015557 Homo sapiens chromodomain helicase DNA binding protein 5 (CHDS),
mRN,
NM_015558 Homo sapiens synovial sarcoma translocation gene on chromosome 18-
like
NM_015560 Homo Sapiens optic atrophy 1 (autosomal dominant) (OPA1 ), nuclear
gene a
NM_015565 Homo sapiens zinc finger protein 294 (ZNF294), mRNA
NM_015567 Homo sapiens SLIT and NTRK-like family, member 5 (SLITRKS), mRNA
NM_015568 Homo sapiens protein phosphatase 1, regulatory (inhibitor) subunit
16B (PPF
NM_015569 Homo sapiens dynamin 3 (DNM3), mRNA
NM_015575 Homo sapiens trinucleotide repeat containing 15 (TNRC15), mRNA
NM_015576 Homo sapiens CAZ-associated structural protein (CAST), mRNA
NM_015578 Homo sapiens chromosome 19 open reading frame 13 (C19orf13), mRNA
NM_015585 Homo sapiens chromosome 20 open reading frame 26 (C20orf26), mRNA
NM_015589 Homo sapiens sterile alpha motif domain containing 4 (SAMD4), mRNA
NM_015597 Homo Sapiens G-protein signalling modulator 1 (AGS3-like, C.
elegans) (GP;
NM_015600 Homo Sapiens chromosome 20 open reading frame 22 (C20ort22), mRNA
NM_015602 Homo sapiens lamina-associated polypeptide 1 B (LAP1 B), mRNA
NM_015604 Homo sapiens WD repeat domain 21 (WDR21), transcript variant 1, mRNA
NM_015605 Homo sapiens DKFZP566K0524 protein (DKFZP566K0524), mRNA
NM 015608 Homo sapiens chromosome 10 open reading frame 137 (C10orf137), mRNA
NM 015609 Homo sapiens putative MAPK activating protein PM20,PM21 (DKFZp566C04
NM_015617 Homo sapiens pygopus 1 (PYG01), mRNA
NM_015627 Homo sapiens LDL receptor adaptor protein (ARH), mRNA
NM_015631 Homo sapiens chromosome 10 open reading frame 61 (C10orf61), mRNA
NM_015633 Homo sapiens FGFR1 oncogene partner 2 (FGFR1 OP2), mRNA
NM 015634 Homo sapiens KIAA1279 (KIAA1279), mRNA
NM 015635 Homo sapiens DKFZP434C212 protein (DKFZP434C212), mRNA
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NM 015639 Homo sapiens GTPase activating RANGAP domain-like 2 pseudogene (GAF
NM 015649 Homo sapiens interferon regulatory factor 2 binding protein 1
(IRF2BP1 ), mF<
NM_015655 Homo sapiens zinc finger protein 337 (ZNF337), mRNA
NM_015659 Homo sapiens DKFZP564M182 protein (DKFZP564M182), mRNA
NM_015660 Homo sapiens immunity associated protein 2 (HIMAP2), mRNA
NM 015662 Homo sapiens selective LIM binding factor, rat homolog (SLB), mRNA
NM_015666 Homo sapiens GTP binding protein 5 (putative) (GTPBPS), mRNA
NM_015667 Homo sapiens chromosome 9 open reading frame 36 (C9orf36), mRNA
NM_015668 Homo sapiens DKFZP4341092 protein (DKFZP4341092), mRNA
NM 015687 Homo sapiens filamin A interacting protein 1 (FILIP1), mRNA
NM_015690 Homo sapiens serine/threonine kinase 36 (fused homolog, Drosophila)
(STK
NM_015691 Homo sapiens KIAA1280 protein (KIAA1280), mRNA
NM_015692 Homo sapiens C3 and PZP-like, alpha-2-macroglobulin domain
containing 8
NM_015693 Homo Sapiens PDZ domain containing 6 (PDZK6), mRNA
NM_015694 Homo sapiens KIAA1285 protein (KIAA1285), mRNA
NM_015713 Homo sapiens ribonucleotide reductase M2 B (TP53 inducible) (RRM2B),
mF
NM_015723 Homo sapiens intracellular membrane-associated calcium-independent
phos
NM 015905 Homo sapiens transcriptional intermediary factor 1 (TIF1 ),
transcript variant 1
NM_015979 Homo sapiens cofactor required for Sp1 transcriptional activation,
subunit 3,
NM_016105 Homo Sapiens FK506 binding protein 7 (FKBP7), transcript variant 1,
mRNA
NM_016133 Homo sapiens insulin induced gene 2 (INSIG2), mRNA
NM_016320 Homo sapiens nucleoporin 98kDa (NUP98), transcript variant 1, mRNA
NM_016544 Homo Sapiens Ras-associated protein Rap1 (RBJ), mRNA
NM_017419 Homo sapiens amiloride-sensitive cation channel 5, intestinal
(ACCNS), mR~
NM 017437 Homo Sapiens cleavage and polyadenylation specific factor 2, 100kDa
(CPSI
NM_017440 Homo sapiens nuclear protein double minute 1 (MDM1), mRNA
NM_017510 Homo sapiens gp25L2 protein (HSGP25L2G), mRNA
NM_017516 Homo sapiens RAB39, member RAS oncogene family (RAB39), mRNA
NM_017519 Homo sapiens AT rich interactive domain 1B (SW11-like) (ARID1B),
transcrip
NM_017520 Homo sapiens M-phase phosphoprotein, mpp8 (HSMPPB), mRNA
NM_017525 Homo sapiens myotonic dystrophy protein kinase like protein
(HSMDPKIN), t
NM 017527 Homo sapiens cDNA for difFerentially expressed C016 gene (LY6K),
mRNA
NM_017539 Homo sapiens dynein, axonemal, heavy polypeptide 3 (DNAH3), mRNA
NM_017549 Homo sapiens upregulated in colorectal cancer gene 1 (UCC1 ), mRNA
NM_017550 Homo sapiens KIAA1193 (KIAA1193), mRNA
NM 017553 Homo sapiens homolog of yeast IN080 (1N080), transcript variant 1,
mRNA
NM_017554 Homo sapiens KIAA1268 protein (KIAA1268), mRNA
NM_017556 Homo sapiens filamin-binding LIM protein-1 (FBLP-1), mRNA
NM 017563 Homo sapiens interleukin 17 receptor D (IL17RD), mRNA
NM_017565 Homo sapiens family with sequence similarity 20, member A (FAM20A),
mRf
NM_017570 Homo Sapiens 5-oxoprolinase (ATP-hydrolysing) (OPLAH), mRNA
NM 017573 Homo sapiens proprotein convertase subtilisin/kexin type 4 (PCSK4),
mRNA
NM_017576 Homo sapiens kinesin family member 27 (KIF27), mRNA
NM_017580 Homo sapiens zinc finger, RAN-binding domain containing 1 (ZRANB1 ),
mRl
NM 017602 Homo sapiens hypothetical protein DKFZp761A052 (DKFZp761A052), mRN~
NM_017619 Homo Sapiens U11/U12 snRNP 65K protein (FLJ25070), mRNA
NM_017628 Homo Sapiens hypothetical protein FLJ20032 (FLJ20032), mRNA
NM 017641 Homo sapiens kinesin family member 21A (KIF21A), mRNA
NM_017666 Homo sapiens suppressor of hairy wing homolog 3 (Drosophila)
(SUHW3), n
NM_017672 Homo Sapiens transient receptor potential cation channel, subfamily
M, mem
NM_017725 Homo sapiens hypothetical protein FLJ20249 (FLJ20249), transcript
variant
NM_017747 Homo sapiens ankyrin repeat and KH domain containing 1 (ANKHD1),
transe
NM_017754 Homo sapiens chromosome 6 open reading frame 107 (C6orf107), mRNA
NM_017758 Homo Sapiens hypothetical protein FLJ20308 (FLJ20308), mRNA
NM_017771 Homo Sapiens PX domain containing serine/threonine kinase (PXK),
mRNA
NM_017804 Homo sapiens CTFB, chromosome transmission fidelity factor 8 homolog
(S.
NM 017861 Homo sapiens hypothetical protein FLJ20522 (FLJ20522), mRNA
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NM_017871 Homo Sapiens hypothetical protein FLJ20542 (FLJ20542), mRNA
NM 017879 Homo sapiens hypothetical protein FLJ20557 (FLJ20557), mRNA
NM 017969 Homo Sapiens hypothetical protein FLJ10006 (FLJ10006), mRNA
NM 017978 Homo sapiens ankyrin repeat and KH domain containing 1 (ANKHD1),
transc
NM 018003 Homo Sapiens uveal autoantigen with coiled-coil domains and ankyrin
repeal
NM_018069 Homo sapiens hypothetical protein FLJ10352 (FLJ10352), transcript
variant;
NM_018117 Homo sapiens WD repeat domain 11 (WDR11), mRNA
NM_018151 Homo sapiens telomere-associated protein RIF1 homolog (Rif1), mRNA
NM_018177 Homo sapiens Nedd4 binding protein 2 (N4BP2), mRNA
NM_018193 Homo Sapiens hypothetical protein FLJ10719 (FLJ10719), mRNA
NM_018218 Homo sapiens ubiquitin specific protease 40 (USP40), mRNA
NM_018237 Homo sapiens cell division cycle and apoptosis regulator 1 (CCAR1),
mRNA
NM_018284 Homo Sapiens guanylate binding protein 3 (GBP3), mRNA
NM_018325 Homo sapiens chromosome 9 open reading frame 72 (C9orf72),
transcript vs
NM_018334 Homo sapiens leucine rich repeat neuronal 3 (LRRN3), mRNA
NM_018369 Homo sapiens DEP domain containing 1 B (DEPDC1 B), mRNA
NM_018392 Homo sapiens hypothetical protein FLJ11331 (FLJ11331), mRNA
NM_018397 Homo sapiens choline dehydrogenase (CHDH), mRNA
NM 018405 Homo sapiens hypothetical protein, clone 2746033 (HSA272196), mRNA
NM 018414 Homo sapiens sialyltransferase 7 ((alpha-N-acetylneuraminyl-2,3-beta-
galaci
NM_018420 Homo sapiens solute carrier family 22 (organic cation transporter),
member 1
NM_018424 Homo sapiens erythrocyte membrane protein band 4.1 like 4B (EPB41
L4B),
NM_018429 Homo Sapiens B double prime 1, subunit of RNA polymerase III
transcription
NM_018462 Homo sapiens chromosome 3 open reading frame 10 (C3orf10), mRNA
NM_018646 Homo sapiens transient receptor potential cation channel, subfamily
V, mem
NM_018689 Homo sapiens KIAA1199 (KIAA1199), mRNA
NM 018703 Homo sapiens retinoblastoma binding protein 6 (RBBP6), transcript
variant 2
NM 018704 Homo sapiens hypothetical protein DKFZp547A023 (DKFZp547A023), mRN~
NM 018708 Homo sapiens fem-1 homolog a (C.elegans) (FEM1A), mRNA
NM 018710 Homo sapiens hypothetical protein DKFZp762O076 (DKFZp7620076), mRN
NM_018711 Homo Sapiens hypothetical protein DKFZp761H039 (DKFZp761H039), mRN.
NM_018712 Homo sapiens hypothetical protein DKFZp547C176 (DKFZp547C176), mRN,
NM_018714 Homo sapiens component of oligomeric golgi complex 1 (COG1), mRNA
NM_018715 Homo Sapiens RCC1-like (TD-60), mRNA
NM_018717 Homo sapiens mastermind-like 3 (Drosophila) (MAML3), mRNA
NM_018837 Homo sapiens sulfatase 2 (SULF2), transcript variant 1, mRNA
NM_018847 Homo sapiens ketch-like 9 (Drosophila) (KLHL9), mRNA
NM 018981 Homo sapiens DnaJ (Hsp40) homolog, subfamily C, member 10 (DNAJC10);
NM 018987 Homo sapiens sema domain, seven thrombospondin repeats (type 1 and
typ
NM_018998 Homo sapiens F-box and WD-40 domain protein 5 (FBXWS), transcript
varia
NM_018999 Homo sapiens KIAA1128 protein (KIAA1128), mRNA
NM_019001 Homo sapiens 5'-3' exoribonuclease 1 (XRN1), mRNA
NM_019007 Homo Sapiens hypothetical protein FLJ20811 (FLJ20811), mRNA
NM_019010 Homo sapiens keratin 20 (KRT20), mRNA
NM_019015 Homo sapiens chondroitin sulfate glucuronyltransferase (CSGIcA-T),
mRNA
NM_019022 Homo sapiens FLJ20793 protein (FLJ20793), mRNA
NM_019026 Homo sapiens putative membrane protein (LOC54499), mRNA
NM_019029 Homo sapiens carboxypeptidase, vitellogenic-like (CPVL), transcript
variant
NM_019030 Homo sapiens DEAH (Asp-Glu-Ala-His) box polypeptide 29 (DHX29), mRNA
NM_019032 Homo sapiens thrombospondin repeat containing 1 (TSRC1 ), mRNA
NM 019036 Homo sapiens 3-hydroxymethyl-3-methylglutaryl-Coenzyme A lyase-like
1 (H
NM 019051 Homo sapiens mitochondrial ribosomal protein L50 (MRPL50), nuclear
gene
NM_019053 Homo sapiens SEC15-like 1 (S. cerevisiae) (SEC15L1), mRNA
NM_019055 Homo sapiens roundabout homolog 4, magic roundabout (Drosophila)
(ROBS
NM_019065 Homo sapiens EF hand calcium binding protein 2 (EFCBP2), mRNA
NM_019072 Homo sapiens small glutamine-rich tetratricopeptide repeat (TPR)-
containing
NM_019075 Homo sapiens UDP glycosyltransferase 1 family, polypeptide A10
(UGT1A1C
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NM_019077 Homo sapiens UDP glycosyltransferase 1 family, polypeptide A7
(UGT1A7),
NM_019078 Homo Sapiens UDP glycosyltransferase 1 family, polypeptide A5
(UGT1A5),
NM 019085 Homo sapiens F-box and leucine-rich repeat protein 19 (FBXL19), mRNA
NM_019092 Homo sapiens hypothetical protein KIAA1164 (KIAA1164), mRNA
NM_019104 Homo sapiens protein F25965 (F25965), mRNA
NM_019107 Homo sapiens chromosome 19 open reading frame 10 (C19orf10), mRNA
NM_019590 Homo Sapiens KIAA1217 (KIAA1217), mRNA
NM_019593 Homo sapiens hypothetical protein KIAA1434 (KIAA1434), mRNA
NM_019594 Homo Sapiens leucine rich repeat containing 8 (LRRCB), mRNA
NM_019850 Homo sapiens neuronal guanine nucleotide exchange factor (NGEF),
mRNA
NM_020063 Homo sapiens Bares-like 2 (Drosophila) (BARHL2), mRNA
NM_020116 Homo sapiens follistatin-like 5 (FSTLS), mRNA
NM_020124 Homo sapiens interferon, kappa (IFNK), mRNA
NM_020170 Homo Sapiens nicalin (LOC56926), mRNA
NM_020172 Homo sapiens SPPL2b (SPPL2B), mRNA
NM_020175 Homo sapiens hypothetical protein from EUROIMAGE 1967720 (LOC56931)
NM_020192 Homo sapiens chromosome 7 open reading frame 36 (C7orf36), mRNA
NM_020204 Homo sapiens LIM homeobox 9 (LHX9), mRNA
NM 020207 Homo sapiens chromosome 9 open reading frame 102 (C9orf102), mRNA
NM 020209 Homo Sapiens src homology 2 domain-containing transforming protein D
(SI-
NM_020210 Homo sapiens sema domain, immunoglobulin domain (1g), transmembrane
c
NM 020211 Homo sapiens RGM domain family, member A (RGMA), mRNA
NM 020212 Homo sapiens hypothetical protein from EUROIMAGE 384293 (LOC56964),
NM 020214 Homo sapiens hypothetical protein from EUROIMAGE 1977056 (LOC56965)
NM 020219 Homo sapiens carcinoembryonic antigen-like 1 (CEAL1), mRNA
NM_020223 Homo sapiens family with sequence similarity 20, member C (FAM20C),
mRl
NM_020311 Homo sapiens chemokine orphan receptor 1 (CMKOR1), mRNA
NM_020312 Homo sapiens hypothetical protein DKFZp434K046 (DKFZP434K046), mRN.
NM_020318 Homo sapiens pappalysin 2 (PAPPA2), transcript variant 1, mRNA
NM 020319 Homo sapiens ankyrin repeat and MYND domain containing 2 (ANKMY2),
ml
NM 020320 Homo Sapiens arginyl-tRNA synthetase-like (RARSL), mRNA
NM_020336 Homo sapiens KIAA1219 protein (KIAA1219), mRNA
NM_020338 Homo sapiens retinoic acid induced 17 (RAI17), mRNA
NM_020340 Homo sapiens KIAA1244 (KIAA1244), mRNA
NM_020341 Homo sapiens p21(CDKN1A)-activated kinase 7 (PAK7), transcript
variant 1,
NM_020376 Homo sapiens transport-secretion protein 2.2 (TTS-2.2), mRNA
NM_020378 Homo sapiens K562 cell-derived leucine-zipper-like protein 1 (KLP1
), mRNA
NM_020383 Homo sapiens X-prolyl aminopeptidase (aminopeptidase P) 1, soluble
(XPNF
NM_020409 Homo sapiens mitochondria) ribosomal protein L47 (MRPL47), nuclear
gene
NM_020416 Homo sapiens protein phosphatase 2 (formerly 2A), regulatory subunit
B (PF
NM 020417 Homo sapiens T-box 20 (TBX20), mRNA
NM_020420 Homo sapiens deleted in azoospermia 4 (DAZ4), mRNA
NM_020429 Homo Sapiens SMAD specific E3 ubiquitin protein ligase 1 (SMURF1),
transc
NM_020432 Homo sapiens putative homeodomain transcription factor 2 (PHTF2),
mRNA
NM_020438 Homo sapiens dolichyl pyrophosphate phosphatase 1 (DOLPP1), mRNA
NM_020440 Homo sapiens prostaglandin F2 receptor negative regulator (PTGFRN),
mR~
NM_020447 Homo sapiens chromosome 15 open reading frame 17 (C15orf17), mRNA
NM_020451 Homo sapiens selenoprotein N, 1 (SEPN1), transcript variant 1, mRNA
NM_020452 Homo sapiens ATPase, Class I, type 8B, member 2 (ATP8B2), mRNA
NM_020453 Homo Sapiens ATPase, Class V, type 10D (ATP10D), mRNA
NM_020455 Homo sapiens G protein-coupled receptor 126 (GPR126), mRNA
NM_020456 Homo sapiens chromosome 13 open reading frame 1 (C13orf1), mRNA
NM_020457 Homo sapiens THAP domain containing 11 (THAP11), mRNA
NM 020462 Homo sapiens KIAA1181 protein (KIAA1181), mRNA
NM 020463 Homo sapiens KIAA1387 protein (KIAA1387), mRNA
NM 020468 Homo sapiens sorting nexin 14 (SNX14), transcript variant 2, mRNA
NM 020531 Homo sapiens chromosome 20 open reading frame 3 (C20orf3), mRNA
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NM 020532 Homo sapiens reticulon 4 (RTN4), transcript variant 1, mRNA
NM 020536 Homo sapiens CSRP2 binding protein (CSRP2BP), transcript variant 1,
mR~
NM 020546 Homo sapiens adenylate cyclase 2 (brain) (ADCY2), mRNA
NM_020631 Homo sapiens putative NFkB activating protein (KIAA0720), transcript
varian
NM 020647 Homo Sapiens junctophilin 1 (JPH1), mRNA
NM 020693 Homo sapiens Down syndrome cell adhesion molecule like 1 (DSCAML1),
m
NM 020695 Homo Sapiens transcription elongation factor B polypeptide 3 binding
protein
NM 020696 Homo sapiens KIAA1143 protein (KIAA1143), mRNA
NM 020697 Homo sapiens potassium voltage-gated channel, delayed-rectifier,
subfamily
NM 020698 Homo sapiens KIAA1145 protein (KIAA1145), mRNA
NM 020699 Homo Sapiens transcription repressor p66 beta component of the MeCP1
cot
NM_020701 Homo sapiens KIAA1160 protein (KIAA1160), mRNA
NM_020702 Homo sapiens KIAA1161 (KIAA1161), mRNA
NM 020706 Homo sapiens splicing factor, arginine/serine-rich 15 (SFRS15), mRNA
NM_020710 Homo sapiens KIAA1185 protein (KIAA1185), mRNA
NM_020713 Homo sapiens KIAA1196 protein (KIAA1196), mRNA
NM 020714 Homo Sapiens zinc finger protein 490 (ZNF490), mRNA
NM 020718 Homo sapiens ubiquitin specific protease 31 (USP31), mRNA
NM 020728 Homo sapiens KIAA1228 protein (KIAA1228), mRNA
NM 020732 Homo sapiens AT rich interactive domain 1B (SW11-like) (ARID1B),
transcrip
NM 020739 Homo sapiens cell cycle progression 1 (CCPG1 ), mRNA
NM_020740 Homo sapiens ankyrin repeat and FYVE domain containing 1 (ANKFY1),
trar
NM'020742 Homo sapiens neuroligin 4, X-linked {NLGN4X), transcript variant 1,
mRNA
NM 020744 Homo sapiens metastasis associated family, member 3 (MTA3), mRNA
NM 020745 Homo sapiens alanyl-tRNA synthetase like (AARSL), mRNA
NM_020746 Homo sapiens KIAA1271 protein (KIAA1271), mRNA
NM_020748 Homo sapiens KIAA1287 protein (KIAA1287), mRNA
NM 020750 Homo sapiens exportin 5 (XP05), mRNA
NM_020751 Homo sapiens component of oligomeric golgi complex 6 (COG6), mRNA
NM 020752 Homo sapiens G protein-coupled receptor 158 (GPR158), mRNA
NM_020753 Homo sapiens CASK interacting protein 2 (CASKIN2), mRNA
NM_020755 Homo sapiens tumor differentially expressed 2 (TDE2), mRNA
NM 020761 Homo sapiens raptor (raptor), mRNA
NM 020762 Homo sapiens SLIT-ROBO Rho GTPase activating protein 1 (SRGAP1), mR
NM 020765 Homo Sapiens retinoblastoma-associated factor 600 (RBAF600), mRNA
NM_020769 Homo sapiens KIAA1318 protein (KIAA1318), mRNA
NM 020771 Homo sapiens HECT domain and ankyrin repeat containing, E3 ubiquitin
pro
NM 020772 Homo Sapiens 82-kD FMRP Interacting Protein (182-FIP), mRNA
NM_020773 Homo sapiens TBC1 domain family, member 14 (TBC1 D14), mRNA
NM_020774 Homo sapiens mindbomb homolog 1 (Drosophila) (MIB1), mRNA
NM_020775 Homo Sapiens maba1 (KIAA1324), mRNA
NM_020778 Homo Sapiens likely ortholog of mouse myocytic
inductionldifferentiation orig
NM 020779 Homo sapiens WD repeat domain 35 (WDR35), mRNA
NM 020781 Homo sapiens zinc finger protein 398 {ZNF398), transcript variant 2,
mRNA
NM_020783 Homo sapiens synaptotagmin IV (SYT4), mRNA
NM_020786 Homo Sapiens pyruvate dehydrogenase phosphatase isoenzyme 2 (PDP2),
r
NM_020787 Homo sapiens zinc finger protein 624 (ZNF624), mRNA
NM_020789 Homo Sapiens immunoglobulin superfamily, member 9 (IGSF9), mRNA
NM~020791 Homo sapiens serine/threonine protein kinase TA01 homolog (KIAA1361
), n
NM_020792 Homo Sapiens KIAA1363 protein (KIAA1363), mRNA
NM_020795 Homo sapiens neuroligin 2 (NLGN2), mRNA
NM 020799 Homo sapiens associated molecule with fhe SH3 domain of STAM (AMSNj
Ii
NM 020800 Homo sapiens KIAA1374 protein (KIAA1374), mRNA
NM_020801 Homo sapiens arrestin domain containing 3 (ARRDC3), mRNA
NM_020803 Homo sapiens ketch-like 8 (Drosophila) (KLHL8), mRNA
NM_020804 Homo sapiens protein kinase C and casein kinase substrate in neurons
1 (Pi
NM,020808 Homo sapiens signal-induced proliferation-associated 1 like 2
(SIPA1L2), mF
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NM 020809 Homo sapiens Rho GTPase activating protein 20 (ARHGAP20), mRNA
NM_020810 Homo sapiens KIAA1393 (KIAA1393), mRNA
NM_020812 Homo sapiens dedicator of cytokinesis 6 (DOCK6), mRNA
NM_020813 Homo sapiens zinc finger protein 471 (ZNF471 ), mRNA
NM_020816 Homo sapiens kinesin family member 17 (KIF17), mRNA
NM_020817 Homo sapiens KIAA1407 protein (KIAA1407), mRNA
NM_020818 Homo sapiens KIAA1409 (KIAA1409), mRNA
NM_020820 Homo sapiens phosphatidylinositol 3,4,5-trisphosphate-dependent RAC
excP
NM_020824 Homo sapiens Rho GTPase activating protein 21 (ARHGAP21), mRNA
NM 020825 Homo sapiens Crm, cramped-like (Drosophila) (CRAMP1 L), mRNA
NM 020826 Homo sapiens synaptotagmin XIII (SYT13), mRNA
NM_020828 Homo sapiens zinc finger protein 28 homolog (mouse) (ZFP28), mRNA
NM_020832 Homo sapiens KIAA1441 protein (KIAA1441), mRNA
NM_020834 Homo sapiens KIAA1443 (KIAA1443), mRNA
NM_020839 Homo sapiens WD repeat endosomal protein (KIAA1449), mRNA
NM_020844 Homo sapiens KIAA1456 protein (KIAA1456), mRNA
NM_020845 Homo sapiens phosphatidylinositol transfer protein, membrane-
associated 2
NM_020847 Homo sapiens trinucleotide repeat containing 6 (TNRC6), mRNA
NM_020850 Homo sapiens Ran-binding protein 10 (RANBP10), mRNA
NM_020851 Homo sapiens KIAA1465 protein (KIAA1465), mRNA
NM_020854 Homo Sapiens KIAA1468 (KIAA1468), mRNA
NM_020856 Homo sapiens zinc finger protein 537 (ZNF537), mRNA
NM_020858 Homo Sapiens sema domain, transmembrane domain (TM), and cytoplasmic
NM_020859 Homo sapiens Shroom-related protein (ShrmL), mRNA
NM_020860 Homo sapiens stromal interaction molecule 2 (STIM2), mRNA
NM_020861 Homo sapiens zinc finger and BTB domain containing 2 (ZBTB2), mRNA
NM_020863 Homo sapiens zinc finger protein 406 (ZNF406), mRNA
NM_020867 Homo sapiens ubiquitin associated protein 2 (UBAP2), transcript
variant 2, rr
NM_020868 Homo sapiens dipeptidylpeptidase 10 (DPP10), mRNA
NM_020870 Homo sapiens SH3 multiple domains 2 (SH3MD2), mRNA
NM_020871 Homo sapiens leucine-rich repeats and calponin homology (CH) domain
con
NM_020873 Homo sapiens leucine rich repeat neuronal 1 (LRRN1), mRNA
NM_020875 Homo Sapiens Fraser syndrome 1 (FRAS1 ), transcript variant 3, mRNA
NM_020880 Homo Sapiens zinc finger protein 530 (ZNF530), mRNA
NM_020882 Homo sapiens KIAA1510 protein (KIAA1510), mRNA
NM_020889 Homo Sapiens PHD finger protein 12 (PHF12), mRNA
NM_020890 Homo sapiens KIAA1524 protein (KIAA1524), mRNA
NM 020892 Homo Sapiens deltex homolog 2 (Drosophila) (DTX2), mRNA
NM 020895 Homo sapiens KIAA1533 (KIAA1533), mRNA
NM 020897 Homo Sapiens hyperpolarization activated cyclic nucleotide-gated
potassium
NM 020899 Homo sapiens zinc finger and BTB domain containing 4 (ZBTB4), mRNA
NM 020914 Homo sapiens chromosome 17 open reading frame 27 (C17orf27), mRNA
NM_020918 Homo sapiens glycerol-3-phosphate acyltransferase, mitochondria)
(GPAM),
NM_020922 Homo Sapiens protein kinase, lysine deficient 3 (PRKWNK3),
transcript varia
NM_020925 Homo sapiens KIAA1573 protein (KIAA1573), mRNA
NM_020926 Homo Sapiens BCL6 co-repressor (BCOR), transcript variant 2, mRNA
NM_020927 Homo sapiens KIAA1576 protein (KIAA1576), mRNA
NM_020932 Homo sapiens melanoma antigen, family E, 1 (MAGEE1), mRNA
NM_020935 Homo sapiens ubiquitin specific protease 37 (USP37), mRNA
NM_020936 Homo sapiens DEAD (Asp-Glu-Ala-Asp) box polypeptide 55 (DDX55), mRNP
NM_020939 Homo Sapiens copine V (CPNES), mRNA
NM_020944 Homo sapiens glucosidase, beta (bile acid) 2 (GBA2), mRNA
NM_020947 Homo sapiens KIAA1609 protein (KIAA1609), mRNA
NM_020948 Homo sapiens mesoderm induction early response 1 (MI-ER1), mRNA
NM_020951 Homo sapiens zinc finger protein 529 (ZNF529), mRNA
NM 020952 Homo sapiens transient receptor potential cation channel, subfamily
M, mem
NM 020954 Homo Sapiens KIAA1618 (KIAA1618), mRNA
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NM_020961 Homo sapiens KIAA1627 protein (KIAA1627), mRNA
NM 020962 Homo sapiens likely ortholog of mouse neighbor of Punc E11 (NOPE),
mRNi
NM_020964 Homo sapiens KIAA1632 protein (KIAA1632), mRNA
NM_020965 Homo sapiens membrane-associated guanylate kinase-related (MAGI-3)
(M~
NM 020970 Homo Sapiens KIAA1641 (KIAA1641), mRNA
NM_020971 Homo sapiens spectrin, beta, non-erythrocytic 4 (SPTBN4), mRNA
NM 021006 Homo sapiens chemokine (C-C motif) ligand 3-like 1 (CCL3L1), mRNA
NM_021009 Homo sapiens ubiquitin C (UBC), mRNA
NM_021035 Homo sapiens KIAA1404 protein (KIAA1404), mRNA
NM 021044 Homo sapiens desert hedgehog homolog (Drosophila) (DHH), mRNA
NM_021045 Homo sapiens zinc finger protein 248 (ZNF248), mRNA
NM_021059 Homo Sapiens histone 2, H3c (HIST2H3C), mRNA
NM_021061 Homo sapiens zinc finger protein 647 (ZNF647), mRNA
NM_021072 Homo sapiens hyperpolarization activated cyclic nucleotide-gated
potassium
NM_021088 Homo sapiens zinc finger protein 2 (A1-5) (ZNF2), mRNA
NM_021089 Homo sapiens zinc finger protein 8 (clone HF.18) (ZNF8), mRNA
NM 021116 Homo Sapiens adenylate cyclase 1 (brain) (ADCY1), mRNA
NM_021117 Homo sapiens cryptochrome 2 (photolyase-like) (CRY2), mRNA
NM 021143 Homo Sapiens zinc finger protein 20 (KOX 13) (ZNF20), mRNA
NM_021148 Homo sapiens zinc finger protein 273 (ZNF273), mRNA
NM_021149 Homo Sapiens coactosin-like 1 (Dictyostelium) (COTL1 ), mRNA
NM 021164 Homo sapiens splicing factor 4 (SF4), transcript variant b, mRNA
NM_021165 Homo Sapiens hypothetical protein from clone 24828 (KIAA1747), mRNA
NM 021180 Homo sapiens transcription factor CP2-like 4 (TFCP2L4), transcript
variant 1
NM_021202 Homo sapiens tumor protein p53 inducible nuclear protein 2
(TP531NP2), mF
NM_021217 Homo sapiens zinc finger protein 77 (pT1 ) (ZNF77), mRNA
NM 021218 Homo sapiens chromosome 9 open reading frame 80 (C9orf80), mRNA
NM_021222 Homo sapiens TcD37 homolog (HTCD37), mRNA
NM_021224 Homo sapiens zinc finger protein 462 (ZNF462), mRNA
NM_021227 Homo sapiens DC2 protein (DC2), mRNA
NM_021228 Homo sapiens serine arginine-rich pre-mRNA splicing factor SR-A1 (SR-
A1 ),
NM_021237 Homo sapiens selenoprotein K (SELK), mRNA
NM_021250 Homo sapiens leukocyte Ig-like receptor 9 (LIR9), transcript variant
1, mRNA
NM_021260 Homo sapiens zinc finger, FYVE domain containing 1 (ZFYVE1 ),
transcript v.
NM 021636 Homo Sapiens leucine-rich repeat-containing G protein-coupled
receptor 6 (L
NM_021649 Homo sapiens toll-like receptor adaptor molecule 2 (TICAM2), mRNA
NM_021652 Homo Sapiens SMA4 (SMA4), mRNA
NM 021915 Homo sapiens zinc finger protein 69 (CosS) (ZNF69), mRNA
NM_021916 Homo sapiens zinc finger protein 70 (Cos17) (ZNF70), mRNA
NM_021936 Homo sapiens pappalysin 2 (PAPPA2), transcript variant 2, mRNA
NM_021937 Homo sapiens elongation factor for selenoprotein translation (SELB),
mRNA
NM_022045 Homo sapiens Mdm2, transformed 3T3 cell double minute 2, p53 binding
pro
NM_022075 Homo sapiens LAG1 longevity assurance homolog 2 (S. cerevisiae)
(LASS2;
NM_022080 Homo Sapiens N-ethylmaleimide-sensitive factor attachment protein,
beta (N,
NM_022085 Homo sapiens thioredoxin domain containing 5 (TXNDCS), transcript
variant
NM_022092 Homo sapiens CTF18, chromosome transmission fidelity factor 18
homolog i
NM_022106 Homo sapiens chromosome 20 open reading frame 177 (C20orf177), mRNA
NM_022115 Homo sapiens PR domain containing 15 (PRDM15), mRNA
NM_022138 Homo sapiens SPARC related modular calcium binding 2 (SMOC2), mRNA
NM_022160 Homo sapiens DMRT-like family A1 (DMRTA1 ), mRNA
NM_022166 Homo Sapiens xylosyltransferase I (XYLT1), mRNA
NM 022351 Homo sapiens EF hand calcium binding protein 1 (EFCBP1), mRNA
NM_022475 Homo sapiens hedgehog interacting protein (HHIP), mRNA
NM_022478 Homo sapiens cadherin-like 24 (CDH24), mRNA
NM_022479 Homo Sapiens Williams-Beuren syndrome chromosome region 17 (WBSCR1
NM_022486 Homo Sapiens sushi domain containing 1 (SUSD1), mRNA
NM 022491 Homo sapiens likely ortholog of mouse Sds3 (SDS3), mRNA
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NM 022572 Homo Sapiens myofibrillogenesis regulator 1 (MR-1), mRNA
NM 022733 Homo sapiens hypothetical protein AL133206 (LOC64744), mRNA
NM 022742 Homo Sapiens hypothetical protein DKFZp434G156 (DKFZP434G156), mR~
NM 022745 Homo sapiens ATP synthase mitochondria) F1 complex assembly factor 1
(A
NM 022757 Homo Sapiens hypothetical protein FLJ12892 (FLJ12892), mRNA
NM 022824 Homo sapiens F-box and leucine-rich repeat protein 17 (FBXL17), mRNA
NM 022833 Homo sapiens chromosome 9 open reading frame 88 (C9orF88), mRNA
NM 022835 Homo sapiens likely ortholog of mouse common-site lymphoma/leukemia
GE
NM 022913 Homo sapiens vasculin (DKFZp761 C169), mRNA
NM 023002 Homo sapiens hyaluronan and proteoglycan link protein 4 (HAPLN4),
mRNA
NM 023006 Homo Sapiens kallikrein 15 (KLK15), transcript variant 1, mRNA
NM 023939 Homo sapiens hypothetical protein MGC2752 (MGC2752), mRNA
NM 023943 Homo sapiens hypothetical protein MGC3040 (MGC3040), mRNA
NM_024007 Homo Sapiens early B-cell factor (EBF), mRNA
NM_024019 Homo sapiens neurogenin 2 (NEUROG2), mRNA
NM 024100 Homo sapiens WD repeat domain 18 (WDR18), mRNA
NM 024316 Homo sapiens leukocyte receptor cluster (LRC) member 1 (LENG1), mRNA
NM 024335 Homo sapiens Iroquois homeobox protein 6 (IRX6), mRNA
NM 024336 Homo sapiens Iroquois homeobox protein 3 (IRX3), mRNA
NM 024342 Homo sapiens glucocorticoid receptor DNA binding factor 1 (GRLF1),
transa
NM 024344 Homo sapiens calpain 3, (p94) (CAPN3), transcript variant 2, mRNA
NM 024420 Homo sapiens phospholipase A2, group IVA (cytosolic, calcium-
dependent) I
NM 024493 Homo Sapiens zinc finger protein 306 (ZNF306), mRNA
NM 024496 Homo sapiens chromosome 14 open reading frame 4 (C14orf4), mRNA
NM 024511 Homo sapiens chromosome 4 open reading frame 15 (C4orf15), mRNA
NM 024517 Homo sapiens PHD finger protein 2 (PHF2), transcript variant 2, mRNA
NM 024553 Homo Sapiens hypothetical protein FLJ20097 (FLJ20097), mRNA
NM 024621 Homo sapiens hypothetical protein FLJ12604 (FLJ12604), mRNA
NM 024625 Homo Sapiens zinc finger CCCH type, antiviral 1 (ZC3HAV1),
transcript varia
NM 024684 Homo sapiens PTD015 protein (PTD015), mRNA
NM 024742 Homo sapiens armadillo repeat containing 5 (ARMCS), mRNA
NM 024769 Homo sapiens adipocyte-specific adhesion molecule (ASAM), mRNA
NM 024870 Homo Sapiens DEP domain containing 2 (DEPDC2), transcript variant 1,
mR
NM 024878 Homo sapiens CGI-72 protein (CGI-72), transcript variant 4, mRNA
NM 024933 Homo sapiens hypothetical protein FLJ12056 (FLJ12056), mRNA
NM 024953 Homo Sapiens hypothetical protein FLJ13089 (FLJ13089), mRNA
NM 025169 Homo sapiens zinc finger protein 167 (ZNF167), transcript variant 2,
mRNA
NM 025196 Homo sapiens GrpE-like 1, mitochondria) (E, coli) (GRPEL1), mRNA
NM_025202 Homo sapiens EF hand domain containing 1 (EFHD1), mRNA
NM 025219 Homo sapiens DnaJ (Hsp40) homolog, subfamily C, member 5 (DNAJCS), m
NM 025224 Homo sapiens BTB (POZ) domain containing 4 (BTBD4), mRNA
NM_025248 Homo sapiens SNAP25-interacting protein (SNIP), mRNA
NM_025252 Homo sapiens Ras association (RaIGDS/AF-6) and pleckstrin homology
dory
NM'025256 Homo sapiens HLA-B associated transcript 8 (BAT8), transcript
variant NG3f
NM_030625 Homo sapiens CXXC finger 6 (CXXC6), mRNA
NM_030627 Homo sapiens cytoplasmic polyadenylation element binding protein 4
(CPEB
NM_030628 Homo sapiens KIAA1698 protein (KIAA1698), mRNA
NM_030629 Homo Sapiens c-Maf inducing protein (CMIP), transcript variant Tc-
mip, mR~
NM_030630 Homo sapiens chromosome 17 open reading frame 28 (C17orf28), mRNA
NM_030633 Homo sapiens KIAA1712 (KIAA1712), mRNA
NM 030634 Homo sapiens zinc finger protein 436 (ZNF436), mRNA
NM~030636 Homo sapiens KIAA1706 protein (KIAA1706), mRNA
NM 030637 Homo Sapiens DDHD domain containing 1 (DDHD1), mRNA
NM 030639 Homo Sapiens KIAA1701 protein (KIAA1701), mRNA
NM_030640 Homo sapiens dual specificity phosphatase 16 (DUSP16), mRNA
NM_030644 Homo sapiens apolipoprotein L, 3 (APOL3), transcript variant
alpha/b, mRNP
NM 030645 Homo Sapiens KIAA1720 protein (KIAA1720), mRNA
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NM_030650 Homo Sapiens KIAA1715 (KIAA1715), mRNA
NM_030789 Homo sapiens histocompatibility (minor) 13 (HM13), transcript
variant 1, mRi
NM_030812 Homo sapiens actin like protein (LOC81569), mRNA
NM_030883 Homo sapiens olfactory receptor, family 2, subfamily H, member 1
(OR2H1),
NM_030906 Homo sapiens serine/threonine kinase 33 (STK33), mRNA
NM_030919 Homo sapiens chromosome 20 open reading frame 129 (C20orf129), mRNA
NM_030922 Homo sapiens non-imprinted in Prader-Willi/Angelman syndrome 2
(NIPA2),
NM_030923 Homo sapiens hypothetical protein DKFZp566N034 (DKFZP566N034), mRN
NM 030949 Homo sapiens protein phosphatase 1, regulatory (inhibitor) subunit
14C (PPf
NM_030957 Homo Sapiens a disintegrin-like and metalloprotease (reprolysin
type) with th
NM_030961 Homo sapiens tripartite motif-containing 56 (TRIM56), mRNA
NM_030962 Homo sapiens Charcot-Marie-Tooth neuropathy 482 (autosomal
recessive, v
NM_031303 Homo sapiens similar to RIKEN cDNA 4933439808 gene (MGC33211 ), mR~
NM_031444 Homo sapiens chromosome 22 open reading frame 13 (C22orf13), mRNA
NM_031448 Homo sapiens chromosome 19 open reading frame 12 (C19orf12), mRNA
NM_031454 Homo sapiens selenoprotein O (SELO), mRNA
NM_031467 Homo sapiens solute carrier family 4, sodium bicarbonate
cotransporter, mer
NM_031490 Homo sapiens peroxisomal Ion protease (LONP), mRNA
NM_031888 Homo sapiens pro-melanin-concentrating hormone-like 2 (PMCHL2), mRNA
NM_031895 Homo sapiens calcium channel, voltage-dependent, gamma subunit 8
(CACI
NM_031912 Homo sapiens synaptotagmin XV (SYT15), transcript variant a, mRNA
NM_031913 Homo sapiens chr3 synaptotagmin (CHR3SYT), mRNA
NM 031914 Homo sapiens synaptotagmin XIV-like (SYT14L), mRNA
NM 031935 Homo sapiens hemicentin (FIBL-6), mRNA
NM 032017 Homo sapiens Ser/Thr-like kinase (MGC4796), mRNA
NM 032111 Homo sapiens mitochondria) ribosomal protein L14 (MRPL14), nuclear
gene
NM_032119 Homo sapiens monogenic, audiogenic seizure susceptibility 1 homolog
(mou
NM_032123 Homo sapiens kin of IRRE like 2 (Drosophila) (KIRREL2), transcript
variant 1
NM_032132 Homo Sapiens HORMA domain containing protein (NOHMA), mRNA
NM_032137 Homo sapiens hypothetical protein DKFZp434N1817 (DKFZP434N1817), mf
NM_032156 Homo sapiens C1q domain containing 1 (C1ODC1), transcript variant 3,
mRl
NM_032160 Homo Sapiens chromosome 18 open reading frame 4 (C18orf4), mRNA
NM_032165 Homo sapiens hypothetical protein FLJ12303 (FLJ12303), mRNA
NM_032168 Homo Sapiens hypothetical protein FLJ12519 (FLJ12519), mRNA
NM_032194 Homo sapiens brix domain containing 1 (BXDC1 ), mRNA
NM_032195 Homo sapiens SON DNA binding protein (SON), transcript variant b,
mRNA
NM_032217 Homo sapiens ankyrin repeat domain 17 (ANKRD17), transcript variant
1, ml
NM_032222 Homo Sapiens hypothetical protein FLJ22374 (FLJ22374), mRNA
NM_032226 Homo sapiens zinc finger, CCHC domain containing 7 (ZCCHC7), mRNA
NM_032228 Homo sapiens male sterility domain containing 2 (MLSTD2), mRNA
NM_032230 Homo sapiens hypothetical protein FLJ22789 (FLJ22789), mRNA
NM_032279 Homo sapiens hypothetical protein DKFZp76111011 (DKFZp76111011), mR~
NM_032282 Homo sapiens hypothetical protein DKFZp547D155 (DKFZp547D155), mRN,
NM_032283 Homo Sapiens zinc finger, DHHC domain containing 18 (ZDHHC18), mRNA
NM_032285 Homo sapiens hypothetical protein MGC3207 (MGC3207), mRNA
NM_032286 Homo sapiens hypothetical protein MGC5309 (MGC5309), mRNA
NM 032422 Homo Sapiens G protein-coupled receptor 123 (GPR123), mRNA
NM_032423 Homo sapiens zinc finger protein 528 (ZNF528), mRNA
NM_032425 Homo sapiens KIAA1822 (KIAA1822), mRNA
NM_032427 Homo Sapiens mastermind-like 2 (Drosophila) (MAML2), mRNA
NM_032429 Homo sapiens leucine zipper, putative tumor suppressor 2 (LZTS2),
mRNA
NM_032430 Homo sapiens KIAA1811 protein (KIAA1811), mRNA
NM_032431 Homo sapiens HRD1 protein (HRD1), transcript variant 1, mRNA
NM_032432 Homo sapiens actin binding LIM protein family, member 2 (ABLIM2),
mRNA
NM_032433 Homo sapiens zinc finger protein 333 (ZNF333), mRNA
NM 032434 Homo sapiens zinc finger protein 512 (ZNF512), mRNA
NM 032435 Homo sapiens mixed lineage kinase 4 (KIAA1804), mRNA
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NM_032436 Homo sapiens chromosome 13 open reading frame 8 (C13orf8), mRNA
NM_032439 Homo Sapiens phytanoyl-CoA hydroxylase interacting protein-like
(PHYHIPL;
NM_032440 Homo sapiens ligand-dependent corepressor (MLR2), mRNA
NM_032444 Homo Sapiens BTB (POZ) domain containing 12 (BTBD12), mRNA
NM_032448 Homo sapiens KIAA1838 (KIAA1838), mRNA
NM_032452 Homo sapiens junctophilin 4 (JPH4), mRNA
NM_032458 Homo sapiens PHD finger protein 6 (PHF6), mRNA
NM_032477 Homo sapiens mitochondria) ribosomal protein L41 (MRPL41 ), nuclear
gene
NM_032478 Homo sapiens mitochondria) ribosomal protein L38 (MRPL38), nuclear
gene
NM_032479 Homo sapiens mitochondria) ribosomal protein L36 (MRPL36), nuclear
gene
NM_032482 Homo Sapiens DOT1-like, histone H3 methyltransferase (S. cerevisiae)
(DO)
NM_032497 Homo sapiens zinc finger protein 559 (ZNF559), mRNA
NM 032501 Homo sapiens acetyl-Coenzyme A synthetase 2 (AMP forming)-like
(ACAS21
NM_032505 Homo sapiens T-cell activation ketch repeat protein (TA-KRP), mRNA
NM 032506 Homo sapiens KIAA1841 protein (KIAA1841), mRNA
NM 032508 Homo sapiens family with sequence similarity 11, member A (FAM11A),
mRP
NM 032511 Homo sapiens chromosome 6 open reading frame 168 (C6orf168), mRNA
NM 032512 Homo sapiens PDZ domain containing 4 (PDZK4), mRNA
NM_032517 Homo sapiens lysozyme-like 1 (LYZL1), mRNA
NM_032528 Homo sapiens beta-galactoside alpha-2,6-sialyltransferase II
(ST6Galll), mR
NM_032531 Homo Sapiens kin of IRRE like 3 (Drosophila) (KIRREL3), mRNA
NM_032536 Homo sapiens netrin G2 (NTNG2), mRNA
NM_032539 Homo sapiens SLIT and NTRK-like family, member 2 (SLITRK2), mRNA
NM_032550 Homo Sapiens KIAA1914 (KIAA1914), transcript variant 2, mRNA
NM_032552 Homo sapiens DAB2 interacting protein (DAB21P), mRNA
NM_032569 Homo sapiens cytokine-like nuclear factor n-pac (N-PAC), mRNA
NM_032590 Homo sapiens F-box and leucine-rich repeat protein 10 (FBXL10), mRNA
NM_032636 Homo sapiens differential display and activated by p53 (DDA3), mRNA
NM_032869 Homo sapiens chronic myelogenous leukemia tumor antigen 66 (CML66),
ml
NM_032870 Homo Sapiens chromosome 6 open reading frame 111 (C6orf111), mRNA
NM_032947 Homo sapiens putative small membrane protein NID67 (NID67), mRNA
NM_033026 Homo sapiens piccolo (presynaptic cytomatrix protein) (PCLO),
transcript var
NM 033046 Homo sapiens rhotekin (RTKN), mRNA
NM 033052 Homo Sapiens DMRT-like family C2 (DMRTC2), mRNA
NM_033053 Homo sapiens DMRT-like family C1 (DMRTC1 ), mRNA
NM_033055 Homo Sapiens hippocampus abundant transcript 1 (HIAT1), mRNA
NM_033063 Homo sapiens microtubule-associated protein 6 (MAP6), transcript
variant 1,
NM_033064 Homo Sapiens ataxia, cerebellar, Cayman type (caytaxin) (ATCAY),
mRNA
NM_033067 Homo sapiens DMRT-like family B with proline-rich C-terminal, 1
(DMRTB1 ),
NM_033071 Homo sapiens spectrin repeat containing, nuclear envelope 1 (SYNE1
), trap:
NM 033082 Homo sapiens cytokine induced protein 29 kDa (CIP29), mRNA
NM 033086 Homo sapiens FGD1 family, member 3 (FGD3), mRNA
NM_033088 Homo sapiens family with sequence similarity 40, member A (FAM40A),
mRP
NM_033090 Homo Sapiens GREB1 protein (GREB1 ), transcript variant b, mRNA
NM_033107 Homo Sapiens hypothetical protein BC004923 (LOC85865), mRNA
NM_033109 Homo sapiens polyribonucleotide nucleotidyltransferase 1 (PNPT1),
mRNA
NM_033112 Homo sapiens chromosome 6 open reading frame 153 (C6orf153), mRNA
NM_033121 Homo sapiens ankyrin repeat domain 13 (ANKRD13), mRNA
NM_033129 Homo sapiens scratch homolog 2, zinc finger protein (Drosophila)
(SCRT2),
NM_033141 Homo sapiens mitogen-activated protein kinase kinase kinase 9
(MAP3K9), r
NM_033160 Homo sapiens DKFZP572C163 protein (DKFZP572C163), mRNA
NM_033161 Homo sapiens surfeit 4 (SURF4), mRNA
NM_033200 Homo sapiens hypothetical protein BC002942 (BC002942), mRNA
NM_033201 Homo sapiens hypothetical gene BC008967 (BC008967), mRNA
NM_033206 Homo sapiens hypothetical gene FLJ00060 (FLJ00060), mRNA
NM 033253 Homo sapiens 5'-nucleotidase, cytosolic IB (NT5C1 B), transcript
variant 2, m
NM 033267 Homo sapiens Iroquois homeobox protein 2 (IRX2), mRNA
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NM_033271 Homo sapiens BTB (POZ) domain containing 6 (BTBD6), mRNA
NM 033276 Homo sapiens Ku70-binding protein 3 (KUB3), mRNA
NM 033288 Homo sapiens zinc finger protein 160 (ZNF160), transcript variant 1,
mRNA
NM_033364 Homo Sapiens chromosome 3 open reading frame 15 (C3orf15), mRNA
NM 033375 Homo sapiens myosin IC (MY01C), mRNA
NM 033386 Homo sapiens molecule interacting with Rab13 (MIRAB13), mRNA
NM_033387 Homo sapiens chromosome 9 open reading frame 59 (C9orf59), mRNA
NM_033389 Homo sapiens slingshot homolog 2 (Drosophila) (SSH2), mRNA
NM_033392 Homo sapiens mitogen-activated protein kinase 8 interacting protein
3 (MAPI
NM_033393 Homo sapiens KIAA1727 protein (KIAA1727), mRNA
NM_033396 Homo sapiens tankyrase 1 binding protein 1, 182kDa (TNKS1BP1), mRNA
NM_033397 Homo Sapiens KIAA1754 (KIAA1754), mRNA
NM_033402 Homo sapiens KIAA1764 protein (KIAA1764), mRNA
NM_033404 Homo sapiens kinase non-catalytic C-lobe domain (KIND) containing 1
(KND
NM_033405 Homo Sapiens peroxisomal proliferator-activated receptor A
interacting comp
NM_033407 Homo sapiens dedicator of cytokinesis 7 (DOCK7), mRNA
NM_033425 Homo sapiens DIX domain containing 1 (DIXDC1), mRNA
NM_033426 Homo sapiens KIAA1737 (KIAA1737), mRNA
NM_033429 Homo sapiens calmodulin-like 4 (CALML4), mRNA
NM_033449 Homo sapiens FCH and double SH3 domains 1 (FCHSD1), mRNA
NM_033450 Homo sapiens ATP-binding cassette, sub-family C (CFTRIMRP), member
10
NM_033452 Homo sapiens tripartite motif containing 47 (TRIM47), mRNA
NM_033505 Homo sapiens selenoprotein I, 1 (SELI), mRNA
NM_033510 Homo sapiens dispatched homolog 2 (Drosophila) (DISP2), mRNA
NM_033512 Homo sapiens TSPY-like 5 (TSPYLS), mRNA
NM_033513 Homo sapiens chromosome 19 open reading frame 20 (C19orf20), mRNA
NM_033520 Homo sapiens chromosome 19 open reading frame 33 (Cl9orf33), mRNA
NM_033542 Homo sapiens chromosome 20 open reading frame 35 (C20orf35), mRNA
NM_033548 Homo sapiens similar to ZINC FINGER PROTEIN 257 (BONE MARROW ZI~
NM_033553 Homo Sapiens guanylate cyclase activator 2A (guanylin) (GUCA2A),
mRNA
NM_033557 Homo sapiens similar to putative transmembrane protein; homolog of
yeast
NM_033631 Homo sapiens leucine zipper protein 1 (LUZP1 ), mRNA
NM_033647 Homo sapiens helicase (DNA) B (HELB), mRNA
NM_033666 Homo Sapiens integrin, beta 1 (fibronectin receptor, beta
polypeptide, antigei
NM_033667 Homo sapiens integrin, beta 1 (fibronectin receptor, beta
polypeptide, antigei
NM_033668 Homo sapiens integrin, beta 1 (fibronectin receptor, beta
polypeptide, antigei
NM_033669 Homo sapiens integrin, beta 1 (fibronectin receptor, beta
polypeptide, antigei
NM_052843 Homo sapiens obscurin, cytoskeletal calmodulin and titin-interacting
RhoGEf
NM_052846 Homo Sapiens elastin microfibril interfaces 3 (EMILIN3), mRNA
NM_052847 Homo sapiens guanine nucleotide binding protein (G protein), gamma 7
(GN
NM_052849 Homo Sapiens hypothetical protein MGC20481 (MGC20481), mRNA
NM_052850 Homo sapiens growth arrest and DNA-damage-inducible, gamma
interacting
NM_052857 Homo Sapiens hypothetical protein MGC20398 (MGC20398), mRNA
NM 052864 Homo sapiens TRAF2 binding protein (T2BP), mRNA
NM 052867 Homo Sapiens voltage gated channel like 1 (VGCNL1), mRNA
NM 052878 Homo sapiens chromosome 19 open reading frame 36 (C19orf36), mRNA
NM 052892 Homo sapiens polycystic kidney disease 1-like 2 (PKD1 L2),
transcript variant
NM_052896 Homo sapiens CUB and Sushi multiple domains 2 (CSMD2), mRNA
NM_052897 Homo sapiens methyl-CpG binding domain protein 6 (MBD6), mRNA
NM_052899 Homo Sapiens G protein-regulated induces of neurite outgrowth 1
(KIAA1893
NM_052900 Homo Sapiens CUB and Sushi multiple domains 3 (CSMD3), transcript
varia~
NM_052901 Homo sapiens solute carrier family 25 (mitochondria) carrier;
phosphate cam
NM_052902 Homo sapiens serine/threonine kinase 11 interacting protein
(STK111P), mRl
NM_052903 Homo sapiens tubulin, gamma complex associated protein 5 (TUBGCPS),
m
NM_052904 Homo sapiens KIAA1900 (KIAA1900), mRNA
NM 052905 Homo sapiens formin-like 2 (FMNL2), mRNA
NM 052909 Homo Sapiens KIAA1909 protein (KIAA1909), mRNA
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NM 052910 Homo sapiens SLIT and NTRK-like family, member 1 (SLITRK1 ), mRNA
NM 052911 Homo sapiens establishment factor-like protein (EF01 ), mRNA
NM 052913 Homo sapiens KIAA1913 (KIAA1913), mRNA
NM 052917 Homo sapiens UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-
acetylga
NM 052923 Homo sapiens zinc finger protein 452 (ZNF452), mRNA
NM 052924 Homo sapiens rhophilin, Rho GTPase binding protein 1 (RHPN1), mRNA
NM_052925 Homo sapiens leukocyte receptor cluster (LRC) member 8 (LENGB), mRNA
NM 052926 Homo sapiens paraneoplastic antigen like 5 (PNMA5), mRNA
NM 052928 Homo Sapiens SET and MYND domain containing 4 (SMYD4), mRNA
NM 052937 Homo sapiens similar to hypothetical protein FLJ10883 (LOC115294),
mRN~
NM 052964 Homo sapiens mast cell immunoreceptor signal transducer (MIST), mRNA
NM_052965 Homo sapiens chromosome 1 open reading frame 19 (C1orf19), mRNA
NM_053041 Homo Sapiens COMM domain containing 7 (COMMD7), mRNA
NM_053044 Homo sapiens serine protease HTRA3 (HTRA3), mRNA
NM_053051 Homo sapiens LYST-interacting protein LIP8 (LIPB), mRNA
NM_053052 Homo sapiens SVAP1 protein (IMAGE3451454), mRNA
NM_053277 Homo sapiens chloride intracellular channel 6 (CLIC6), mRNA
NM_053279 Homo sapiens chromosome 8 open reading frame 13 (C8orf13), mRNA
NM_053282 Homo sapiens SH2 domain-containing molecule EAT2 (EAT2), mRNA
NM_054104 Homo sapiens olfactory receptor, family 6, subfamily C, member 3
(OR6C3),
NM_054105 Homo sapiens olfactory receptor, family 6, subfamily C, member 2
(OR6C2),
NM_057163 Homo Sapiens gonadotropin-releasing hormone (type 2) receptor 2
(GNRHR
NM_058163 Homo sapiens hypothetical protein DT1 P1A10 (DT1 P1A10), mRNA
NM_058243 Homo Sapiens bromodomain containing 4 (BRD4), transcript variant
long, mF
NM_080574 Homo sapiens chromosome 20 open reading frame 70 (C20orf70), mRNA
NM_080614 Homo sapiens WAP four-disulfide core domain 3 (WFDC3), transcript
varian
NM_080618 Homo sapiens CCCTC-binding factor (zinc finger protein)-like
(CTCFL), mRh
NM_080622 Homo sapiens chromosome 20 open reading frame 135 (C20orf135), mRNA
NM_080725 Homo sapiens chromosome 20 open reading frame 139 (C20orf139), mRNA
NM_080747 Homo sapiens keratin protein K6irs (K61RS2), mRNA
NM_080751 Homo sapiens transmembrane channel-like 2 (TMC2), mRNA
NM_080753 Homo sapiens WAP four-disulfide core domain 10A (WFDC10A), mRNA
NM_080757 Homo sapiens chromosome 20 open reading frame 127 (C20orf127), mRNA
NM_080764 Homo sapiens suppressor of hairy wing homolog 2 (Drosophila)
(SUHW2), n
NM_080827 Homo sapiens WAP four-disulfide core domain 6 (WFDC6), mRNA
NM_080833 Homo sapiens chromosome 20 open reading frame 151 (C20orf151), mRNA
NM_080836 Homo sapiens serine/threonine kinase 35 (STK35), mRNA
NM_080865 Homo sapiens G protein-coupled receptor 62 (GPR62), mRNA
NM_080866 Homo sapiens solute carrier family 22 (organic anion/cation
transporter), mei
NM 080868 Homo Sapiens ankyrin repeat and SOCS box-containing 17 (ASB17), mRNA
NM 080869 Homo sapiens WAP four-disulfide core domain 12 (WFDC12), mRNA
NM_080875 Homo sapiens skeletrophin (LOC142678), mRNA
NM_080877 Homo sapiens solute carrier family 34 (sodium phosphate), member 3
(SLC~
NM_080911 Homo sapiens uracil-DNA glycosylase (UNG), nuclear gene encoding
mitoch
NM_080928 Homo sapiens ankyrin repeat and SOCS box-containing 15 (ASB15), mRNA
NM_101395 Homo sapiens dual-specificity tyrosine-(Y)-phosphorylation regulated
kinase
NM_130391 Homo sapiens protein tyrosine phosphatase, receptor type, D (PTPRD),
tran;
NM_130392 Homo sapiens protein tyrosine phosphatase, receptor type, D (PTPRD),
tram
NM_130393 Homo sapiens protein tyrosine phosphatase, receptor type, D (PTPRD),
tram
NM_130435 Homo sapiens protein tyrosine phosphatase, receptor type, E (PTPRE),
tran;
NM_130436 Homo sapiens dual-specificity tyrosine-(Y)-phosphorylation regulated
kinase
NM_130437 Homo Sapiens dual-specificity tyrosine-(Y)-phosphorylation regulated
kinase
NM_130438 Homo sapiens dual-specificity tyrosine-(Y)-phosphorylation regulated
kinase
NM_130440 Homo sapiens protein tyrosine phosphatase, receptor type, F (PTPRF),
tram
NM_130442 Homo sapiens engulfment and cell motility 1 (ced-12 homolog, C.
elegans) (I
NM_130444 Homo sapiens collagen, type XVIII, alpha 1 (COL18A1 ), transcript
variant 3, i
NM_130445 Homo Sapiens collagen, type XVIII, alpha 1 (COL18A1), transcript
variant 2, i
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NM_130465 Homo sapiens F-box protein 23 (FBXO23), mRNA
NM_130466 Homo sapiens ubiquitin protein ligase E3B (UBE3B), transcript
variant 1, mR
NM_130470 Homo sapiens MAP-kinase activating death domain (MADD), transcript
varia
NM_130471 Homo sapiens MAP-kinase activating death domain (MADD), transcript
varia
NM_130472 Homo sapiens MAP-kinase activating death domain (MADD), transcript
varia
NM_130473 Homo sapiens MAP-kinase activating death domain (MADD), transcript
varia
NM_130474 Homo sapiens MAP-kinase activating death domain (MADD), transcript
varia
NM_130475 Homo sapiens MAP-kinase activating death domain (MADD), transcript
varia
NM_130476 Homo sapiens MAP-kinase activating death domain (MADD), transcript
varia
NM_130760 Homo sapiens mucosal vascular addressin cell adhesion molecule 1
(MADC.
NM_130761 Homo sapiens mucosal vascular addressin cell adhesion molecule 1
(MADC.
NM_130762 Homo sapiens mucosal vascular addressin cell adhesion molecule 1
(MADC,
NM_130766 Homo sapiens skeletal muscle and kidney enriched inositol
phosphatase (SN
NM_130771 Homo sapiens osteoclast-associated receptor (OSCAR), transcript
variant 3,
NM_130775 Homo sapiens RAGE-5 protein (RAGE-5), mRNA
NM_130776 Homo sapiens G antigen, family D, 4 (GAGED4), transcript variant 2,
mRNA
NM_130777 Homo sapiens G antigen, family D, 3 (GAGED3), mRNA
NM_130788 Homo sapiens WW domain containing oxidoreductase (WWOX), transcript
v
NM_130790 Homo sapiens WW domain containing oxidoreductase (WWOX), transcript
v
NM_130791 Homo sapiens WW domain containing oxid0reductase (WWOX), transcript
v
NM_130792 Homo sapiens WW domain containing oxidoreductase (WWOX), transcript
v
NM_130793 Homo sapiens nucleolar protein family 6 (RNA-associated) (NOL6),
transcrip
NM_130794 Homo sapiens cystatin 11 (CST11), transcript variant 1, mRNA
NM_130797 Homo sapiens dipeptidylpeptidase 6 (DPP6), transcript variant 1,
mRNA
NM_130798 Homo sapiens synaptosomal-associated protein, 23kDa (SNAP23),
transcrip
NM_130799 Homo sapiens multiple endocrine neoplasia I (MEND, transcript
variant 2, m
NM_130800 Homo sapiens multiple endocrine neoplasia I (MEND, transcript
variant e1 B,
NM_130801 Homo sapiens multiple endocrine neoplasia I (MEN1 ), transcript
variant e1 C,
NM_130802 Homo sapiens multiple endocrine neoplasia I (MEND, transcript
variant e1 D,
NM_130803 Homo sapiens multiple endocrine neoplasia I (MEN1 ), transcript
variant e1 E,
NM_130804 Homo sapiens multiple endocrine neoplasia I (MEND, transcript
variant e1 F'
NM_130806 Homo sapiens leucine-rich repeat-containing G protein-coupled
receptor 8 (L
NM_130807 Homo sapiens MOB1, Mps One Binder kinase activator-like 2A (yeast)
(MOB
NM_130808 Homo sapiens copine IV (CPNE4), mRNA
NM_130809 Homo sapiens hypothetical protein MGC12103 (LOC133619), mRNA
NM_130810 Homo sapiens dyslexia susceptibility 1 candidate 1 (DYX1C1), mRNA
NM_130811 Homo sapiens synaptosomal-associated protein, 25kDa (SNAP25),
transcrip
NM_130830 Homo sapiens leucine rich repeat containing 15 (LRRC15), mRNA
NM_130831 Homo sapiens optic atrophy 1 (autosomal dominant) (OPA1), nuclear
gene a
NM_130832 Homo sapiens optic atrophy 1 (autosomal dominant) (OPA1 ), nuclear
gene a
NM_130833 Homo sapiens optic atrophy 1 (autosomal dominant) (OPA1 ), nuclear
gene a
NM_130834 Homo sapiens optic atrophy 1 (autosomal dominant) (OPA1 ), nuclear
gene a
NM_130835 Homo sapiens optic atrophy 1 (autosomal dominant) (OPA1 ), nuclear
gene a
NM_130836 Homo sapiens optic atrophy 1 (autosomal dominant) (OPA1 ), nuclear
gene a
NM_130837 Homo sapiens optic atrophy 1 (autosomal dominant) (OPA1 ), nuclear
gene a
NM_130838 Homo sapiens ubiquitin protein ligase E3A (human papilloma virus E6-
assoc
NM_130839 Homo sapiens ubiquitin protein ligase E3A (human papilloma virus E6-
assoc
NM_130840 Homo sapiens ATPase, H+ transporting, lysosomal VO subunit a isoform
4 (~
NM_130841 Homo sapiens ATPase, H+ transporting, lysosomal VO subunit a isoform
4 (~
NM_130842 Homo sapiens protein tyrosine phosphatase, receptor type, N
polypeptide 2 i
NM_130843 Homo sapiens protein tyrosine phosphatase, receptor type, N
polypeptide 2 i
NM_130844 Homo sapiens WW domain containing oxidoreductase (WWOX), transcript
v
NM_130845 Homo sapiens syntrophin, beta 2 (dystrophin-associated protein A1,
59kDa,
NM_130846 Homo sapiens protein tyrosine phosphatase, receptor type, R (PTPRR),
tran:
NM 130847 Homo sapiens angiomotin like 1 (AMOTL1), mRNA
NM 130848 Homo sapiens dendritic cell nuclear protein 1 (DCNP1), mRNA
NM_130849 Homo sapiens solute carrier family 39 (zinc transporter), member 4
(SLC39A
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NM 130850 Homo Sapiens bone morphogenetic protein 4 (BMP4), transcript variant
2, m
NM 130851 Homo sapiens bone morphogenetic protein 4 (BMP4), transcript variant
3, m
NM 130852 Homo Sapiens palate, lung and nasal epithelium carcinoma associated
(PLU
NM 130853 Homo sapiens protein tyrosine phosphatase, receptor type, S (PTPRS),
tran;
NM_130854 Homo sapiens protein tyrosine phosphatase, receptor type, S (PTPRS),
tran;
NM_130855 Homo sapiens protein tyrosine phosphatase, receptor type, S (PTPRS),
tran;
NM_130896 Homo sapiens WAP four-disulfide core domain 8 (W FDCB), transcript
varian
NM_130897 Homo sapiens dynein, cytoplasmic, light polypeptide 2B (DNCL2B),
mRNA
NM_130898 Homo sapiens CAMP responsive element binding protein 3-like 4
(CREB3L4~
NM_130899 Homo sapiens hypothetical protein MGC26988 (MGC26988), mRNA
NM_130900 Homo sapiens retinoic acid early transcript 1 L (RAET1 L), mRNA
NM_130901 Homo sapiens chromosome 15 open reading frame 16 (C15orf16), mRNA
NM_130902 Homo sapiens cytochrome c oxidase subunit VIIb2 (COX7B2), mRNA
NM_130906 Homo Sapiens peptidylprolyl isomerase (cyclophilin)-like 3 (PPIL3),
transcript
NM_131915 Homo sapiens similar to hypothetical protein DKFZp434K191 (H.
sapiens) (L
NM_131916 Homo sapiens peptidylprolyl isomerase (cyclophilin)-like 3 (PPIL3),
transcript
NM_131917 Homo Sapiens Fas (TNFRSF6) associated factor 1 (FAF1 ), transcript
variant
NM_133168 Homo sapiens osteoclast-associated receptor (OSCAR), transcript
variant 5,
NM_133169 Homo sapiens osteoclast-associated receptor (OSCAR), transcript
variant 4,
NM_133170 Homo sapiens protein tyrosine phosphatase, receptor type, T (PTPRT),
tram
NM_133171 Homo sapiens engulfment and cell motility 2 (ced-12 homolog, C.
elegans) (I
NM_133172 Homo Sapiens amyloid beta (A4) precursor protein-binding, family B,
membe
NM_133173 Homo sapiens amyloid beta (A4) precursor protein-binding, family B,
membe
NM_133174 Homo sapiens amyloid beta (A4) precursor protein-binding, family B,
membe
NM_133175 Homo Sapiens amyloid beta (A4) precursor protein-binding, family B,
membe
NM_133176 Homo sapiens amyloid beta (A4) precursor protein-binding, family B,
membe
NM_133177 Homo sapiens protein tyrosine phosphatase, receptor type, U (PTPRU),
tran:
NM_133178 Homo sapiens protein tyrosine phosphatase, receptor type, U (PTPRU),
tran:
NM_133179 Homo sapiens G antigen, family D, 4 (GAGED4), transcript variant 1,
mRNA
NM_133180 Homo sapiens EPSB-like 1 (EPS8L1), transcript variant 1, mRNA
NM_133181 Homo sapiens EPS8-like 3 (EPS8L3), transcript variant 2, mRNA
NM_133259 Homo sapiens leucine-rich PPR-motif containing (LRPPRC), mRNA
NM 133261 Homo sapiens PDZ domain protein GIPC3 (GIPC3), mRNA
NM 133262 Homo sapiens ATPase, H+ transporting, lysosomal 13kDa, V1 subunit G
isol
NM_133263 Homo Sapiens peroxisome proliferative activated receptor, gamma,
coactivat
NM_133264 Homo sapiens WIRE protein (WIRE), mRNA
NM_133265 Homo sapiens angiomotin (AMOT), mRNA
NM_133266 Homo sapiens SH3 and multiple ankyrin repeat domains 2 (SHANK2),
transc
NM_133267 Homo Sapiens homeobox protein GSH-2 (GSH-2), mRNA
NM 133268 Homo sapiens oxysterol binding protein-like 1A (OSBPL1A), transcript
varian
NM 133269 Homo sapiens Fc fragment of IgA, receptor for (FCAR), transcript
variant 2, r
NM_133271 Homo sapiens Fc fragment of IgA, receptor for (FCAR), transcript
variant 3, r
NM_133272 Homo sapiens Fc fragment of IgA, receptor for (FCAR), transcript
variant 4, r
NM_133273 Homo sapiens Fc fragment of IgA, receptor for (FCAR), transcript
variant 5, r
NM_133274 Homo sapiens Fc fragment of IgA, receptor for (FCAR), transcript
variant 6, r
NM_133277 Homo sapiens Fc fragment of IgA, receptor for (FCAR), transcript
variant 7, r
NM_133278 Homo sapiens Fc fragment of IgA, receptor for (FCAR), transcript
variant 8, r
NM_133279 Homo Sapiens Fc fragment of IgA, receptor for (FCAR), transcript
variant 9, r
NM_133280 Homo Sapiens Fc fragment of IgA, receptor for (FCAR), transcript
variant 10,
NM_133282 Homo sapiens RAD1 homolog (S. pombe) (RAD1 ), transcript variant 2,
mRN
NM_133325 Homo sapiens PHD finger protein 10 (PHF10), transcript variant 2,
mRNA
NM_133326 Homo sapiens ATPase, H+ transporting, lysosomal 13kDa, V1 subunit G
isoi
NM_133327 Homo sapiens sema domain, transmembrane domain (TM), and cytoplasmic
NM_133328 Homo sapiens death effector domain containing 2 (DEDD2), mRNA
NM_133329 Homo sapiens potassium voltage-gated channel, subfamily G, member 3
(K(
NM 133330 Homo sapiens Wolf-Hirschhorn syndrome candidate 1 (WHSC1),
transcript
NM 133331 Homo sapiens Wolf-Hirschhorn syndrome candidate 1 (WHSC1),
transcript ~
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NM 133332 Homo sapiens Wolf Hirschhorn syndrome candidate 1 (WHSC1),
transcript v
NM 133333 Homo sapiens Wolf-Hirschhorn syndrome candidate 1 (WHSC1),
transcript v
NM_133334 Homo sapiens Wolf-Hirschhorn syndrome candidate 1 (WHSC1),
transcript
NM_133335 Homo sapiens Wolf-Hirschhorn syndrome candidate 1 (WHSC1),
transcript ~
NM_133336 Homo sapiens Wolf-Hirschhorn syndrome candidate 1 (WHSC1),
transcript ~
NM_133337 Homo sapiens fer-1-like 3, myoferlin (C, elegans) (FER1 L3),
transcript variar
NM_133338 Homo Sapiens RAD17 homolog (S, pombe) (F:AD17), transcript variant
1, mF
NM_133339 Homo sapiens RAD17 homolog (S. pombe) (RAD17), transcript variant 2,
mF
NM 133340 Homo sapiens RAD17 homolog (S. pombe) (RAD17), transcript variant 3,
mF
NM_133341 Homo sapiens F;AD17 homolog (S. pombe) (RAD17), transcript variant
4, mF
NM_133342 Homo sapiens RAD17 homolog (S. pombe) (RAD17), transcript variant 5,
mF
NM_133343 Homo sapiens RAD17 homolog (S. pombe) (FtADl7), transcript variant
6, mF
NM_133344 Homo Sapiens RAD17 homolog (S, pombe) (RAD17), transcript variant 7,
mF
NM_133367 Homo sapiens chromosome 6 open reading frame 33 (C6orf33), mRNA
NM_133368 Homo Sapiens KIAA1972 protein (KIAA1972), mRNA
NM 1.33370 Homo sapiens splicing factor YT521-B (YT521), mRNA
NM 133371 Homo Sapiens myozenin 3 (MYOZ3), mRNA
NM_733373 Homo sapiens phospholipase C, delta 3 (PLCD3), mRNA
NM_133375 Homo sapiens hypothetical protein MGC4562 (MGC4562), mRNA
NM_133376 Homo Sapiens integrin, beta 1 (fibronectin receptor, beta
polypeptide, antigei
NM_133377 Homo sapiens RAD1 homolog (S. pombej (RAD1 ), transcript variant 3,
mRN
NM_133378 Homo sapiens titin (TTNj, transcript variant N2-A, mRNA
NM_133379 Homo sapiens titin (TTN), transcript variant novex-3, mRNA
NM_133430 Homo sapiens G antigen, family D, 2 (GAGED2), transcript variant 3,
mRNA
NM_133431 Homo sapiens G antigen, family D, 2 (GAGED2), transcript variant 2,
mRNA
NM_133432 Homo sapiens titin (TTN), transcript variant novex-1, mRNA
NM_133433 Homo sapiens Nipped-B homolog (Drosophila) (NIPBL), transcript
variant A,
NM_133436 Homo sapiens asparagine synthetase (ASNS), transcript variant 1,
mRNA
NM 133437 Homo sapiens titin (TTN), transcript variant novex-2, mRNA
NM~133439 Homo sapiens transcriptional adaptor 2 (ADA2 homolog, yeast)-like
(TADA21
NM_~133443 Homo Sapiens glutamic pyruvate transaminase (alanine
aminotransferase) 2
NM_133444 Homo sapiens zinc finger protein 526 (ZNF526), mRNA
NM 133445 Homo sapiens glutamate receptor, ionotropic, N-methyl-D-aspartate 3A
(GRI
NM_~133446 Homo Sapiens centaurin, gamma-like family, member 1 (CTGLF1), mRNA
NM 133448 Homo sapiens KIAA1944 protein (KIAA1944), mRNA
NM_~133450 Homo Sapiens KIAA1977 protein (KIAA1977), mRNA
NM_133452 Homo sapiens RAVER1 (RAVER1), mRNA
NM_133455 Homo Sapiens EMI domain containing 1 (EMID1), mRNA
NM_133456 Homo sapiens apical protein 2 (APXL2), mRNA
NM_133457 Homo sapiens EMI domain containing 2 (EMID2), mRNA
NM_133459 Homo sapiens KIAA1983 protein (FLJ30681), mRNA
NM_133462 Homo sapiens tetratricopeptide repeat domain 14 (TTC14), mRNA
NM_133466 Homo sapiens zinc finger protein 545 (ZNF545), mRNA
NM_133467 Nomo sapiens Cbp/p300-interacting transactivator, with Glu/Asp-rich
carboxa
NM_133468 Homo sapiens BMP-binding endothelial regulator precursor protein
(BMPER;
NM_133473 Homo sapiens zinc finger protein 431 (ZNF431), mRNA
NM_133474 Homo Sapiens KIAA1982 protein (KIAA1982), mRNA
NM_133476 Homo sapiens zinc finger protein 384 (ZNF384), mRNA
NM_133478 Homo sapiens solute carrier family 4, sodium bicarbonate
cotransporter, mer
NM_133479 Homo sapiens solute carrier family 4, sodium bicarbonate
cotransporter, mer
NM_133480 Homo sapiens transcriptional adaptor 3 (NGG1 homolog, yeast)-like
(TADA3
NM 133481 Homo sapiens transcriptional adaptor 3 (NGG1 homolog, yeast)-like
(TADA3
NM 133482 Homo sapiens RAD50 homolog (S. cerevisiae) (RAD50), transcript
variant 2,
fVM_133483 Homo sapiens RAC/CDC42 exchange factor (GEFT), transcript variant
2, mF
NM 133484 Homo sapiens TRAF family member-associated NFKB activator (TANK),
tray
NM~_133486 Homo sapiens muscleblind-like 3 (Drosophila) (MBNL3), mRNA
NM_133487 Homo sapiens RAD51 homolog (RecA homolog, E. coli) (S. cerevisiae)
(RAC
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NM 133489 Homo sapiens solute carrier family 26, member 10 (SLC26A10), mRNA
NM_133490 Homo sapiens potassium voltage-gated channel, subfamily G, member 4
(K(
NM_133491 Homo sapiens spermidine/spermine N1-acetyltransferase 2 (SAT2), mRNA
NM_133492 Homo sapiens N-acylsphingosine amidohydrolase (alkaline ceramidase)
3 (~
NM_133493 Homo sapiens CD109 antigen (Gov platelet alloantigens) (CD109), mRNA
NM_133494 Homo sapiens NIMA (never in mitosis gene a)-related kinase 7 (NEK7),
mRf~
NM_133496 Homo Sapiens solute carrier family 30 (zinc transporter), member 7
{SLC30A
NM_133497 Homo sapiens potassium channel, subfamily V, member 2 (KCNV2), mRNA
NM_133498 Homo sapiens sperm acrosome associated 4 (SPACA4), mRNA
NM_133499 Homo sapiens synapsin I (SYN1), transcript variant Ib, mRNA
NM_133502 Homo sapiens zinc finger protein 274 (ZNF274), transcript variant
ZNF274c,
NM_133503 Homo Sapiens decorin (DCN), transcript variant A2, mRNA
NM_733504 Homo sapiens decorin {DCN), transcript variant B, mRNA
NM_133505 Homo Sapiens decorin {DCN), transcript variant C, mRNA
NM_133506 Homo sapiens decorin (DCN), transcript variant D, mRNA
NM_133507 Homo sapiens decorin (DCN), transcript variant E, mRNA
NM_133509 Homo Sapiens RAD51-like 1 (S. cerevisiae) (RAD51 L1 ), transcript
variant 3,
NM_133510 Homo sapiens RAD51-like 1 (S. cerevisiae) {RAD51L1), transcript
variant 2,
NM 133625 Homo sapiens synapsin II (SYN2), transcript variant Ila, mRNA
NM~_133627 Homo Sapiens RAD51-like 3 (S. cerevisiae) (RAD51 L3), transcript
variant 2,
NM 133628 Homo sapiens RAD51-like 3 (S. cerevisiae) (RAD51 L3j, transcript
variant 3,
NM~_133629 Homo Sapiens RAD51-like 3 (S. cerevisiae) (RAD51 L3), transcript
variant 4,
NM_133630 Homo sapiens RAD51-like 3 (S, cerevisiae) (RAD51 L3), transcript
variant 5,
NM_133631 Homo sapiens roundabout, axon guidance receptor, homolog 1
(Drosophila)
NM_133632 Homo sapiens synapsin III (SYN3), transcript variant Illb, mRNA
NM 133633 Homo sapiens synapsin III (SYN3), transcript variant Illc, mRNA
NM~_133634 Homo Sapiens protein O-fucosyltransferase 2 (POFUT2), transcript
variant 2,
NM_133635 Homo sapiens protein O-fucosyltransferase 2 (POFUT2), transcript
variant 3,
NM 133636 Homo sapiens DNA helicase HEL308 {HEL308), mRNA
NM~_133637 Homo Sapiens DEAQ box polypeptide 1 (RNA-dependent ATPase) (DQX1 ),
r
NM_133638 Homo sapiens a disintegrin-like and metalloprotease (reprolysin
type) with th
NM_133639 Homo Sapiens ras homoiog gene family, member V (RHOV), mRNA
NM_133640 Homo sapiens surfeit 5 (SURFS), transcript variant b, mRNA
NM_133642 Homo sapiens like-glycosyltransferase {LARGE), transcript variant 2,
mRNA
NM 133644 Homo sapiens GTP binding protein 3 (mitochondrial) (GTPBP3), mRNA
NM 133645 Homo sapiens mitochondrial translation optimization 1 homolog (S.
cerevisia
NM_~133646 Homo sapiens sterile alpha motif and leucine zipper containing
kinase AZK (;
NM_133650 Homo sapiens spectrin repeat containing, nuclear envelope 1 (SYNE1
), trap;
NM_134258 Homo sapiens transducin (beta)-like 1Y-linked (TBL1Y), transcript
variant 2, i
NM_134259 Homo sapiens transducin (beta)-like 1Y-linked (TBL1Y), transcript
variant 3, i
NM_134260 Homo sapiens RAR-related orphan receptor A (RORA), transcript
variant 2, r
NM_134261 Homo Sapiens RAR-related orphan receptor A (RORA), transcript
variant 1, r
NM_134262 Homo sapiens RAR-related orphan receptor A (RORA), transcript
variant 4, r
NM_134263 Homo Sapiens solute carrier family 26, member 6 (SLC26A6),
transcript varis
NM_134264 Homo sapiens WD repeat and SOCS box-containing 1 (WSB1), transcript
va
NM_134265 Homo sapiens WD repeat and SOCS box-containing 1 (WSB1), transcript
va
NM_134266 Homo sapiens solute carrier family 26, member 7 (SLC26A7),
Transcript vari~
NM 134268 Homo sapiens cytoglobin (CYGB), mRNA
NM~_134269 Homo Sapiens srnoothelin (SMTN), transcript variant 2, mRNA
NM_134270 Homo sapiens smoothelin {SMTN), transcript variant 1, mRNA
NM_134323 Homo sapiens TAR (HIV) RNA binding protein 2 (TARBP2), transcript
variant
NM_134324 Homo sapiens TAR (HIV) RNA binding protein 2 (TARBP2), transcript
variant
NM_134325 Homo sapiens solute carrier family 26, member 9 (SLC26A9),
transcript varia
NM_134421 Homo sapiens hippocalcin-like 1 (HPCAL1 ), transcript variant 2,
mRNA
NM 134422 Homo sapiens RAD52 homolog {S. cerevisiae) (RAD52), transcript
variant dE
NM 134423 Homo sapiens RAD52 homolog (S. cerevisiae) (RAD52), transcript
variant ga
NM 134424 Homo sapiens RAD52 homolog (S. cerevisiae) (RAD52), transcript
variant bE
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NM_134425 Homo sapiens solute carrier family 26 (sulfate transporter), member
1 (SLC2
NM_134426 Homo sapiens solute carrier family 26, member 6 (SLC26A6),
transcript vari~
NM_134427 Homo sapiens regulator of G-protein signalling 3 (RGS3), transcript
variant 4
NM_134428 Homo sapiens regulatory factor X, 3 (influences HLA class II
expression) (RF
NM_134431 Homo Sapiens solute carrier organic anion transporter family, member
1 A2 (;
NM_134433 Homo sapiens regulatory factor X, 2 (influences HLA class II
expression) (RF
NM_134434 Homo sapiens RAD54 homolog B (S, cerevisiae) (RAD54B), transcript
variar
NM_134440 Homo sapiens regulatory factor X-associated ankyrin-containing
protein (RF:
NM_134441 Homo sapiens relaxin 2 (H2) (RLN2), transcript variant 1, mRNA
NM_134442 Homo sapiens cAMP responsive element binding protein 1 (CREB1 ),
transcr
NM_134444 Homo sapiens NACHT, leucine rich repeat and PYD containing 4
(NALP4), n
NM_134445 Homo sapiens CD99 antigen-like 2 (CD99L2), mRNA
NM_134446 Homo sapiens CD99 antigen-like 2 (CD99L2), mRNA
NM_134447 Homo sapiens chromosome 19 open reading frame 2 (C19orf2),
transcript v~
NM_134470 Homo Sapiens interleukin 1 receptor accessory protein (1L1 RAP),
transcript v
NM_138270 Homo sapiens alpha thalassemia/mental retardation syndrome X-linked
(RAI
NM_138271 Homo Sapiens alpha thalassemia/mental retardation syndrome X-linked
(RAI
NM_138272 Homo sapiens chromosome 6 open reading frame 25 (C6orf25),
transcript v~
NM_138273 Homo sapiens chromosome 6 open reading frame 25 (C6orf25),
transcript v~
NM_138274 Homo sapiens chromosome 6 open reading frame 25 (C6orf25),
transcript vs
NM_138275 Homo sapiens chromosome 6 open reading frame 25 (C6orf25),
transcript v~
NM_138276 Homo sapiens chromosome 6 open reading frame 25 (C6orf25),
transcript v~
NM_138277 Homo sapiens chromosome 6 open reading frame 25 (C6orf25),
transcript v~
NM_138278 Homo sapiens BCL2/adenovirus E1B 19kD interacting protein like
(BNIPL), r
NM_138279 Homo sapiens BCL2/adenovirus E1B 19kD interacting protein like
(BNIPL), r
NM_138280 Homo Sapiens citrate lyase beta like (CLYBL), transcript variant 1,
mRNA
NM_138281 Homo sapiens distal-less homeobox 4 (DLX4), transcript variant 1,
mRNA
NM_138282 Homo sapiens ATPase, H+ transporting, lysosomal 13kDa, V1 subunit G
isoi
NM_138283 Homo sapiens cystatin-like 1 (CSTL1), mRNA
NM_138284 Homo sapiens interleukin 17D (IL17D), mRNA
NM_138285 Homo sapiens nucleoporin 35kDa (NUP35), mRNA
NM_138286 Homo sapiens hypothetical protein FLJ31526 (LOC148213), mRNA
NM_138287 Homo sapiens rhysin 2 (BBAP), mRNA
NM_138288 Homo sapiens chromosome 14 open reading frame 147 (C14orf147), mRNA
NM_138289 Homo sapiens actin-related protein T1 (ACTRT1), mRNA
NM_138290 Homo sapiens Rap2-binding protein 9 (RPIB9), mRNA
NM_138292 Homo sapiens ataxia telangiectasia mutated (includes complementation
grog
NM_138293 Homo sapiens ataxia telangiectasia mutated (includes complementation
grog
NM_138294 Homo sapiens expressed in prostate and testis (PATE), mRNA
NM_138295 Homo sapiens polycystic kidney disease 1 like 1 (PKD1 L1 ), mRNA
NM_138296 Homo sapiens pre T-cell antigen receptor alpha (PTCRA), mRNA
NM_138297 Homo sapiens mucin 4, tracheobronchial (MUC4), transcript variant 5,
mRN~
NM_138298 Homo sapiens mucin 4, tracheobronchial (MUC4), transcript variant 2,
mRNE
NM_138299 Homo sapiens mucin 4, tracheobronchial (MUC4), transcript variant 3,
mRN~
NM_138300 Homo Sapiens pygopus 2 (PYG02), mRNA
NM_138316 Homo sapiens pantothenate kinase 1 (PANK1), transcript variant
gamma, ml
NM_138317 Homo sapiens potassium channel, subfamily K, member 10 (KCNK10),
trans
NM_138318 Homo Sapiens potassium channel, subfamily K, member 10 (KCNK10),
trans
NM_138319 Homo sapiens proprotein convertase subtilisin/kexin type 6 (PCSK6),
transcr
NM_138320 Homo Sapiens proprotein convertase subtilisin/kexin type 6 (PCSK6),
transcr
NM_138321 Homo sapiens proprotein convertase subtilisin/kexin type 6 (PCSK6),
transcr
NM_138322 Homo sapiens proprotein convertase subtilisin/kexin type 6 (PCSK6),
transcr
NM_138323 Homo sapiens proprotein convertase subtilisin/kexin type 6 (PCSK6),
transcr
NM_138324 Homo sapiens proprotein convertase subtilisin/kexin type 6 (PCSK6),
transcr
NM_138325 Homo sapiens proprotein convertase subtilisin/kexin type 6 (PCSK6),
transcr
NM 138326 Homo sapiens aminocarboxymuconate semialdehyde decarboxylase (ACMS
NM 138327 Homo sapiens trace amine receptor 1 (TRAR1), mRNA
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NM_138328 Homo sapiens rhomboid, veinlet-like 4 (Drosophila) (RHBDL4), mRNA
NM_138329 Homo sapiens NACHT, leucine rich repeat and PYD containing 6
(NALP6), n
NM_138330 Homo Sapiens TRAF6-inhibitory zinc finger protein (TIZ), mRNA
NM_138331 Homo Sapiens ribonuclease, RNase A family, 8 (RNASE8), mRNA
NM_138333 Homo sapiens chromosome 9 open reading frame 42 (C9orf42), mRNA
NM_138334 Homo sapiens hypothetical transmembrane protein SBBI54 (SBBI54),
mRN~
NM_138335 Homo sapiens glucosamine-6-phosphate deaminase 2 (GNPDA2), mRNA
NM_138336 Homo sapiens helicase/primase complex protein (LOC150678), mRNA
NM_138337 Homo sapiens myeloid inhibitory C-type lectin-like receptor (MICL),
transcript
NM_138338 Homo sapiens polymerase (RNA) III (DNA directed) polypeptide H
(22.9kD) ~
NM_138340 Homo sapiens abhydrolase domain containing 3 (ABHD3), mRNA
NM_138341 Homo sapiens hypothetical protein BC000282 (LOC89894), mRNA
NM_138342 Homo sapiens hypothetical protein BC008326 (LOC89944), mRNA
NM_138343 Homo sapiens kinesin-like 8 (KNSL8), transcript variant 4, mRNA
NM_138344 Homo sapiens chromosome 14 open reading frame 152 (C14on'152), mRNA
NM_138346 Homo sapiens hypothetical protein MGC33867 (MGC33867), mRNA
NM_138347 Homo sapiens zinc finger protein 551 (ZNF551 ), mRNA
NM_138348 Homo sapiens hypothetical protein BC007706 (LOC90268), mRNA
NM_138349 Homo Sapiens hypothetical protein BC004507 (LOC90313), mRNA
NM_138350 Homo sapiens hypothetical protein MGC33488 (MGC33488), mRNA
NM_138352 Homo sapiens atherin (LOC90378), mRNA
NM_138355 Homo Sapiens secernin 2 (Ses2), mRNA
NM_138356 Homo sapiens hypothetical protein BC007586 (LOC90525), mRNA
NM_138357 Homo Sapiens chromosome 10 open reading frame 42 (C10orf42), mRNA
NM_138358 Homo sapiens hypothetical protein BC011833 (LOC90580), mRNA
NM_138360 Homo Sapiens hypothetical protein BC008134 (LOC90668), mRNA
NM_138361 Homo sapiens leucine rich repeat and sterile alpha motif containing
1 (LRSA
NM_138362 Homo sapiens hypothetical protein BC000919 (LOC90736), mRNA
NM_138363 Homo sapiens hypothetical protein BC009518 (LOC90799), mRNA
NM_138364 Homo sapiens hypothetical protein BC004337 (LOC90826), mRNA
NM_138368 Homo sapiens hypothetical protein BC004895 (LOC91056), mRNA
NM_138369 Homo sapiens family with sequence similarity 44, member B (FAM44B),
mRP
NM_138371 Homo sapiens hypothetical protein MGC16044 (MGC16044), mRNA
NM_138372 Homo sapiens hypothetical protein BC001610 (LOC91661), mRNA
NM_138373 Homo Sapiens myeloid-associated differentiation marker (MYADM), mRNA
NM_138375 Homo sapiens Cdk5 and Abl enzyme substrate 1 (CABLES1), mRNA
NM_138376 Homo sapiens tetratricopeptide repeat domain 5 (TTCS), mRNA
NM_138379 Homo sapiens T-cell immunoglobulin and mucin domain containing 4
(TIMD~
NM_138381 Homo sapiens hypothetical protein BC008322 (MGC15763), mRNA
NM_138383 Homo sapiens hypothetical protein BC002770 (LOC92154), mRNA
NM_138384 Homo Sapiens shadow of prion protein (Sprn), mRNA
NM_138385 Homo sapiens hypothetical protein BC009331 (LOC92305), mRNA
NM_138386 Homo sapiens hypothetical protein BC008207 (LOC92345), mRNA
NM_138387 Homo Sapiens glucose 6 phosphatase, catalytic, 3 (G6PC3), mRNA
NM_138389 Homo sapiens hypothetical protein BC001096 (LOC92689), mRNA
NM_138390 Homo sapiens hypothetical protein BC008604 (LOC92691), mRNA
NM_138391 Homo sapiens chromosome 1 open reading frame 37 (C1orf37), mRNA
NM_138392 Homo Sapiens hypothetical protein BC007653 (LOC92799), mRNA
NM_138393 Homo sapiens chromosome 19 open reading frame 32 (C19orf32), mRNA
NM_138394 Homo sapiens hypothetical protein BC008217 (LOC92906), mRNA
NM_138395 Homo sapiens mitochondria) methionyl-tRNA synthetase (MetRS), mRNA
NM_138396 Homo sapiens hypothetical protein BC009489 (LOC92979), mRNA
NM_138397 Homo sapiens hypothetical protein BC012317 (LOC93082), mRNA
NM_138399 Homo Sapiens hypothetical protein BC007772 (LOC93109), mRNA
NM_138401 Homo sapiens hypothetical protein BC011840 (LOC93343), mRNA
NM 138402 Homo sapiens hypothetical protein BC004921 (LOC93349), mRNA
NM 138403 Homo Sapiens myosin light chain 2, precursor lymphocyte-specific
(MYLC2P
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NM_138408 Homo sapiens chromosome 6 open reading frame 51 (C6orf51), mRNA
NM_138409 Homo sapiens chromosome 6 open reading frame 117 (C6orf117), mRNA
NM_138410 Homo sapiens chemokine-like factor super family 7 (CKLFSF7),
transcript va
NM_138412 Homo Sapiens retinol dehydrogenase 13 (all-trans and 9-cis) (RDH13),
mRN
NM_138413 Homo sapiens chromosome 10 open reading frame 65 (C10orf65), mRNA
NM_138414 Homo sapiens hypothetical protein BC011981 (LOC112869), mRNA
NM_138415 Homo sapiens hypothetical protein BC012187 (LOC112885), mRNA
NM_138416 Homo sapiens hypothetical protein BC011001 (LOC112937), mRNA
NM_138417 Homo sapiens hypothetical protein BC012173 (MGC20419), mRNA
NM_138418 Homo sapiens hypothetical protein MGC15416 (MGC15416), mRNA
NM_138419 Homo sapiens DUF729 domain containing 1 (DUFD1), mRNA
NM_138421 Homo Sapiens hypothetical protein BC012010 (LOC113174), mRNA
NM_138422 Homo sapiens hypothetical protein BC011824 (LOC113179), mRNA
NM_138423 Homo sapiens H63 breast cancer expressed gene (H63), transcript
variant 1
NM_138424 Homo Sapiens kinesin family member 12 (KIF12), mRNA
NM_138425 Homo sapiens likely ortholog of mouse gene rich cluster, C10 gene
(GRCC1~
NM_138428 Homo sapiens hypothetical protein BC011880 (LOC113444), mRNA
NM_138429 Homo sapiens claudin 15 (CLDN15), mRNA
NM_138430 Homo sapiens ADP-ribosylhydrolase like 1 (ADPRHL1), transcript
variant 1, i
NM_138431 Homo sapiens hypothetical protein BC011982 (LOC113655), mRNA
NM_138432 Homo sapiens serine dehydratase-like (SDSL), mRNA
NM_138433 Homo sapiens hypothetical protein BC009980 (MGC16635), mRNA
NM_138434 Homo sapiens chromosome 7 open reading frame 29 (C7orf29), mRNA
NM_138435 Homo sapiens hypothetical protein BC011204 (LOC113828), mRNA
NM_138436 Homo Sapiens hypothetical protein BC013035 (LOC114926), mRNA
NM_138437 Homo sapiens GASP2 protein (GASP2), mRNA
NM_138439 Homo sapiens hypothetical protein BC014089 (LOC114984), mRNA
NM_138440 Homo sapiens hypothetical protein BC013767 (LOC114990), mRNA
NM_138441 Homo sapiens chromosome 6 open reading frame 150 (C6orf150), mRNA
NM_138442 Homo sapiens hypothetical protein BC013949 (LOC115098), mRNA
NM_138443 Homo sapiens coiled-coil domain containing 5 (spindle associated)
(CCDCS)
NM_138444 Homo sapiens potassium channel tetramerisation domain containing 12
(KC'
NM_138445 Homo Sapiens G protein-coupled receptor 146 (GPR146), mRNA
NM_138446 Homo Sapiens chromosome 7 open reading frame 30 (C7orf30), mRNA
NM_138447 Homo sapiens hypothetical protein BC014000 (LOC115509), mRNA
NM_138448 Homo sapiens acylphosphatase 2, muscle type (ACYP2), mRNA
NM_138450 Homo sapiens ADP-ribosylation factor-like 11 (ARL11), mRNA
NM_138451 Homo sapiens hypothetical protein BC013151 (LOC115811), mRNA
NM_138452 Homo sapiens dehydrogenase/reductase (SDR family) member 1 (DHRS1),
NM_138453 Homo sapiens RAB3C, member RAS oncogene family (RAB3C), mRNA
NM_138454 Homo sapiens thioredoxin-like 6 (TXNL6), mRNA
NM_138455 Homo sapiens collagen triple helix repeat containing 1 (CTHRC1 ),
mRNA
NM_138456 Homo sapiens hypothetical protein BC012330 (MGC20410), mRNA
NM_138457 Homo sapiens forkhead box P4 (FOXP4), mRNA
NM_138458 Homo sapiens hypothetical protein BC014022 (LOC116143), mRNA
NM_138459 Homo sapiens chromosome 6 open reading frame 68 (C6orf68), mRNA
NM_138460 Homo Sapiens chemokine-like factor super family 5 (CKLFSFS),
transcript va
NM_138461 Homo sapiens hypothetical protein BC013113 (LOC116211), mRNA
NM_138462 Homo sapiens zinc finger, MYND domain containing 19 (ZMYND19), mRNA
NM_138463 Homo sapiens hypothetical protein BC014072 (LOC116238), mRNA
NM_138465 Homo Sapiens GLI-Kruppel family member GLI4 (GLI4), mRNA
NM_138467 Homo sapiens hypothetical protein BC009514 (LOC127253), mRNA
NM_138468 Homo sapiens amyotrophic lateral sclerosis 2 (juvenile) chromosome
region,
NM_138471 Homo sapiens hypothetical protein BC007540 (LOC144097), mRNA
NM_138473 Homo Sapiens Sp1 transcription factor (SP1), mRNA
NM 138476 Homo sapiens hypothetical protein MGC5987 (MGC5987), mRNA
NM 138477 Homo Sapiens congenital dyserythropoietic anemia, type I (CDAN1),
mRNA
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NM_138479 Homo sapiens hypothetical protein BC007899 (LOC148898), mRNA
NM_138482 Homo sapiens hypothetical protein BC009264 (LOC151534), mRNA
NM_138484 Homo sapiens shugoshin-like 1 (S. pombe) (SGOL1), mRNA
NM_138487 Homo sapiens hypothetical protein BC007882 (LOC152217), mRNA
NM_138492 Homo Sapiens hypothetical protein MGC21644 (MGC21644), transcript
varia
NM_138494 Homo sapiens vav-1 interacting Kruppel-like protein (VIK),
transcript variant
NM_138497 Homo sapiens hypothetical protein BC008050 (LOC158435), mRNA
NM_138499 Homo sapiens PWWP domain containing 2 (PWWP2), mRNA
NM_138501 Homo sapiens glycoprotein, synaptic 2 (GPSN2), mRNA
NM_138551 Homo sapiens thymic stromal lymphopoietin (TSLP), transcript variant
2, mR
NM_138553 Homo Sapiens B-cell CLUlymphoma 11A (zinc finger protein) (BCL11A),
tran
NM_138554 Homo sapiens toll-like receptor 4 (TLR4), transcript variant 1, mRNA
NM_138555 Homo sapiens kinesin family member 23 (KIF23), transcript variant 1,
mRNA
NM_138556 Homo sapiens toll-like receptor 4 (TLR4), transcript variant 2, mRNA
NM_138557 Homo sapiens toll-like receptor 4 (TLR4), transcript variant 4, mRNA
NM_138558 Homo sapiens protein phosphatase 1, regulatory (inhibitor) subunit 8
(PPP1 F
NM_138559 Homo sapiens B-cell CLUlymphoma 11A (zinc finger protein) (BCL11A),
tran
NM_138563 Homo sapiens kallikrein 15 (KLK15), transcript variant 2, mRNA
NM_138564 Homo sapiens kallikrein 15 (KLK15), transcript variant 3, mRNA
NM_138565 Homo sapiens cortactin (CTTN), transcript variant 2, mRNA
NM_138566 Homo Sapiens glutaminase 2 (liver, mitochondrial) (GLS2), nuclear
gene enc
NM_138567 Homo sapiens synaptotagmin VIII (SYTB), mRNA
NM_138568 Homo sapiens protein 7 transactivated by hepatitis B virus X antigen
(HBxAg
NM_138569 Homo Sapiens chromosome 6 open reading frame 142 (C6orf142), mRNA
NM_138570 Homo sapiens hypothetical protein MGC15523 (MGC15523), mRNA
NM_138571 Homo Sapiens histidine triad nucleotide binding protein 3 (HINT3),
mRNA
NM_138572 Homo sapiens taube nuss homolog (mouse) (TBN), mRNA
NM_138573 Homo sapiens neuregulin 4 (LOC145957), mRNA
NM_138574 Homo sapiens PWWP domain containing 1 (PWWP1), mRNA
NM_138575 Homo sapiens hypothetical protein MGC5352 (MGC5352), mRNA
NM_138576 Homo sapiens B-cell CLUlymphoma 11 B (zinc finger protein) (BCL11
B), tran
NM_138578 Homo sapiens BCL2-like 1 (BCL2L1), nuclear gene encoding
mitochondrial t
NM_138608 Homo sapiens metallophosphoesterase 1 (MPPE1), mRNA
NM_138609 Homo sapiens H2A histone family, member Y (H2AFY), transcript
variant 1, r
NM_138610 Homo Sapiens H2A histone family, member Y (H2AFY), transcript
variant 3, r
NM_138612 Homo sapiens hyaluronan synthase 3 (HAS3), transcript variant 2,
mRNA
NM_138614 Homo Sapiens DEAH (Asp-Glu-Ala-His) box polypeptide 30 (DHX30),
transcr
NM_138615 Homo sapiens DEAH (Asp-Glu-Ala-His) box polypeptide 30 (DHX30),
transcr
NM_138616 Homo sapiens Rhesus blood group, CcEe antigens (RHCE), transcript
variar
NM_138617 Homo sapiens Rhesus blood group, CcEe antigens (RHCE), transcript
variar
NM_138618 Homo sapiens Rhesus blood group, CcEe antigens (RHCE), transcript
variar
NM_138619 Homo sapiens golgi associated, gamma adaptin ear containing, ARF
binding
NM_138620 Homo sapiens DEAD (Asp-Glu-Ala-Asp) box polypeptide 31 (DDX31),
transc
NM_138621 Homo sapiens BCL2-like 11 (apoptosis facilitator) (BCL2L11 ),
transcript varia
NM_138622 Homo Sapiens BCL2-like 11 (apoptosis facilitator) (BCL2L11 ),
transcript vari~
NM_138623 Homo sapiens BCL2-like 11 (apoptosis facilitator) (BCL2L11 ),
transcript varia
NM_138624 Homo sapiens BCL2-like 11 (apoptosis facilitator) (BCL2L11 ),
transcript varia
NM_138625 Homo sapiens BCL2-like 11 (apoptosis facilitator) (BCL2L11),
transcript vari~
NM_138626 Homo sapiens BCL2-like 11 (apoptosis facilitator) (BCL2L11 ),
transcript vari~
NM_138627 Homo sapiens BCL2-like 11 (apoptosis facilitator) (BCL2L11 ),
transcript vari~
NM_138632 Homo sapiens Tara-like protein (HRIHFB2122), transcript variant 2,
mRNA
NM_138633 Homo sapiens A kinase (PRKA) anchor protein 7 (AKAP7), transcript
variant
NM_138634 Homo sapiens microseminoprotein, beta- (MSMB), transcript variant
PSP57,
NM_138635 Homo sapiens H2A histone family, member V (H2AFV), transcript
variant 2, r
NM_138636 Homo sapiens toll-like receptor 8 (TLRB), transcript variant 2, mRNA
NM_138637 Homo sapiens dudulin 2 (TSAP6), mRNA
NM_138638 Homo sapiens cofilin 2 (muscle) (CFL2), transcript variant 2, mRNA
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NM_138639 Homo sapiens BCL2-like 12 (proline rich) (BCL2L12), transcript
variant 1, mF
NM_138640 Homo sapiens golgi associated, gamma adaptin ear containing, ARF
binding
NM_138643 Homo Sapiens calcium-binding tyrosine-(Y)-phosphorylation regulated
(fibro~
NM_138644 Homo sapiens calcium-binding tyrosine-(Y)-phosphorylation regulated
(fibro~
NM_138687 Homo Sapiens phosphatidylinositol-4-phosphate 5-kinase, type II,
beta (PIP5
NM_138688 Homo sapiens toll-like receptor 9 (TLR9), transcript variant B, mRNA
NM_138691 Homo sapiens transmembrane channel-like 1 (TMC1), mRNA
NM_138693 Homo sapiens Kruppel-like factor 14 (KLF14), mRNA
NM_138694 Homo Sapiens polycystic kidney and hepatic disease 1 (autosomal
recessive
NM_138697 Homo sapiens taste receptor, type 1, member 1 (TAS1 R1 ), transcript
variant
NM_138698 Homo sapiens prematurely terminated mRNA decay factor-like (LOC91431
),
NM_138699 Homo sapiens hypothetical protein BC006130 (LOC93622), mRNA
NM_138700 Homo sapiens tripartite motif-containing 40 (TRIM40), mRNA
NM_138701 Homo sapiens chromosome 7 open reading frame 11 (C7orf11), mRNA
NM_138702 Homo sapiens melanoma antigen, family C, 3 (MAGEC3), transcript
variant 1
NM_138703 Homo sapiens melanoma antigen, family E, 2 (MAGEE2), mRNA
NM_138704 Homo sapiens necdin-like 2 (NDNL2), mRNA
NM_138705 Homo sapiens calglandulin-like protein (CAGLP), mRNA
NM_138706 Homo sapiens beta-1,3-N-acetylglucosaminyltransferase protein
(IMAGE:49i
NM_138707 Homo sapiens B-cell CLL/lymphoma 7B (BCL7B), transcript variant 2,
mRNP
NM_138709 Homo sapiens DAB2 interacting protein (DAB21P), mRNA
NM_138711 Homo Sapiens peroxisome proliferative activated receptor, gamma
(PPARG)
NM_138712 Homo sapiens peroxisome proliferative activated receptor, gamma
(PPARG)
NM_138713 Homo sapiens nuclear factor of activated T-cells 5, tonicity-
responsive (NFA-
NM_138714 Homo sapiens nuclear factor of activated T-cells 5, tonicity-
responsive (NFA-
NM_138715 Homo sapiens macrophage scavenger receptor 1 (MSR1), transcript
variant
NM_138716 Homo sapiens macrophage scavenger receptor 1 (MSR1 ), transcript
variant
NM_138717 Homo sapiens palmitoyl-protein thioesterase 2 (PPT2), transcript
variant 2, n
NM_138718 Homo sapiens solute carrier family 26, member 8 (SLC26A8),
transcript varia
NM_138720 Homo sapiens histone 1, H2bd (HIST1 H2BD), transcript variant 2,
mRNA
NM_138722 Homo Sapiens BCL2-like 14 (apoptosis facilitator) (BCL2L14),
transcript vari~
NM_138723 Homo sapiens BCL2-like 14 (apoptosis facilitator) (BCL2L14),
transcript varia
NM_138724 Homo Sapiens BCL2-like 14 (apoptosis facilitator) (BCL2L14),
transcript varia
NM_138726 Homo sapiens ATP-binding cassette, sub-family C (CFTR/MRP), member
13
NM_138727 Homo sapiens suppression of tumorigenicity 7 like (ST7L), transcript
variant
NM_138728 Homo sapiens suppression of tumorigenicity 7 like (ST7L), transcript
variant
NM_138729 Homo sapiens suppression of tumorigenicity 7 like (ST7L), transcript
variant.
NM_138730 Homo sapiens high mobility group nucleosomal binding domain 3
(HMGN3),
NM_138731 Homo sapiens mirror-image polydactyly 1 (MIPOL1), mRNA
NM_138732 Homo Sapiens neurexin 2 (NRXN2), transcript variant alpha-2, mRNA
NM_138733 Homo sapiens phosphoglycerate kinase 2 (PGK2), mRNA
NM_138734 Homo sapiens neurexin 2 (NRXN2), transcript variant beta, mRNA
NM_138735 Homo sapiens neurexin 1 (NRXN1), transcript variant beta, mRNA
NM_138736 Homo sapiens guanine nucleotide binding protein (G protein), alpha
activatin
NM_138737 Homo sapiens hephaestin (HEPH), transcript variant 1, mRNA
NM_138738 Homo sapiens SH2 domain containing phosphatase anchor protein 1
(SPAP
NM_138739 Homo sapiens SH2 domain containing phosphatase anchor protein 1
(SPAP
NM_138740 Homo Sapiens NICE-3 protein (NICE-3), mRNA
NM_138761 Homo sapiens BCL2-associated X protein (BAX), transcript variant
alpha, mF
NM_138762 Homo sapiens BCL2-associated X protein (BAX), transcript variant
gamma, r
NM_138763 Homo Sapiens BCL2-associated X protein (BAX), transcript variant
delta, mR
NM_138764 Homo sapiens BCL2-associated X protein (BAX), transcript variant
epsilon, n
NM_138765 Homo sapiens BCL2-associated X protein (BAX), transcript variant
sigma, m
NM_138766 Homo sapiens peptidylglycine alpha-amidating monooxygenase (PAM),
tram
NM_138768 Homo sapiens myeloma overexpressed gene (in a subset of t(11;14)
positive
NM_138769 Homo sapiens ras homolog gene family, member T2 (RHOT2), mRNA
NM_138770 Homo sapiens hypothetical protein BC016861 (LOC90557), mRNA
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NM_138771 Homo sapiens alpha-1,3(6)-mannosylglycoprotein beta-1,6-N-acetyl-
glucosa
NM_138773 Homo sapiens hypothetical protein BC017169 (LOC91137), mRNA
NM_138774 Homo sapiens chromosome 19 open reading frame 22 (Cl9orf22), mRNA
NM_138775 Homo sapiens hypothetical protein BC015183 (LOC91801 ), mRNA
NM_138777 Homo sapiens mitochondrial ribosome recycling factor (MRRF),
transcript va
NM_138778 Homo sapiens chromosome 9 open reading frame 112 (C9orf112), mRNA
NM_138779 Homo sapiens hypothetical protein BC015148 (LOC93081), mRNA
NM_138780 Homo sapiens synaptotagmin-like 5 (SYTLS), mRNA
NM_138781 Homo sapiens similar to envelope protein (LOC113386), mRNA
NM_138783 Homo sapiens zinc finger protein Zip67 (ZIP67), mRNA
NM_138784 Homo sapiens hypothetical protein BC014341 (LOC116123), mRNA
NM_138785 Homo Sapiens chromosome 6 open reading frame 72 (C6orf72), mRNA
NM_138786 Homo sapiens hypothetical protein BC014339 (LOC116441), mRNA
NM_138787 Homo sapiens hypothetical protein BC009561 (LOC119710), mRNA
NM_138788 Homo sapiens hypothetical protein BC016153 (LOC120224), mRNA
NM_138789 Homo sapiens hypothetical protein BC019238 (LOC120379), mRNA
NM_138790 Homo Sapiens hypothetical protein BC015003 (LOC122618), mRNA
NM_138791 Homo sapiens chromosome 14 open reading frame 148 (C14orf148), mRNA
NM_138792 Homo sapiens senescence downregulated leo1-like (LOC123169), mRNA
NM_138793 Homo sapiens ectonucleoside triphosphate diphosphohydrolase 8
(ENTPD8;
NM_138794 Homo sapiens lysophospholipase-like 1 (LYPLAL1 ), mRNA
NM_138795 Homo sapiens ADP-ribosylation factor-like 10B (ARL10B), mRNA
NM_138796 Homo sapiens hypothetical protein BC014608 (LOC128153), mRNA
NM_138797 Homo sapiens hypothetical protein BC014641 (LOC129138), mRNA
NM_138798 Homo sapiens hypothetical protein BC018453 (LOC129531), mRNA
NM_138799 Homo sapiens O-acyltransferase (membrane bound) domain containing 2
(0
NM_138800 Homo sapiens tripartite motif-containing 43 (TRIM43), mRNA
NM_138801 Homo sapiens galactose mutarotase (aldose 1-epimerase) (GALM), mRNA
NM_138802 Homo sapiens hypothetical protein BC018415 (LOC130617), mRNA
NM_138803 Homo sapiens hypothetical protein BC015395 (LOC130940), mRNA
NM_138804 Homo sapiens hypothetical protein BC014602 (LOC130951), mRNA
NM_138805 Homo sapiens family with sequence similarity 3, member D (FAM3D),
mRNA
NM_138806 Homo Sapiens MOX2 receptor (MOX2R), transcript variant 1, mRNA
NM_138807 Homo sapiens hypothetical protein BC015088 (MGC16471), mRNA
NM_138808 Homo sapiens hypothetical protein BC015210 (LOC132200), mRNA
NM_138809 Homo sapiens hypothetical protein BC001573 (LOC134147), mRNA
NM_138810 Homo sapiens T-cell activation GTPase activating protein (TAGAP),
transcri~
NM_138811 Homo sapiens chromosome 7 open reading frame 31 (C7orf31 ), mRNA
NM_138812 Homo sapiens hypothetical protein BC019250 (LOC143241 ), mRNA
NM_138813 Homo sapiens ATPase, Class I, type 8B, member 3 (ATP8B3), mRNA
NM_138814 Homo sapiens GS2 like (LOC150379), mRNA
NM_138815 Homo sapiens hypothetical protein BC018070 (LOC151871), mRNA
NM_138817 Homo Sapiens solute carrier family 7, (cationic amino acid
transporter, y+ sy.
NM_138818 Homo sapiens chromosome 9 open reading frame 65 (C9orf65), mRNA
NM_138819 Homo sapiens hypothetical protein BC017868 (LOC159091), mRNA
NM_138820 Homo sapiens hypothetical protein MGC2198 (MGC2198), mRNA
NM_138821 Homo sapiens peptidylglycine alpha-amidating monooxygenase (PAM),
tran;
NM_138822 Homo sapiens peptidylglycine alpha-amidating monooxygenase (PAM),
tram
NM_138923 Homo Sapiens TAF1 RNA polymerase II, TATA box binding protein (TBP)-
as.
NM_138924 Homo sapiens guanidinoacetate N-methyltransferase (GAMT), transcript
vari
NM_138925 Homo sapiens SON DNA binding protein (SON), transcript variant a,
mRNA
NM_138926 Homo sapiens SON DNA binding protein (SON), transcript variant c,
mRNA
NM_138927 Homo sapiens SON DNA binding protein (SON), transcript variant f,
mRNA
NM_138928 Homo sapiens molybdenum cofactor synthesis 1 (MOCS1 ), transcript
variant
NM_138929 Homo sapiens diablo homolog (Drosophila) (DIABLO), nuclear gene
encodin
NM_138930 Homo sapiens diablo homolog (Drosophila) (DIABLO), nuclear gene
encodin
NM_138931 Homo sapiens B-cell CLUlymphoma 6 (zinc finger protein 51 ) (BCL6),
transc
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NM_138932 Homo sapiens apobec-1 complementation factor (ACF), transcript
variant 2,
NM_138933 Homo sapiens apobec-1 complementation factor (ACF), transcript
variant 3,
NM_138934 Homo sapiens palmitoyl-protein thioesterase 2 (PPT2), transcript
variant 3, n
NM_138937 Homo Sapiens pancreatitis-associated protein (PAP), transcript
variant 3, mF
NM_138938 Homo sapiens pancreatitis-associated protein (PAP), transcript
variant 2, mF
NM_138939 Homo sapiens MOX2 receptor (MOX2R), transcript variant 2, mRNA
NM_138940 Homo sapiens MOX2 receptor (MOX2R), transcript variant 3, mRNA
NM_138957 Homo sapiens mitogen-activated protein kinase 1 (MAPK1), transcript
varian
NM_138958 Homo sapiens autocrine motility factor receptor (AMFR), transcript
variant 2,
NM_138959 Homo sapiens yang-like 1 (van gogh, Drosophila) (VANGL1), mRNA
NM_138960 Homo sapiens TGFB-induced factor 2-like, X-linked (TGIF2LX), mRNA
NM_138961 Homo sapiens endothelial cell adhesion molecule (ESAM), mRNA
NM_138962 Homo sapiens musashi homolog 2 (Drosophila) (MSI2), transcript
variant 1, i
NM_138963 Homo sapiens ribosomal protein S4, Y-linked 2 (RPS4Y2), mRNA
NM_138964 Homo sapiens G protein-coupled receptor 73 (GPR73), mRNA
NM_138966 Homo Sapiens neuropilin (NRP) and tolloid (TLL)-like 1 (NET01),
transcriptv
NM_138967 Homo sapiens secretory carrier membrane protein 5 (SCAMPS), mRNA
NM_138969 Homo sapiens retinal short chain dehydrogenase reductase (RDH-E2),
mRN
NM_138970 Homo sapiens neurexin 3 (NRXN3), transcript variant beta, mRNA
NM_138971 Homo sapiens beta-site APP-cleaving enzyme 1 (BACE1 ), transcript
variant
NM_138972 Homo Sapiens beta-site APP-cleaving enzyme 1 (BACE1 ), transcript
variant
NM_138973 Homo sapiens beta-site APP-cleaving enzyme 1 (BACE1 ), transcript
variant
NM_138980 Homo sapiens mitogen-activated protein kinase 10 (MAPK10),
transcript vari
NM_138981 Homo sapiens mitogen-activated protein kinase 10 (MAPK10),
transcript vari
NM_138982 Homo sapiens mitogen-activated protein kinase 10 (MAPK10),
transcript vari
NM_138983 Homo Sapiens oligodendrocyte transcription factor 1 (OLIG1 ), mRNA
NM_138991 Homo sapiens beta-site APP-cleaving enzyme 2 (BACE2), transcript
variant
NM_138992 Homo sapiens beta-site APP-cleaving enzyme 2 (BACE2), transcript
variant
NM_138993 Homo sapiens mitogen-activated protein kinase 11 (MAPK11 ),
transcript vari
NM_138994 Homo sapiens contactin associated protein-like 4 (CNTNAP4),
transcript vari
NM_138995 Homo Sapiens myosin IIIB (MY03B), mRNA
NM_138996 Homo sapiens contactin associated protein-like 5 (CNTNAPS),
transcript vari
NM_138998 Homo sapiens DEAD (Asp-Glu-Ala-Asp) box polypeptide 39 (DDX39),
transc
NM_138999 Homo Sapiens neuropilin (NRP) and tolloid (TLL)-like 1 (NET01),
transcript v
NM_139002 Homo sapiens hemochromatosis (HFE), transcript variant 2, mRNA
NM_139003 Homo sapiens hemochromatosis (HFE), transcript variant 3, mRNA
NM_139004 Homo sapiens hemochromatosis (HFE), transcript variant 4, mRNA
NM_139005 Homo sapiens hemochromatosis (HFE), transcript variant 5, mRNA
NM_139006 Homo sapiens hemochromatosis (HFE), transcript variant 6, mRNA
NM_139007 Homo sapiens hemochromatosis (HFE), transcript variant 7, mRNA
NM_139008 Homo sapiens hemochromatosis (HFE), transcript variant 8, mRNA
NM_139009 Homo sapiens hemochromatosis (HFE), transcript variant 9, mRNA
NM_139010 Homo Sapiens hemochromatosis (HFE), transcript variant 10, mRNA
NM_139011 Homo sapiens hemochromatosis (HFE), transcript variant 11, mRNA
NM_139012 Homo sapiens mitogen-activated protein kinase 14 (MAPK14),
transcript vari
NM_139013 Homo sapiens mitogen-activated protein kinase 14 (MAPK14),
transcript vari
NM_139014 Homo sapiens mitogen-activated protein kinase 14 (MAPK14),
transcript vari
NM_139015 Homo Sapiens signal peptide peptidase 3 (SPPL3), mRNA
NM_139016 Homo sapiens hypothetical gene LOC128439 (LOC128439), mRNA
NM_139017 Homo sapiens interleukin 31 receptor A (1L31 RA), mRNA
NM_139018 Homo Sapiens NK inhibitory receptor precursor (NKIR), mRNA
NM_139021 Homo sapiens extracellular signal-regulated kinase 8 (ERKB), mRNA
NM_139022 Homo sapiens pan-hematopoietic expression (PHEMX), transcript
variant 1,
NM_139024 Homo sapiens pan-hematopoietic expression (PHEMX), transcript
variant 3,
NM_139025 Homo sapiens a disintegrin-like and metalloprotease (reprolysin
type) with th
NM 139026 Homo Sapiens a disintegrin-like and metalloprotease (reprolysin
type) with th
NM 139027 Homo sapiens a disintegrin-like and metalloprotease (reprolysin
type) with th
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NM_139028 Homo sapiens a disintegrin-like and metalloprotease (reprolysin
type) with th
NM_139030 Homo sapiens CD151 antigen (CD151 ), transcript variant 2, mRNA
NM_139032 Homo sapiens mitogen-activated protein kinase 7 (MAPK7), transcript
varian
NM_139033 Homo sapiens mitogen-activated protein kinase 7 (MAPK7), transcript
varian
NM_139034 Homo Sapiens mitogen-activated protein kinase 7 (MAPK7), transcript
varian
NM_139035 Homo sapiens SW I/SNF related, matrix associated, actin dependent
regulate
NM_139045 Homo sapiens SWI/SNF related, matrix associated, actin dependent
regulate
NM_139046 Homo sapiens mitogen-activated protein kinase 8 (MAPKB), transcript
varian
NM_139047 Homo sapiens mitogen-activated protein kinase 8 (MAPKB), transcript
varian
NM_139048 Homo sapiens SWI/SNF related, matrix associated, actin dependent
regulate
NM_139049 Homo Sapiens mitogen-activated protein kinase 8 (MAPKB), transcript
varian
NM_139053 Homo sapiens EPSB-like 3 (EPS8L3), transcript variant 1, mRNA
NM_139054 Homo sapiens a disintegrin-like and metalloprotease (reprolysin
type) with th
NM_139055 Homo Sapiens a disintegrin-like and metalloprotease (reprolysin
type) with th
NM_139056 Homo sapiens a disintegrin-like and metalloprotease (reprolysin
type) with th
NM_139057 Homo sapiens a disintegrin-like and metalloprotease (reprolysin
type) with th
NM_139058 Homo sapiens aristaless related homeobox (ARX), mRNA
NM_139062 Homo sapiens casein kinase 1, delta (CSNK1 D), transcript variant 2,
mRNA
NM_139067 Homo sapiens SWI/SNF related, matrix associated, actin dependent
regulate
NM_139068 Homo sapiens mitogen-activated protein kinase 9 (MAPK9), transcript
varian
NM_139069 Homo sapiens mitogen-activated protein kinase 9 (MAPK9), transcript
varian
NM_139070 Homo sapiens mitogen-activated protein kinase 9 (MAPK9), transcript
varian
NM_139071 Homo sapiens SWI/SNF related, matrix associated, actin dependent
regulate
NM_139072 Homo sapiens delta-notch-like EGF repeat-containing transmembrane
(DNE
NM_139073 Homo sapiens spermatogenesis associated 3 (SPATA3), mRNA
NM_139074 Homo sapiens defensin, beta 127 (DEFB127), mRNA
NM_139075 Homo sapiens two pore segment channel 2 (TPCN2), mRNA
NM_139076 Homo sapiens hypothetical protein FLJ13614 (FLJ13614), mRNA
NM_139078 Homo sapiens mitogen-activated protein kinase-activated protein
kinase 5 (h
NM_139118 Homo sapiens YY1 associated protein (YAP), transcript variant 2,
mRNA
NM_139119 Homo sapiens YY1 associated protein (YAP), transcript variant 3,
mRNA
NM_139120 Homo sapiens YY1 associated protein (YAP), transcript variant 4,
mRNA
NM_139121 Homo sapiens YY1 associated protein (YAP), transcript variant 5,
mRNA
NM_139122 Homo sapiens TAF6 RNA polymerase II, TATA box binding protein (TBP)-
as.
NM_139123 Homo Sapiens TAF6 RNA polymerase II, TATA box binding protein (TBP)-
as
NM_139124 Homo sapiens mitogen-activated protein kinase 8 interacting protein
2 (MAPI
NM_139125 Homo sapiens mannan-binding lectin serine protease 1 (C4/C2
activating cot
NM_139126 Homo sapiens peptidylprolyl isomerase (cyclophilin)-like 4 (PPIL4),
mRNA
NM_139131 Homo sapiens nucleoporin 98kDa (NUP98), transcript variant 2, mRNA
NM_139132 Homo sapiens nucleoporin 98kDa (NUP98), transcript variant 4, mRNA
NM_139135 Homo sapiens AT rich interactive domain 1A (SWI- like) (ARID1A),
transcript
NM_139136 Homo sapiens potassium voltage-gated channel, Shaw-related
subfamily, mi
NM_139137 Homo sapiens potassium voltage-gated channel, Shaw-related
subfamily, m~
NM_139155 Homo sapiens a disintegrin-like and metalloprotease (reprolysin
type) with th
NM_139156 Homo sapiens adenosine monophosphate deaminase 2 (isoform L) (AMPD2
NM_139157 Homo sapiens suppression of tumorigenicity 5 (ST5), transcript
variant 2, mF
NM_139158 Homo sapiens amyotrophic lateral sclerosis 2 (juvenile) chromosome
region,
NM_139159 Homo sapiens dipeptidylpeptidase 9 (DPP9), mRNA
NM_139160 Homo sapiens novel 58.3 KDA protein (LOC91614), mRNA
NM_139161 Homo sapiens crumbs homolog 3 (Drosophila) (CRB3), transcript
variant 2, r
NM_139162 Homo sapiens Smith-Magenis syndrome chromosome region, candidate 7
(~
NM_139163 Homo sapiens amyotrophic lateral sclerosis 2 (juvenile) chromosome
region,
NM_139164 Homo sapiens START domain containing 4, sterol regulated (STARD4),
mRP
NM_139165 Homo Sapiens retinoic acid early transcript 1 E (F;AET1 E), mRNA
NM_139166 Homo Sapiens striated muscle activator of Rho-dependent signaling
(STARS
NM_139167 Homo sapiens sarcoglycan zeta (SGCZ), mRNA
NM_139168 Homo sapiens splicing factor, arginine/serine-rich 12 (SFRS12), mRNA
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NM_139169 Homo Sapiens TruB pseudouridine (psi) synthase homolog 1 (E. coli)
(TRUB
NM_139170 Homo sapiens hypothetical protein AF447587 (LOC146562), mRNA
NM_139171 Homo sapiens START domain containing 6 (STARD6), mRNA
NM_139172 Homo sapiens MDAC1 (MDAC1), mRNA
NM_139173 Homo sapiens CG10806-like (LOC150159), mRNA
NM_139174 Homo Sapiens testis nuclear RNA-binding protein-like (LOC161931 ),
mRNA
NM_139175 Homo sapiens ring finger protein 133 (RNF133), mRNA
NM_139176 Homo Sapiens NACHT, leucine rich repeat and PYD containing 7
(NALP7), ti
NM_139177 Homo sapiens solute carrier family 39 (metal ion transporter),
member 11 (S1
NM_139178 Homo sapiens prostate cancer antigen-1 (DEPC-1), mRNA
NM_139179 Homo sapiens KCCR13L (LOC221955), mRNA
NM_139181 Homo sapiens centaurin, delta 2 (CENTD2), transcript variant 1, mRNA
NM_139182 Homo sapiens centaurin, delta 1 (CENTD1 ), transcript variant 2,
mRNA
NM_139199 Homo sapiens bromodomain containing 8 (BRD8), transcript variant 2,
mRN~
NM_139201 Homo sapiens G protein-coupled receptor kinase interactor 2 (GIT2),
transcr
NM_139202 Homo sapiens megalencephalic leukoencephalopathy with subcortical
cysts
NM_139204 Homo sapiens EPSB-like 1 (EPS8L1 ), transcript variant 3, mRNA
NM_139205 Homo sapiens histone deacetylase 5 (HDAC5), transcript variant 2,
mRNA
NM_139207 Homo sapiens nucleosome assembly protein 1-like 1 (NAP1 L1 ),
transcript ve
NM_139208 Homo sapiens mannan-binding lectin serine protease 2 (MASP2),
transcript
NM_139209 Homo sapiens G protein-coupled receptor kinase 7 (GRK7), mRNA
NM_139211 Homo sapiens homeodomain-only protein (HOP), transcript variant 2,
mRNA
NM_139212 Homo Sapiens homeodomain-only protein (HOP), transcript variant 3,
mRNA
NM_139214 Homo Sapiens TGFB-induced factor 2-like, Y-linked (TGIF2LY), mRNA
NM_139215 Homo Sapiens TAF15 RNA polymerase II, TATA box binding protein (TBP)-
a
NM_139235 Homo sapiens nucleolar protein family 6 (RNA-associated) (NOL6),
transcrip
NM_139238 Homo Sapiens ADAMTS-like 1 (ADAMTSL1), transcript variant 1, mRNA
NM_139239 Homo sapiens T-cell activation NFKB-like protein (TA-NFKBH), mRNA
NM_139240 Homo Sapiens LOC92346 (LOC92346), mRNA
NM_139241 Homo sapiens FGD1 family, member 4 (FGD4), mRNA
NM_139242 Homo sapiens methionyl-tRNA formyltransferase, mitochondria)
(MtFMT), mf
NM_139243 Homo sapiens testis nuclear RNA-binding protein (Tenr), mRNA
NM_139244 Homo Sapiens syntaxin binding protein 5 (tomosyn) (STXBPS), mRNA
NM_139245 Homo sapiens protein phosphatase 1 (formerly 2C)-like (PPM1 L), mRNA
NM_139246 Homo sapiens chromosome 9 open reading frame 97 (C9orf97), mRNA
NM_139247 Homo sapiens adenylate cyclase 4 (ADCY4), mRNA
NM_139248 Homo sapiens lipase, member H (LIPH), mRNA
NM_139249 Homo Sapiens membrane-spanning 4-domains, subfamily A, member 6E (M;
NM_139250 Homo sapiens cancer/testis antigen 1A (CTAG1A), mRNA
NM_139264 Homo sapiens ADAMTS-like 1 (ADAMTSL1 ), transcript variant 3, mRNA
NM_139265 Homo sapiens EH-domain containing 4 (EHD4), mRNA
NM_139266 Homo sapiens signal transducer and activator of transcription 1, 91
kDa (STA
NM_139267 Homo Sapiens START domain containing 7 (STARD7), transcript variant
2, n
NM_139273 Homo sapiens cysteinyl-tRNA synthetase (CARS), transcript variant 1,
mRNa
NM_139274 Homo Sapiens acetyl-Coenzyme A synthetase 2 (ADP forming) (ACAS2),
tra
NM_139275 Homo sapiens A kinase (PRKA) anchor protein 1 (AKAP1 ), nuclear gene
enc
NM_139276 Homo Sapiens signal transducer and activator of transcription 3
(acute-phase
NM_139277 Homo sapiens kallikrein 7 (chymotryptic, stratum corneum) (KLK7),
transcript
NM_139278 Homo sapiens leucine-rich repeat LGI family, member 3 (LGI3), mRNA
NM_139279 Homo sapiens multiple coagulation factor deficiency 2 (MCFD2), mRNA
NM_139280 Homo sapiens ORM1-like 3 (S. cerevisiae) (ORMDL3), mRNA
NM_139281 Homo sapiens WD repeat domain 36 (WDR36), mRNA
NM_139282 Homo sapiens paired-like homeobox protein OTEX (OTEX), mRNA
NM_139283 Homo sapiens T-cell activation protein phosphatase 2C (TA-PP2C),
mRNA
NM_139284 Homo Sapiens leucine-rich repeat LGI family, member 4 (LGI4), mRNA
NM_139285 Homo Sapiens growth arrest-specific 2 like 2 (GAS2L2), mRNA
NM 139286 Homo sapiens cell division cycle 26 (CDC26), mRNA
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NM_139289 Homo Sapiens A kinase (PRKA) anchor protein 4 (AKAP4), transcript
variant
NM_139290 Homo sapiens angiopoietin 1 (ANGPT1 ), transcript variant 2, mRNA
NM_139312 Homo sapiens YME1-like 1 (S. cerevisiae) (YME1 L1 ), nuclear gene
encodinc
NM_139313 Homo sapiens YME1-like 1 (S, cerevisiae) (YME1 L1 ), nuclear gene
encodinc
NM_139314 Homo sapiens angiopoietin-like 4 (ANGPTL4), transcript variant 1,
mRNA
NM_139315 Homo sapiens TAF6 RNA polymerase II, TATA box binding protein (TBP)-
as.
NM_139316 Homo Sapiens amphiphysin (Stiff-Man syndrome with breast cancer
128kDa
NM_139317 Homo sapiens baculoviral IAP repeat-containing 7 (livin) (BIRC7),
transcript ~
NM_139318 Homo sapiens potassium voltage-gated channel, subfamily H (eag-
related), i
NM_139319 Homo sapiens solute carrier family 17 (sodium-dependent inorganic
phosph~
NM_139320 Homo sapiens CHRNA7 (cholinergic receptor, nicotinic, alpha
polypeptide 7,
NM_139321 Homo sapiens attractin (ATRN), transcript variant 1, mRNA
NM_139322 Homo sapiens attractin (ATRN), transcript variant 2, mRNA
NM_139323 Homo sapiens tyrosine 3-monooxygenase/tryptophan 5-monooxygenase
acti
NM_139343 Homo sapiens bridging integrator 1 (BIND, transcript variant 1, mRNA
NM_139344 Homo sapiens bridging integrator 1 (BIN1 ), transcript variant 2,
mRNA
NM_139345 Homo Sapiens bridging integrator 1 (BIND, transcript variant 3, mRNA
NM_139346 Homo sapiens bridging integrator 1 (BIND, transcript variant 4, mRNA
NM_139347 Homo sapiens bridging integrator 1 (BIND, transcript variant 5, mRNA
NM_139348 Homo Sapiens bridging integrator 1 (BIN1 ), transcript variant 6,
mRNA
NM_139349 Homo sapiens bridging integrator 1 (BIND, transcript variant 7, mRNA
NM_139350 Homo Sapiens bridging integrator 1 (BIN1 ), transcript variant 9,
mRNA
NM_139351 Homo sapiens bridging integrator 1 (BIND, transcript variant 10,
mRNA
NM_139352 Homo sapiens TATA box binding protein (TBP)-associated factor, RNA
polyn
NM_139353 Homo Sapiens TATA box binding protein (TBP)-associated factor, RNA
polyn
NM_139354 Homo sapiens megakaryocyte-associated tyrosine kinase (MATK),
transcript
NM_139355 Homo sapiens megakaryocyte-associated tyrosine kinase (MATK),
transcript
NM_144488 Homo sapiens regulator of G-protein signalling 3 (RGS3), transcript
variant 6
NM_144489 Homo sapiens regulator of G-protein signalling 3 (RGS3), transcript
variant 5
NM_144490 Homo sapiens A kinase (PRKA) anchor protein 11 (AKAP11 ), transcript
vari~
NM_144492 Homo sapiens claudin 14 (CLDN14), transcript variant 1, mRNA
NM_144494 Homo Sapiens polyglutamine binding protein 1 (PQBP1), mRNA
NM_144495 Homo sapiens polyglutamine binding protein 1 (PQBP1), mRNA
NM_144497 Homo sapiens A kinase (PRKA) anchor protein (gravin) 12 (AKAP12),
transc
NM_144498 Homo sapiens oxysterol binding protein-like 2 (OSBPL2), transcript
variant 2
NM_144499 Homo sapiens guanine nucleotide binding protein (G protein), alpha
transduc
NM_144501 Homo sapiens F11 receptor (F11 R), transcript variant 2, mRNA
NM_144502 Homo sapiens F11 receptor (F11 R), transcript variant 3, mRNA
NM_144503 Homo sapiens F11 receptor (F11 R), transcript variant 4, mRNA
NM_144504 Homo sapiens F11 receptor (F11 R), transcript variant 5, mRNA
NM_144505 Homo sapiens kallikrein 8 (neuropsin/ovasin) (KLK8), transcript
variant 2, mF
NM_144506 Homo sapiens kallikrein 8 (neuropsin/ovasin) (KLK8), transcript
variant 3, mF
NM_144507 Homo Sapiens kallikrein 8 (neuropsin/ovasin) (KLKB), transcript
variant 4, mF
NM_144508 Homo Sapiens AF15q14 protein (AF15Q14), mRNA
NM_144563 Homo sapiens ribose 5-phosphate isomerase A (ribose 5-phosphate
epimer~
NM_144564 Homo Sapiens solute carrier family 39 (zinc transporter), member 3
(SLC39A
NM_144565 Homo sapiens homolog of Drosophila Numb-interacting protein (NIP),
mRNP
NM_144567 Homo sapiens similar to RIKEN cDNA 2610307121 (LOC90806), mRNA
NM_144568 Homo sapiens chromosome 14 open reading frame 9 (C14orf9), mRNA
NM_144569 Homo sapiens hypothetical protein FLJ25348 (FLJ25348), mRNA
NM_144570 Homo sapiens chromosome 16 open reading frame 34 (C16orf34), mRNA
NM_144571 Homo sapiens CCR4-NOT transcription complex, subunit 6-like
(CNOT6L), n
NM_144573 Homo sapiens nexilin (F actin binding protein) (NEXN), mRNA
NM_144574 Homo sapiens WD repeat domain 20 (WDR20), transcript variant 2, mRNA
NM_144575 Homo sapiens calpain 13 (CAPN13), mRNA
NM_144576 Homo sapiens hypothetical protein FLJ32452 (FLJ32452), mRNA
NM 144577 Homo sapiens hypothetical protein FLJ32926 (FLJ32926), mRNA
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NM_144578 Homo Sapiens chromosome 14 open reading frame 32 (C14orf32), mRNA
NM_144579 Homo sapiens sideroflexin 5 (SFXNS), mRNA
NM_144580 Homo sapiens kidney predominant protein NCU-G1 (MGC31963), mRNA
NM_144581 Homo sapiens chromosome 14 open reading frame 149 (C14orf149), mRNA
NM_144582 Homo sapiens testis expressed sequence 261 (TEX261), mRNA
NM_144583 Homo sapiens ATPase, H+ transporting, lysosomal 42kDa, V1 subunit C
isoi
NM_144584 Homo sapiens hypothetical protein FLJ30525 (FLJ30525), mRNA
NM_144585 Homo sapiens solute carrier family 22 (organic anion/cation
transporter), mei
NM_144586 Homo sapiens hypothetical protein MGC29643 (MGC29643), mRNA
NM_144587 Homo sapiens chromosome 10 open reading frame 87 (C10orf87), mRNA
NM_144588 Homo sapiens zinc finger, FYVE domain containing 27 (ZFYVE27),
transcrip
NM_144589 Homo sapiens catechol-O-methyltransferase domain containing 1
(COMTD1
NM_144590 Homo sapiens ankyrin repeat domain 22 (ANKRD22), mRNA
NM_144591 Homo sapiens chromosome 10 open reading frame 32 (C10orf32), mRNA
NM_144593 Homo sapiens Ras homolog enriched in brain like 1 (RHEBL1), mRNA
NM_144594 Homo sapiens hypothetical protein FLJ32942 (FLJ32942), mRNA
NM_144595 Homo sapiens hypothetical protein FLJ30046 (FLJ30046), mRNA
NM_144596 Homo sapiens tetratricopeptide repeat domain 8 (TTCB), transcript
variant 3,
NM_144597 Homo sapiens hypothetical protein MGC29937 (MGC29937), mRNA
NM_144598 Homo Sapiens leucine rich repeat containing 28 (LRRC28), mRNA
NM_144599 Homo sapiens non-imprinted in Prader-Willi/Angelman syndrome 1
(NIPA1),
NM_144600 Homo sapiens hypothetical protein FLJ31153 (FLJ31153), mRNA
NM_144601 Homo sapiens chemokine-like factor super family 3 (CKLFSF3),
transcript va
NM_144602 Homo sapiens hypothetical protein MGC32905 (MGC33367), mRNA
NM_144603 Homo sapiens NADPH oxidase organizer 1 (NOX01), transcript variant
a, ml
NM_144604 Homo sapiens hypothetical protein BC001584 (LOC124245), mRNA
NM_144605 Homo sapiens hypothetical protein FLJ25410 (FLJ25410), mRNA
NM_144606 Homo sapiens folliculin (BHD), transcript variant 2, mRNA
NM_144607 Homo sapiens hypothetical protein FLJ32499 (FLJ32499), mRNA
NM_144608 Homo sapiens hypothetical protein MGC39389 (FLJ32384), mRNA
NM_144609 Homo sapiens hypothetical protein FLJ31795 (FLJ31795), mRNA
NM_144610 Homo Sapiens hypothetical protein FLJ25006 (FLJ25006), mRNA
NM_144611 Homo sapiens hypothetical protein MGC32124 (MGC32124), mRNA
NM_144612 Homo Sapiens lipoxygenase homology domains 1 (LOXHD1), mRNA
NM_144613 Homo sapiens cytochrome c oxidase subunit Vlb, testes-specific
(COXVIB2)
NM_144614 Homo sapiens methyl-CpG binding domain protein 3-like 2 (MBD3L2),
mRN/
NM_144615 Homo sapiens hypothetical protein MGC23244 (MGC23244), mRNA
NM_144616 Homo sapiens homolog of mouse skeletal muscle sarcoplasmic reticulum
pn
NM_144617 Homo sapiens heat shock protein, alpha-crystallin-related, B6
(HSPB6), mRP
NM_144618 Homo sapiens hypothetical protein MGC29891 (MGC29891), mRNA
NM_144620 Homo sapiens hypothetical protein MGC14816 (MGC14816), mRNA
NM_144621 Homo sapiens zinc finger and BTB domain containing 8 (ZBTBB), mRNA
NM_144622 Homo sapiens hypothetical protein FLJ32934 (FLJ32934), mRNA
NM_144623 Homo Sapiens hypothetical protein FLJ32784 (FLJ32784), mRNA
NM_144624 Homo sapiens kinase interacting with leukemia-associated gene
(stathmin)
NM_144625 Homo sapiens hypothetical protein FLJ32978 (FLJ32978), mRNA
NM_144626 Homo Sapiens hypothetical protein MGC17299 (MGC17299), mRNA
NM_144627 Homo sapiens SSTK-interacting protein (SSTK-IP), mRNA
NM_144628 Homo sapiens chromosome 20 open reading frame 140 (C20orf140), mRNA
NM_144629 Homo Sapiens chromosome 2 open reading frame 11 (C2orf11), mRNA
NM_144631 Homo sapiens zinc finger protein 513 (ZNF513), mRNA
NM_144632 Homo sapiens hypothetical protein FLJ30294 (FLJ30294), mRNA
NM_144633 Homo sapiens potassium voltage-gated channel, subfamily H (eag-
related), i
NM_144634 Homo sapiens lysozyme-like 4 (LYZL4), mRNA
NM_144635 Homo Sapiens hypothetical protein MGC21688 (MGC21688), mRNA
NM 144636 Homo sapiens coiled-coil-helix-coiled-coil-helix domain containing 4
(CHCHC
NM 144637 Homo sapiens zinc finger, DHHC domain containing 19 (ZDHHC19), mRNA
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NM_144638 Homo sapiens hypothetical protein MGC29956 (MGC29956), mRNA
NM_144639 Homo sapiens hypothetical protein FLJ31300 (FLJ31300), mRNA
NM_144640 Homo sapiens interleukin 17 receptor E (IL17RE), transcript variant
3, mRNP
NM_144641 Homo Sapiens likely ortholog of mouse protein phosphatase 2C eta
(FLJ323:
NM_144642 Homo sapiens synaptoporin (SYNPR), mRNA
NM_144643 Homo sapiens hypothetical protein FLJ30655 (FLJ30655), mRNA
NM_144644 Homo sapiens spermatogenesis associated 4 (SPATA4), mRNA
NM_144645 Homo sapiens hypothetical protein MGC26744 (MGC26744), mRNA
NM_144646 Homo sapiens immunoglobulin J polypeptide, linker protein for
immunoglobu
NM_144647 Homo sapiens hypothetical protein MGC26610 (MGC26610), mRNA
NM_144648 Homo sapiens hypothetical protein FLJ32786 (FLJ32786), mRNA
NM_144649 Homo sapiens hypothetical protein FLJ33069 (FLJ33069), mRNA
NM_144650 Homo sapiens alcohol dehydrogenase, iron containing, 1 (ADHFE1),
mRNA
NM_144651 Homo sapiens hypothetical protein FLJ25471 (FLJ25471), mRNA
NM_144652 Homo sapiens leucine zipper-EF-hand containing transmembrane protein
2 (
NM_144653 Homo Sapiens BTB (POZ) domain containing 14A (BTBD14A), mRNA
NM_144654 Homo sapiens chromosome 9 open reading frame 116 (C9orf116), mRNA
NM_144657 Homo Sapiens hypothetical protein FLJ30678 (FLJ30678), mRNA
NM_144658 Homo Sapiens dedicator of cytokinesis 11 (DOCK11 ), mRNA
NM_144659 Homo sapiens t-complex 10 (mouse)-like (TCP10L), mRNA
NM_144660 Homo sapiens sterile alpha motif domain containing 8 (SAMDB), mRNA
NM_144661 Homo sapiens chromosome 10 open reading frame 82 (C10orf82), mRNA
NM_144662 Homo sapiens hypothetical protein MGC26605 (MGC26605), mRNA
NM_144663 Homo sapiens NOV1 (NOV1), mRNA
NM_144664 Homo sapiens hypothetical protein MGC33371 (MGC33371 ), mRNA
NM_144665 Homo Sapiens sestrin 3 (SESN3), mRNA
NM_144666 Homo sapiens hypothetical protein FLJ32752 (FLJ32752), mRNA
NM_144667 Homo sapiens hypothetical protein FLJ32894 (FLJ32894), mRNA
NM_144668 Homo sapiens hypothetical protein MGC33630 (MGC33630), mRNA
NM_144669 Homo sapiens hypothetical protein FLJ31978 (FLJ31978), mRNA
NM_144670 Homo sapiens hypothetical protein FLJ25179 (FLJ25179), mRNA
NM_144671 Homo sapiens hypothetical protein FLJ32356 (FLJ32356), mRNA
NM_144672 Homo Sapiens otoancorin (OTOA), mRNA
NM_144673 Homo sapiens chemokine-like factor super family 2 (CKLFSF2), mRNA
NM_144674 Homo sapiens hypothetical protein FLJ32871 (FLJ32871), mRNA
NM_144675 Homo Sapiens hypothetical protein MGC18079 (MGC18079), mRNA
NM_144676 Homo sapiens hypothetical protein MGC23911 (MGC23911), mRNA
NM_144677 Homo sapiens mannosyl (alpha-1,6-)-glycoprotein beta-1,6-N-acetyl-
glucosa
NM_144678 Homo sapiens target of myb1-like 2 (chicken) (TOM1 L2), mRNA
NM_144679 Homo sapiens hypothetical protein FLJ31528 (FLJ31528), mRNA
NM_144681 Homo sapiens hypothetical protein FLJ32734 (FLJ32734), mRNA
NM_144682 Homo sapiens hypothetical protein FLJ31952 (FLJ31952), mRNA
NM_144683 Homo sapiens hypothetical protein MGC23280 (MGC23280), mRNA
NM_144684 Homo sapiens zinc finger protein 480 (ZNF480), mRNA
NM_144685 Homo sapiens homeodomain interacting protein kinase 4 (HIPK4), mRNA
NM_144686 Homo sapiens transmembrane channel-like 4 (TMC4), mRNA
NM_144687 Homo sapiens NACHT, leucine rich repeat and PYD containing 12
(NALP12)
NM_144688 Homo Sapiens hypothetical protein FLJ32658 (FLJ32658), mRNA
NM_144689 Homo sapiens hypothetical protein FLJ32191 (FLJ32191), mRNA
NM_144690 Homo sapiens zinc finger protein 582 (ZNF582), mRNA
NM_144691 Homo Sapiens calpain 12 (CAPN12), mRNA
NM_144692 Homo Sapiens hypothetical protein BC017947 (LOC148137), mRNA
NM_144693 Homo sapiens zinc finger protein 558 (ZNF558), mRNA
NM_144694 Homo sapiens zinc finger protein 570 (ZNF570), mRNA
NM_144695 Homo sapiens hypothetical protein FLJ32421 (FLJ32421), mRNA
NM_144696 Homo sapiens hypothetical protein FLJ32940 (DKFZp686H1423),
transcript
NM_144697 Homo sapiens hypothetical protein BC017397 (LOC148523), mRNA
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NM 144698 Homo sapiens hypothetical protein FLJ25124 (FLJ25124), mRNA
NM_144699 Homo sapiens ATPase, Na+/K+ transporting, alpha 4 polypeptide
(ATP1A4),
NM_144701 Homo sapiens interleukin-23 receptor (IL23R), mRNA
NM_144702 Homo sapiens hypothetical protein FLJ32884 (FLJ32884), mRNA
NM_144703 Homo sapiens chromosome 20 open reading frame 40 (C20orf40), mRNA
NM_144704 Homo sapiens hypothetical protein FLJ30473 (FLJ30473), mRNA
NM_144705 Homo sapiens hypothetical protein MGC27019 (MGC27019), mRNA
NM_144706 Homo sapiens chromosome 2 open reading frame 15 (C2orf15), mRNA
NM_144707 Homo sapiens prominin 2 (PROM2), mRNA
NM_144709 Homo sapiens hypothetical protein FLJ32312 (FLJ32312), mRNA
NM_144710 Homo Sapiens septin 10 (SEPT10), transcript variant 1, mRNA
NM_144711 Homo sapiens hypothetical protein MGC22679 (MGC22679), mRNA
NM_144712 Homo Sapiens solute carrier family 23 (nucleobase transporfers),
member 3
NM_144713 Homo sapiens hypothetical protein FLJ32954 (FLJ32954), mRNA
NM_144714 Homo sapiens hypothetical protein MGC27069 (FLJ25449), mRNA
NM 144715 Homo Sapiens hypothetical protein FLJ25200 (FLJ25200), mRNA
NM_y144716 Homo sapiens hypothetical protein MGC23918 (MGC23918), mRNA
NM_144717 Homo sapiens hypothetical protein MGC34923 (MGC34923), mRNA
NM_144718 Homo Sapiens hypothetical protein AY099107 (LOC152185), mRNA
NM_144719 Homo sapiens hypothetical protein FLJ25467 (FLJ25467), mRNA
NM 144720 Homo sapiens multiple coiled-coil GABABR1-binding protein (MARLIN1),
mF
NMV_144721 Homo Sapiens THAP domain containing 6 (THAP6), mRNA
NM 144722 Homo sapiens KPL2 protein (FLJ23577), transcript variant 2, mRNA
NM~_144723 Homo sapiens hypothetical protein FLJ31121 (FLJ31121 ), mRNA
NM_144724 Homo Sapiens MARVEL domain containing 2 (MARVELD2), mRNA
NM_144725 Homo sapiens hypothetical protein FLJ25439 (FLJ25439), mRNA
NM 144726 Homo sapiens hypothetical protein FLJ31951 (FLJ31951), mRNA
NM~_144727 Homo sapiens crystallin, gamma N (CRYGN), mRNA
NM_144728 Homo sapiens dual specificity phosphatase 10 (DUSP10), transcript
variant
NM 144729 Homo sapiens dual specificity phosphatase 10 (DUSP10), transcript
variant ;
NM~_144732 Homo sapiens heterogeneous nuclear ribonucleoprotein U-like 1
(HNRPUL1
NM_144733 Homo sapiens heterogeneous nuclear ribonucleoprotein U-like 1
(HNRPUL1
NM_144734 Homo sapiens heterogeneous nuclear ribonucleoprotein U-like 1
(HNRPUL1
NM_144736 Homo sapiens hypothetical protein PR01853 (PR01853), transcript
variant 1
NM_144765 Homo sapiens epithelial V-like antigen 1 (EVA1 ), transcript variant
2, mRNA
NM_144766 Homo sapiens regulator of G-protein signalling 13 (RGS13),
transcript varian
NM_144767 Homo sapiens A kinase (PRKA) anchor protein 13 (AKAP13), transcript
varia
NM_144769 Homo sapiens forkhead box 11 (FOXI1 ), transcript variant 2, mRNA
NM 144770 Homo sapiens RNA binding motif protein 11 (RBM11), mRNA
NM~144772 Homo sapiens apolipoprotein A-I binding protein (APOA1 BP), mRNA
NM~_144773 Homo sapiens G protein-coupled receptor73-like 1 (GPR73L1), mRNA
NM_144775 Homo sapiens Smith-Magenis syndrome chromosome region, candidate 8
(~
NM_144776 Homo Sapiens formyltetrahydrofolate dehydrogenase (FTHFD),
transcript vat
NM_144777 Homo sapiens sciellin (SCEL), transcript variant 2, mRNA
NM 144778 Homo sapiens muscleblind-like 2 (Drosophila) (MBNL2), transcript
variant 1,
NM'_144779 Homo Sapiens FXYD domain containing ion transport regulator 5
(FXYDS), tr
NM_144780 Homo sapiens degenerative spermatocyte homolog, lipid desaturase
(Drosol
NM 144781 Homo sapiens programmed cell death 2 (PDCD2), transcript variant 2,
mRN~
NM!_144782 Homo Sapiens carnitine acetyltransferase (CRAT), transcript variant
3, mRNf
NM 144947 Homo Sapiens kallikrein 11 (KLK11 ), transcript variant 2, mRNA
NM'_144949 Homo Sapiens suppressor of cytokine signaling 5 (SOCSS), transcript
variant
NM_144956 Homo sapiens protease, serine, 21 (testisin) (PRSS21 ), transcript
variant 2, t
NM_144957 Homo sapiens protease, serine, 21 (testisin) (PRSS21 ), transcript
variant 3, t
NM~144962 Homo sapiens hypothetical protein MGC22776 (MGC22776), mRNA
NM_144963 Homo Sapiens hypothetical protein FLJ23790 (FLJ23790), mRNA
NM 144964 Homo Sapiens RNA (guanine-9-) methyltransferase domain containing 3
(RC
NM 144965 Homo sapiens tetratricopeptide repeat domain 16 (TTC16), mRNA
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NM_144966 Homo sapiens chromosome 9 open reading frame 154 (C9orf154), mRNA
NM_144967 Homo sapiens hypothetical protein FLJ30058 (FLJ30058), mRNA
NM_144968 Homo Sapiens hypothetical protein FLJ32783 (FLJ32783), mRNA
NM_144969 Homo sapiens zinc finger, DHHC domain containing 15 (ZDHHC15), mRNA
NM_144970 Homo Sapiens hypothetical protein MGC39350 (MGC39350), mRNA
NM_144972 Homo sapiens lactate dehydrogenase A-like 6A (LDHAL6A), mRNA
NM_144973 Homo sapiens hypothetical protein MGC24039 (MGC24039), mRNA
NM_144974 Homo sapiens hypothetical protein FLJ31846 (FLJ31846), mRNA
NM_144975 Homo sapiens hypothetical protein MGC19764 (MGC19764), mRNA
NM_144976 Homo sapiens zinc finger protein 564 (ZNF564), mRNA
NM_144977 Homo sapiens family with sequence similarity 31, member B (FAM31 B),
mRt
NM_144978 Homo sapiens hypothetical protein FLJ32745 (FLJ32745), mRNA
NM_144979 Homo Sapiens hypothetical protein MGC27016 (MGC27016), mRNA
NM_144980 Homo sapiens chromosome 6 open reading frame 118 (C6orf118), mRNA
NM_144981 Homo sapiens hypothetical protein FLJ25059 (FLJ25059), mRNA
NM_144982 Homo sapiens hypothetical protein MGC23401 (MGC23401 ), mRNA
NM_144984 Homo sapiens chromosome 10 open reading frame 72 (C10orf72), mRNA
NM_144985 Homo Sapiens cadherin-like 24 (CDH24), mRNA
NM_144987 Homo sapiens U2(RNU2) small nuclear RNA auxiliary factor 1-like 3
(U2AF1
NM_144988 Homo sapiens hypothetical protein MGC19780 (MGC19780), mRNA
NM_144990 Homo sapiens hypothetical protein FLJ23878 (FLJ23878), mRNA
NM_144991 Homo sapiens chromosome 21 open reading frame 29 (C21orf29), mRNA
NM_144992 Homo sapiens hypothetical protein MGC26733 (MGC26733), mRNA
NM_144994 Homo sapiens ankyrin repeat domain 23 (ANKRD23), mRNA
NM_144995 Homo sapiens DEAH (Asp-Glu-Ala-AsplHis) box polypeptide 57 (DHX57),
try
NM_144996 Homo sapiens hypothetical protein DKFZp761H079 (DKFZp761H079),
trans.
NM_144997 Homo Sapiens folliculin (BHD), transcript variant 1, mRNA
NM_144998 Homo sapiens stimulated by retinoic acid 13 (STRA13), mRNA
NM_144999 Homo sapiens hypothetical protein MGC20806 (MGC20806), mRNA
NM_145000 Homo sapiens hypothetical protein FLJ25422 (FLJ25422), mRNA
NM_145001 Homo Sapiens serine/threonine kinase 32A (STK32A), mRNA
NM_145003 Homo Sapiens hypothetical protein FLJ31164 (FLJ31164), mRNA
NM_145004 Homo sapiens a disintegrin and metalloproteinase domain 32 (ADAM32),
mF
NM_145005 Homo sapiens chromosome 9 open reading frame 72 (C9orf72),
transcript v~
NM_145006 Homo Sapiens sushi domain containing 3 (SUSD3), mRNA
NM_145007 Homo sapiens NACHT, leucine rich repeat and PYD containing 11
(NALP11)
NM_145008 Homo sapiens hypothetical protein FLJ30213 (FLJ30213), mRNA
NM_145010 Homo sapiens chromosome 10 open reading frame 63 (C10orf63), mRNA
NM_145011 Homo sapiens zinc finger protein 25 (KOX 19) (ZNF25), mRNA
NM_145012 Homo sapiens chromosome 10 open reading frame 9 (C10orf9), mRNA
NM_145013 Homo sapiens hypothetical protein MGC35558 (MGC35558), mRNA
NM_145014 Homo sapiens hypothetical protein FLJ32915 (FLJ32915), mRNA
NM_145015 Homo sapiens MAS-related GPR, member F (MRGPRF), mRNA
NM_145016 Homo sapiens BXMAS2-10 (BXMAS2-10), mRNA
NM_145017 Homo sapiens IIIG9 protein (FLJ32771), mRNA
NM_145018 Homo sapiens hypothetical protein FLJ25416 (FLJ25416), mRNA
NM_145019 Homo sapiens hypothetical protein FLJ30707 (FLJ30707), mRNA
NM_145020 Homo sapiens hypothetical protein FLJ32743 (FLJ32743), mRNA
NM_145021 Homo sapiens c-mir, cellular modulator of immune recognition (MIR),
transcr
NM_145023 Homo sapiens coiled-coil domain containing 7 (CCDC7), mRNA
NM_145024 Homo sapiens hypothetical protein FLJ31547 (FLJ31547), mRNA
NM_145025 Homo Sapiens chromosome 6 open reading frame 199 (C6orF199), mRNA
NM_145026 Homo Sapiens spermatogenesis associated, serine-rich 1 (SPATS1),
mRNA
NM_145027 Homo sapiens chromosome 6 open reading frame 102 (C6orf102), mRNA
NM_145028 Homo sapiens chromosome 6 open reading frame 81 (C6orf81), mRNA
NM 145029 Homo sapiens chromosome 6 open reading frame 136 (C6orf136), mRNA
NM 145030 Homo Sapiens hypothetical protein MGC22793 (MGC22793), mRNA
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NM_145032 Homo sapiens F-box and leucine-rich repeat protein 13 (FBXL13), mRNA
NM_145033 Homo sapiens chromosome 21 open reading frame 100 (C21orf100), mRNA
NM_145034 Homo sapiens AF464140 (LOC163590), mRNA
NM_145035 Homo sapiens ADMP (ADMP), mRNA
NM_145036 Homo sapiens hypothetical protein MGC33887 (MGC33887), mRNA
NM_145037 Homo sapiens hypothetical protein MGC15606 (MGC15606), mRNA
NM_145038 Homo sapiens CG10958-like (MGC16372), mRNA
NM_145039 Homo sapiens hypothetical protein MGC16385 (MGC16385), mRNA
NM_145040 Homo sapiens protein kinase C, delta binding protein (PRKCDBP), mRNA
NM_145041 Homo sapiens hypothetical protein MGC20235 (MGC20235), mRNA
NM_145042 Homo sapiens alpha tubulin-like (MGC16703), mRNA
NM_145043 Homo sapiens nei like 2 (E. coli) (NEIL2), mRNA
NM_145044 Homo sapiens zinc finger protein 501 (ZNF501 ), mRNA
NM_145045 Homo sapiens hypothetical protein MGC20983 (MGC20983), mRNA
NM_145046 Homo Sapiens calreticulin 3 (CALR3), mRNA
NM_145047 Homo sapiens oxidored-nitro domain-containing protein (NOR1 ),
transcript v.
NM_145048 Homo sapiens hypothetical protein MGC29898 (MGC29898), mRNA
NM_145049 Homo sapiens hypothetical protein MGC10067 (MGC10067), mRNA
NM_145050 Homo sapiens hypothetical protein MGC27434 (MGC27434), mRNA
NM_145051 Homo sapiens hypothetical protein MGC4734 (MGC4734), mRNA
NM_145052 Homo sapiens hypothetical protein MGC23937 similar to CG4798
(MGC239~
NM_145053 Homo sapiens hypothetical protein MGC20470 (MGC20470), mRNA
NM_145054 Homo sapiens hypothetical protein LOC146845 (LOC146845), mRNA
NM_145055 Homo sapiens chromosome 18 open reading frame 25 (C18orf25), mRNA
NM_145056 Homo sapiens thymus expressed gene 3-like (MGC15476), mRNA
NM_145057 Homo sapiens CDC42 effector protein (Rho GTPase binding) 5
(CDC42EP5;
NM_145058 Homo sapiens hypothetical protein MGC7036 (MGC7036), mRNA
NM_145059 Homo sapiens fucokinase (FUK), mRNA
NM_145060 Homo sapiens chromosome 18 open reading frame 24 (C18orf24), mRNA
NM_145061 Homo sapiens chromosome 13 open reading frame 3 (C13orf3), mRNA
NM_145062 Homo sapiens chromosome 6 open reading frame 113 (C6orf113), mRNA
NM_145063 Homo sapiens chromosome 6 open reading frame 130 (C6orf130), mRNA
NM_145064 Homo Sapiens SH3 and cysteine rich domain 3 (STAC3), mRNA
NM_145065 Homo sapiens pellino 3 alpha (MGC35521), mRNA
NM_145068 Homo sapiens transient receptor potential cation channel, subfamily
V, mem
NM_145071 Homo sapiens cytokine inducible SH2-containing protein (CISH),
transcript v.
NM_145074 Homo Sapiens protease, serine, 25 (PRSS25), nuclear gene encoding
mitoci
NM_145080 Homo sapiens non-SMC (structural maintenance of chromosomes) element
NM_145102 Homo sapiens zinc finger protein 95 homolog (mouse) (ZFP95),
transcript va
NM_145109 Homo sapiens mitogen-activated protein kinase kinase 3 (MAP2K3),
transcri
NM_145110 Homo sapiens mitogen-activated protein kinase kinase 3 (MAP2K3),
transcri
NM_145111 Homo sapiens hypothetical protein DKFZp727G131 (DKFZp727G131), mRN
NM_145112 Homo sapiens MAX protein (MAX), transcript variant 2, mRNA
NM_145113 Homo sapiens MAX protein (MAX), transcript variant 3, mRNA
NM_145114 Homo sapiens MAX protein (MAX), transcript variant 4, mRNA
NM_145115 Homo Sapiens zinc finger protein 498 (ZNF498), mRNA
NM_145116 Homo sapiens MAX protein (MAX), transcript variant 5, mRNA
NM_145117 Homo sapiens neuron navigator 2 (NAV2), transcript variant 2, mRNA
NM_145119 Homo Sapiens praja 1 (PJA1), mRNA
NM_145159 Homo sapiens jagged 2 (JAG2), transcript variant 2, mRNA
NM_145160 Homo sapiens mitogen-activated protein kinase kinase 5 (MAP2K5),
transcri
NM_145161 Homo Sapiens mitogen-activated protein kinase kinase 5 (MAP2K5),
transcri
NM_145162 Homo sapiens mitogen-activated protein kinase kinase 5 (MAP2K5),
transcri
NM_145165 Homo sapiens Churchill domain containing 1 (CHURC1), mRNA
NM_145166 Homo sapiens hypothetical protein KIAA1190 (KIAA1190), mRNA
NM_145167 Homo sapiens phosphatidylinositol glycan, class M (PIGM), mRNA
NM 145168 Homo sapiens NAD(P) dependent steroid dehydrogenase-like (HSPC105),
rr
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NM_145169 Homo sapiens chromosome 6 open reading frame 83 (C6orf83), mRNA
NM_145170 Homo sapiens tetratricopeptide repeat domain 18 (TTC18), mRNA
NM_145171 Homo sapiens glycoprotein hormone beta 5 (GPHB5), mRNA
NM_145172 Homo sapiens testis development protein NYD-SP29 (NYD-SP29), mRNA
NM_145173 Homo Sapiens DIRAS family, GTP-binding RAS-like 1 (DIRAS1), mRNA
NM_145174 Homo sapiens DnaJ (Hsp40) homolog, subfamily B, member 7 (DNAJB7), m
NM_145175 Homo sapiens NSE1 (NSE1), mRNA
NM_145176 Homo sapiens solute carrier family 2 (facilitated glucose
transporter), membe
NM_145177 Homo sapiens dehydrogenase/reductase (SDR family) X-linked (DHRSX),
m
NM_145178 Homo sapiens atonal homolog 7 (Drosophila) (ATOH7), mRNA
NM_145179 Homo sapiens chromosome 21 open reading frame 93 (C21orf93), mRNA
NM_145180 Homo sapiens chromosome 21 open reading frame 94 (C21orf94), mRNA
NM_145182 Homo sapiens PYD and CARD domain containing (PYCARD), transcript
vari,
NM_145183 Homo sapiens PYD and CARD domain containing (PYCARD), transcript
vari,
NM_145185 Homo sapiens mitogen-activated protein kinase kinase 7 (MAP2K7),
mRNA
NM_145186 Homo sapiens ATP-binding cassette, sub-family C (CFTR/MRP), member
11
NM_145187 Homo Sapiens ATP-binding cassette, sub-family C (CFTR/MRP), member
12
NM_145188 Homo sapiens ATP-binding cassette, sub-family C (CFTR/MRP), member
12
NM_145189 Homo sapiens ATP-binding cassette, sub-family C (CFTRIMRP), member
12
NM_145190 Homo sapiens ATP-binding cassette, sub-family C (CFTR/MRP), member
12
NM_145196 Homo sapiens lipoyltransferase 1 (LIPT1 ), transcript variant 2,
mRNA
NM_145197 Homo sapiens lipoyltransferase 1 (LIPT1), transcript variant 3, mRNA
NM_145198 Homo sapiens lipoyltransferase 1 (LIPT1 ), transcript variant 4,
mRNA
NM_145199 Homo sapiens lipoyltransferase 1 (LIPT1 ), transcript variant 5,
mRNA
NM_145200 Homo sapiens calcium binding protein 4 (CABP4), mRNA
NM_145201 Homo sapiens similar to CG3714 gene product (PP3856), mRNA
NM_145202 Homo sapiens proline-rich acidic protein 1 (PRAP1 ), mRNA
NM_145203 Homo sapiens casein kinase 1, alpha 1-like (CSNK1A1L), mRNA
NM_145204 Homo Sapiens SUMO/sentrin specific protease family member 8 (SENPB),
m
NM_145205 Homo sapiens HMG2 like (LOC127540), mRNA
NM_145206 Homo sapiens vesicle transport through interaction with t-SNAREs
homolog
NM_145207 Homo Sapiens spermatogenesis associated 5 (SPATAS), mRNA
NM_145208 Homo sapiens methyl-CpG binding domain protein 3-like 1 (MBD3L1),
mRN/
NM_145212 Homo sapiens mitochondria) ribosomal protein L30 (MRPL30), nuclear
gene
NM_145213 Homo Sapiens mitochondria) ribosomal protein L30 (MRPL30), nuclear
gene
NM_145214 Homo sapiens tripartite motif-containing 11 (TRIM11), mRNA
NM_145230 Homo sapiens chromosome 7 open reading frame 32 (C7orf32), mRNA
NM_145231 Homo sapiens chromosome 14 open reading frame 143 (C14orf143), mRNA
NM_145232 Homo Sapiens LOC90353 (LOC90353), mRNA
NM_145233 Homo sapiens zinc finger protein 625 (ZNF625), mRNA
NM_145234 Homo sapiens chordin-like 1 (CHRDL1), mRNA
NM_145235 Homo sapiens fibronectin type 3 and ankyrin repeat domains 1 (FANK1
), mR
NM_145236 Homo Sapiens UDP-GIcNAc:betaGal beta-1,3-N-
acetylglucosaminyltransfera
NM_145237 Homo sapiens similar to RNA polymerase I transcription factor RRN3
(LOC9~
NM_145238 Homo Sapiens zinc finger protein 31 (KOX 29) (ZNF31), mRNA '
NM_145239 Homo sapiens similar to lymphocyte antigen 6 complex, locus GSB; G5b
pros
NM_145241 Homo sapiens WD repeat domain 31 (WDR31), mRNA
NM_145242 Homo sapiens similar to POSSIBLE GUSTATORY RECEPTOR CLONE PTE
NM_145243 Homo sapiens metalloprotease related protein 1 (MPRP-1), mRNA
NM_145244 Homo Sapiens DNA-damage-inducible transcript 4-like (DDIT4L), mRNA
NM_145245 Homo Sapiens ecotropic viral integration site 5-like (EVISL), mRNA
NM_145246 Homo sapiens chromosome 10 open reading frame 4 (C10orf4),
transcript v~
NM_145247 Homo sapiens chromosome 10 open reading frame 78 (C10orf78),
transcript
NM_145248 Homo sapiens LOC122258 (LOC122258), mRNA
NM_145249 Homo sapiens family with sequence similarity 14, member B (FAM14B),
mRf
NM_145250 Homo sapiens chromosome 14 open reading frame 6 (C14orf6), mRNA
NM 145251 Homo sapiens serine/threonine/tyrosine interacting protein (STYX),
mRNA
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NM_145252 Homo sapiens similar to common salivary protein 1 (LOC124220), mRNA
NM_145253 Homo sapiens LOC124402 (LOC124402), mRNA
NM_145254 Homo sapiens LOC124491 (LOC124491), mRNA
NM_145255 Homo sapiens mitochondrial ribosomal protein L10 (MRPL10), nuclear
gene
NM_145256 Homo Sapiens leucine rich repeat containing 25 (LRRC25), mRNA
NM_145257 Homo sapiens LOC126731 (LOC126731), mRNA
NM_145258 Homo sapiens hypothetical protein MGC22773 (MGC22773), mRNA
NM_145259 Homo sapiens activin A receptor, type IC (ACVR1C), mRNA
NM_145260 Homo sapiens odd-skipped homolog (Drosophila) (ODD), mRNA
NM_145261 Homo sapiens homolog of yeast TIM14 (TIM14), transcript variant 1,
mRNA
NM_145262 Homo sapiens CG9886-like (GLYCTK), mRNA
NM_145263 Homo sapiens LOC132671 (LOC132671), mRNA
NM_145265 Homo sapiens similar to RIKEN cDNA 0610011 N22 (LOC133957), mRNA
NM_145266 Homo sapiens similar to RIKEN cDNA 2700047N05 (LOC134492), mRNA
NM_145267 Homo Sapiens chromosome 6 open reading frame 57 (C6orf57), mRNA
NM_145268 Homo sapiens LOC136263 (LOC136263), mRNA
NM_145269 Homo sapiens similar to CG6405 gene product (LOC137392), mRNA
NM_145270 Homo sapiens similar to hypothetical protein FLJ13841 (LOC146325),
mRN~
NM_145271 Homo sapiens similar to hypothetical protein MGC13138 (LOC146542),
mRf~
NM_145272 Homo sapiens LOC146853 (LOC146853), mRNA
NM_145273 Homo sapiens triggering receptor expressed on myeloid cells 4
(TREM4), mF
NM_145274 Homo sapiens hypothetical protein MGC21518 (MGC21518), mRNA
NM_145275 Homo sapiens kinesin light chain 2-like (KLC2L), transcript variant
2, mRNA
NM_145276 Homo sapiens zinc finger protein 563 (ZNF563), mRNA
NM_145277 Homo sapiens hemochromatosis type 2 (juvenile) (HFE2), transcript
variant t
NM_145278 Homo sapiens LOC148823 (LOC148823), mRNA
NM_145279 Homo sapiens MOB1, Mps One Binder kinase activator-like 2C (yeast)
(MOE
NM_145280 Homo sapiens similar to hepatocellular carcinoma-associated antigen
HCAS!
NM_145282 Homo sapiens similar to CG4995 gene product (LOC153328), mRNA
NM_145283 Homo sapiens chromosome 9 open reading frame 121 (C9orf121), mRNA
NM_145284 Homo sapiens similar to hypothetical protein MGC17347 (LOC159090),
mRi~
NM_145285 Homo sapiens NK2 transcription factor related, locus 3 (Drosophila)
(NKX2-
NM_145286 Homo sapiens stomatin (EPB72)-like 3 (STOML3), mRNA
NM_145287 Homo sapiens zinc finger protein 519 (ZNF519), mRNA
NM_145288 Homo sapiens zinc finger protein 342 (ZNF342), mRNA
NM_145291 Homo sapiens zinc finger protein 509 (ZNF509), mRNA
NM_145292 Homo sapiens UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-
acetylga
NM_145293 Homo Sapiens similar to hypothetical protein FLJ20897 (LOC196549),
mRNf
NM_145294 Homo sapiens similar to RIKEN cDNA 3230401 M21 [Mus musculus] (LOC19
NM_145295 Homo Sapiens zinc finger protein 627 (ZNF627), mRNA
NM_145296 Homo sapiens immunoglobulin superfamily, member 4C (IGSF4C), mRNA
NM_145297 Homo sapiens zinc finger protein 626 (ZNF626), mRNA
NM_145298 Homo sapiens apolipoprotein B mRNA editing enzyme, catalytic
polypeptide~
NM_145299 Homo sapiens similar to Dynein heavy chain at 16F (LOC200383), mRNA
NM_145300 Homo sapiens LOC200420 (LOC200420), mRNA
NM_145301 Homo sapiens similar to CGI-148 protein (LOC201158), mRNA
NM_145303 Homo sapiens similar to RIKEN cDNA 2310008M10 (LOC202459), mRNA
NM_145304 Homo sapiens chromosome 7 open reading frame 33 (C7orf33), mRNA
NM_145305 Homo sapiens similar to solute carrier family 25 , member 16
(LOC203427),
NM_145306 Homo sapiens chromosome 10 open reading frame 35 (C10orf35), mRNA
NM_145307 Homo sapiens pleckstrin homology domain containing, family K member
1 (F
NM_145308 Homo sapiens hypothetical protein BC004224 (LOC220070), mRNA
NM_145309 Homo sapiens Hypothetical 55.1 kDa protein F09G8.5 in chromosome III
(LC
NM_145310 Homo sapiens zinc finger protein 258 (ZNF258), mRNA
NM_145311 Homo Sapiens crystallin, zeta (quinone reductase)-like 1 (CRYZL1),
transcriF
NM_145312 Homo Sapiens zinc finger protein 485 (ZNF485), mRNA
NM_145313 Homo sapiens RasGEF domain family, member 1A (RASGEF1A), mRNA
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NM_145314 Homo sapiens chromosome 10 open reading frame 49 (C10orf49), mRNA
NM_145315 Homo Sapiens lactation elevated 1 (LACED, mRNA
NM_145316 Homo sapiens chromosome 6 open reading frame 128 (C6orf128), mRNA
NM_145320 Homo Sapiens oxysterol binding protein-like 3 (OSBPL3), transcript
variant 2
NM_145321 Homo sapiens oxysterol binding protein-like 3 (OSBPL3), transcript
variant 3
NM_145322 Homo sapiens oxysterol binding protein-like 3 (OSBPL3), transcript
variant 4
NM_145323 Homo sapiens oxysterol binding protein-like 3 (OSBPL3), transcript
variant 5
NM_145324 Homo sapiens oxysterol binding protein-like 3 (OSBPL3), transcript
variant 6
NM_145325 Homo sapiens DNA directed RNA polymerase II polypeptide J-related
gene
NM_145326 Homo sapiens similar to hypothetical protein FLJ13659 (LOC115648),
mRNE
NM_145328 Homo sapiens chromosome 21 open reading frame 66 (C21orf66),
transcript
NM_145330 Homo sapiens mitochondria) ribosomal protein L33 (MRPL33), nuclear
gene
NM_145331 Homo sapiens mitogen-activated protein kinase kinase kinase 7
(MAP3K7),1
NM_145332 Homo sapiens mitogen-activated protein kinase kinase kinase 7
(MAP3K7),1
NM_145333 Homo Sapiens mitogen-activated protein kinase kinase kinase 7
(MAP3K7),1
NM_145341 Homo sapiens programmed cell death 4 (neoplastic transformation
inhibitor)
NM_145342 Homo Sapiens mitogen-activated protein kinase kinase kinase 7
interacting ~
NM_145343 Homo sapiens apolipoprotein L, 1 (APOL1 ), transcript variant 2,
mRNA
NM_145344 Homo sapiens apolipoprotein L, 1 (APOL1 ), transcript variant 3,
mRNA
NM_145345 Homo sapiens socius (SOC), mRNA
NM_145346 Homo sapiens socius (SOC), mRNA
NM_145347 Homo Sapiens kringle containing transmembrane protein 2 (KREMEN2),
tran
NM_145348 Homo sapiens kringle containing transmembrane protein 2 (KREMEN2),
tran
NM_145349 Homo sapiens scavenger receptor class F, member 1 (SCARF1 ),
transcript v
NM_145350 Homo Sapiens scavenger receptor class F, member 1 (SCARF1 ),
transcript ~
NM_145351 Homo sapiens scavenger receptor class F, member 1 (SCARF1 ),
transcript v
NM_145352 Homo sapiens scavenger receptor class F, member 1 (SCARF1 ),
transcript ~
NM_145637 Homo sapiens apolipoprotein L, 2 (APOL2), transcript variant beta,
mRNA
NM_145638 Homo Sapiens oxysterol binding protein-like 5 (OSBPLS), transcript
variant 2
NM_145639 Homo sapiens apolipoprotein L, 3 (APOL3), transcript variant
alpha/c, mRNA
NM_145640 Homo sapiens apolipoprotein L, 3 (APOL3), transcript variant
alpha/d, mRNA
NM_145641 Homo Sapiens apolipoprotein L, 3 (APOL3), transcript variant beta/a,
mRNA
NM_145642 Homo sapiens apolipoprotein L, 3 (APOL3), transcript variant beta/b,
mRNA
NM_145644 Homo sapiens mitochondria) ribosomal protein L35 (MRPL35), nuclear
gene
NM_145645 Homo sapiens Williams-Beuren Syndrome critical region protein 20
copy B (~
NM_145646 Homo sapiens DEAH (Asp-Glu-Ala-Asp/His) box polypeptide 57 (DHX57),
try
NM_145647 Homo Sapiens unknown MGC21654 product (MGC21654), mRNA
NM_145648 Homo sapiens solute carrier family 15, member 4 (SLC15A4), mRNA
NM_145649 Homo Sapiens glucosaminyl (N-acetyl) transferase 2, I-branching
enzyme (G
NM_145650 Homo sapiens mucin 15 (MUC15), mRNA
NM_145651 Homo sapiens ligand binding protein RYD5 (RYDS), mRNA
NM_145652 Homo sapiens WAP four-disulfide core domain 5 (WFDCS), mRNA
NM_145653 Homo sapiens transcription elongation factor B polypeptide 3C
(elongin A3) I
NM_145654 Homo sapiens RAD52 homolog B (S, cerevisiae) (RAD52B), mRNA
NM_145655 Homo Sapiens glucosaminyl (N-acetyl) transferase 2, I-branching
enzyme (G
NM_145657 Homo sapiens GS homeobox 1 (GSH1), mRNA
NM_145658 Homo sapiens sperm equatorial segment protein 1 (SPESP1), mRNA
NM_145659 Homo sapiens interleukin 27 (1L27), mRNA
NM_145660 Homo sapiens apolipoprotein L, 4 (APOL4), transcript variant b, mRNA
NM_145662 Homo sapiens SPANX family, member A2 (SPANXA2), mRNA
NM_145663 Homo sapiens Dbf4-related factor 1 (DRF1), transcript variant 1,
mRNA
NM_145664 Homo sapiens SPANX family, member B2 (SPANXB2), mRNA
NM_145665 Homo sapiens SPANX family, member E (SPANXE), mRNA
NM_145685 Homo sapiens BRF1 homolog, subunit of RNA polymerase III
transcription in
NM_145686 Homo Sapiens mitogen-activated protein kinase kinase kinase kinase 4
(MAF
NM 145687 Homo Sapiens mitogen-activated protein kinase kinase kinase kinase 4
(MAF
NM 145689 Homo Sapiens amyloid beta (A4) precursor protein-binding, family B,
membe
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NM_145690 Homo sapiens tyrosine 3-monooxygenase/tryptophan 5-monooxygenase
acti
NM_145691 Homo sapiens ATP synthase mitochondrial F1 complex assembly factor 2
(A
NM_145693 Homo sapiens lipin 1 (LPIN1), mRNA
NM_145695 Homo sapiens diacylglycerol kinase, beta 90kDa (DGKB), transcript
variant ~
NM_145696 Homo sapiens BRF1 homolog, subunit of RNA polymerase III
transcription in
NM_145697 Homo sapiens cell division cycle associated 1 (CDCA1), transcript
variant 1,
NM_145698 Homo Sapiens acyl-Coenzyme A binding domain containing 5 (ACBDS),
mRl
NM_145699 Homo sapiens apolipoprotein B mRNA editing enzyme, catalytic
polypeptide~
NM_145701 Homo Sapiens cell division cycle associated 4 (CDCA4), transcript
variant 2,
NM_145702 Homo sapiens tigger transposable element derived 1 (TIGD1 ), mRNA
NM_145714 Homo sapiens ataxin 2 related protein (A2LP), transcript variant B,
mRNA
NM_145715 Homo sapiens tigger transposable element derived 2 (TIGD2), mRNA
NM_145716 Homo sapiens single stranded DNA binding protein 3 (SSBP3), mRNA
NM_145719 Homo sapiens tigger transposable element derived 3 (TIGD3), mRNA
NM_145720 Homo sapiens tigger transposable element derived 4 (TIGD4), mRNA
NM_145725 Homo Sapiens TNF receptor-associated factor 3 (TRAF3), transcript
variant '
NM_145726 Homo sapiens TNF receptor-associated factor 3 (TRAF3), transcript
variant
NM_145727 Homo sapiens lipoprotein, Lp(a)-like 2 (LPAL2), transcript variant
2, mRNA
NM_145728 Homo Sapiens desmuslin (DMN), transcript variant A, mRNA
NM_145729 Homo sapiens rnitochondrial ribosomal protein L24 (MRPL24), nuclear
gene
NM_145730 Homo sapiens adaptor-related protein complex 1, beta 1 subunit (AP1
B1 ), try
NM_145731 Homo Sapiens synaptogyrin 1 (SYNGR1 ), transcript variant 1 b, mRNA
NM_145733 Homo sapiens septin 3 (SEPT3), transcript variant A, mRNA
NM_145734 Homo sapiens septin 3 (SEPT3), transcript variant C, mRNA
NM_145735 Homo sapiens Rho guanine nucleotide exchange factor (GEF) 7
(ARHGEF7;
NM_145738 Homo sapiens synaptogyrin 1 (SYNGR1 ), transcript variant 1 c, mRNA
NM_145739 Homo sapiens oxysterol binding protein-like 6 (OSBPL6), transcript
variant 2
NM_145740 Homo sapiens glutathione S-transferase A1 (GSTA1), mRNA
NM_145747 Homo sapiens thioredoxin reductase 2 (TXNRD2), nuclear gene encoding
mi
NM_145748 Homo sapiens thioredoxin reductase 2 (TXNRD2), nuclear gene encoding
mi
NM_145751 Homo Sapiens TNF receptor-associated factor 4 (TRAF4), transcript
variant
NM_145752 Homo sapiens CDP-diacylglycerol--inositol 3-phosphatidyltransferase
(phos~
NM_145753 Homo Sapiens pleckstrin homology-like domain, family B, member 2
(PHLDE
NM_145754 Homo sapiens kinesin family member C2 (KIFC2), mRNA
NM_145755 Homo sapiens TPR domain containing STI2 (STI2), mRNA
NM_145756 Homo sapiens zinc finger protein 396 (ZNF396), mRNA
NM_145759 Homo Sapiens TNF receptor-associated factor 5 (TRAFS), transcript
variant
NM_145762 Homo sapiens GDNF family receptor alpha 4 (GFRA4), transcript
variant 2, r
NM_145763 Homo sapiens GDNF family receptor alpha 4 (GFRA4), transcript
variant 3, r
NM_145764 Homo sapiens rnicrosomal glutathione S-transferase 1 (MGST1 ),
transcript v
NM_145791 Homo Sapiens rnicrosomal glutathione S-transferase 1 (MGST1 ),
transcript v
NM_145792 Homo sapiens rnicrosomal glutathione S-transferase 1 (MGST1),
transcript v
NM_145793 Homo sapiens GDNF family receptor alpha 1 (GFRA1 ), transcript
variant 2, r
NM_145794 Homo sapiens downstream neighbor of SON (DONSON), transcript variant
2
NM_145795 Homo Sapiens downstream neighbor of SON (DONSON), transcript variant
3
NM_145796 Homo sapiens pogo transposable element with ZNF domain (POGZ),
transcr
NM_145798 Homo sapiens oxysterol binding protein-like 7 (OSBPL7), transcript
variant 1
NM_145799 Homo Sapiens septin 6 (SEPT6), transcript variant I, mRNA
NM_145800 Homo Sapiens septin 6 (SEPT6), transcript variant III, mRNA
NM_145802 Homo sapiens septin 6 (SEPT6), transcript variant V, mRNA
NM_145803 Homo sapiens TNF receptor-associated factor 6 (TRAF6), transcript
variant '
NM_145804 Homo sapiens ankyrin repeat and BTB (POZ) domain containing 2
(ABTB2),
NM_145805 Homo sapiens ISL2 transcription factor, LIM/homeodomain, (islet-2)
(ISL2), r
NM_145806 Homo sapiens zinc finger protein 511 (ZNF511 ), mRNA
NM_145807 Homo Sapiens hypothetical protein BC018697 (LOC126147), mRNA
NM 145808 Homo sapiens myotrophin (MTPN), mRNA
NM 145809 Homo sapiens TL132 protein (LOC220594), mRNA
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NM_145810 Homo sapiens cell division cycle associated 7 (CDCA7), transcript
variant 2,
NM_145811 Homo sapiens calcium channel, voltage-dependent, gamma subunit 5
(CACI
NM_145812 Homo sapiens programmed cell death 8 (apoptosis-inducing factor)
(PDCD8
NM_145813 Homo sapiens programmed cell death 8 (apoptosis-inducing factor)
(PDCD8
NM_145814 Homo sapiens calcium channel, voltage-dependent, gamma subunit 6
(CACI
NM_145815 Homo sapiens calcium channel, voltage-dependent, gamma subunit 6
(CACI
NM_145818 Homo sapiens component of oligomeric golgi complex 4 (COG4),
transcript v
NM_145858 Homo sapiens crystallin, zeta (quinone reductase)-like 1 (CRYZL1 ),
transcri~
NM_145859 Homo sapiens programmed cell death 10 (PDCD10), transcript variant
2, mF
NM_145860 Homo Sapiens programmed cell death 10 (PDCD10), transcript variant
3, mF
NM_145861 Homo Sapiens EDAR-associated death domain (EDARADD), transcript
varia
NM_145862 Homo sapiens CHK2 checkpoint homolog (S. pombe) (CHEK2), transcript
va
NM_145863 Homo sapiens ankyrin repeat and SOCS box-containing 3 (ASB3),
transcript
NM_145864 Homo sapiens kallikrein 3, (prostate specific antigen) (KLK3),
transcript varia
NM_145865 Homo sapiens hypothetical protein FLJ38819 (FLJ38819), mRNA
NM_145867 Homo Sapiens leukotriene C4 synthase (LTC4S), transcript variant 1,
mRNA
NM_145868 Homo sapiens annexin A11 (ANXA11 ), transcript variant b, mRNA
NM_145869 Homo Sapiens annexin A11 (ANXA11 ), transcript variant c, mRNA
NM_145870 Homo sapiens glutathione transferase zeta 1 (maleylacetoacetate
isomerase
NM_145871 Homo sapiens glutathione transferase zeta 1 (maleylacetoacetate
isomerase
NM_145872 Homo sapiens ankyrin repeat and SOCS box-containing 4 (ASB4),
transcript
NM_145886 Homo Sapiens leucine-rich repeats and death domain containing
(LRDD), tra
NM_145887 Homo sapiens leucine-rich repeats and death domain containing
(LRDD), tra
NM_145888 Homo sapiens kallikrein 10 (KLK10), transcript variant 2, mRNA
NM_145891 Homo sapiens ataxin 2-binding protein 1 (A2BP1), transcript variant
1, mRN~
NM_145892 Homo sapiens ataxin 2-binding protein 1 (A2BP1 ), transcript variant
2, mRNE
NM_145893 Homo sapiens ataxin 2-binding protein 1 (A2BP1 ), transcript variant
3, mRN~
NM_145894 Homo Sapiens kallikrein 12 (KLK12), transcript variant 2, mRNA
NM_145895 Homo sapiens kallikrein 12 (KLK12), transcript variant 3, mRNA
NM_145896 Homo sapiens prefoldin 5 (PFDNS), transcript variant 2, mRNA
NM_145897 Homo sapiens prefoldin 5 (PFDNS), transcript variant 3, mRNA
NM_145898 Homo Sapiens chemokine (C-C motif) ligand 23 (CCL23), transcript
variant C
NM_145899 Homo sapiens high mobility group AT-hook 1 (HMGA1 ), transcript
variant 1, i
NM_145901 Homo sapiens high mobility group AT-hook 1 (HMGA1 ), transcript
variant 3, i
NM_145902 Homo sapiens high mobility group AT-hook 1 (HMGA1 ), transcript
variant 4, i
NM_145903 Homo sapiens high mobility group AT-hook 1 (HMGA1 ), transcript
variant 5, i
NM_145904 Homo Sapiens high mobility group AT-hook 1 (HMGA1 ), transcript
variant 6, i
NM_145905 Homo sapiens high mobility group AT-hook 1 (HMGA1 ), transcript
variant 7, i
NM_145906 Homo sapiens RIO kinase 3 (yeast) (RIOK3), transcript variant 2,
mRNA
NM_145909 Homo sapiens zinc finger protein 323 (ZNF323), mRNA
NM_145910 Homo sapiens NIMA (never in mitosis gene a)- related kinase 11
(NEK11), rr
NM_145911 Homo sapiens zinc finger protein 23 (KOX 16) (ZNF23), mRNA
NM_145912 Homo Sapiens NFAT activation molecule 1 (NFAM1), mRNA
NM_145913 Homo sapiens solute carrier family 5 (iodide transporter), member 8
(SLCSA~
NM_145914 Homo sapiens zinc finger protein 38 (ZNF38), mRNA
NM_145918 Homo sapiens cathepsin L (CTSL), transcript variant 2, mRNA
NM_146387 Homo sapiens mitochondrial ribosomal protein L4 (MRPL4), nuclear
gene en
NM_146388 Homo Sapiens mitochondrial ribosomal protein L4 (MRPL4), nuclear
gene en
NM_146421 Homo sapiens glutathione S-transferase M1 (GSTM1 ), transcript
variant 2, rr
NM_147127 Homo sapiens Ellis van Creveld syndrome 2 (limbin) (EVC2), mRNA
NM_147128 Homo sapiens zinc and ring finger 2 (ZNRF2), mRNA
NM_147129 Homo sapiens hypothetical protein LOC259173 (FLJ36525), transcript
variar
NM_147130 Homo sapiens natural cytotoxicity triggering receptor 3 (NCR3), mRNA
NM_147131 Homo sapiens galactose-1-phosphate uridylyltransferase (GALT),
transcript
NM_147132 Homo sapiens galactose-1-phosphate uridylyltransferase (GALT),
transcript
NM 147133 Homo sapiens nuclear transcription factor, X-box binding 1 (NFX1),
transcrip
NM 147134 Homo sapiens nuclear transcription factor, X-box binding 1 (NFX1 ),
transcrip
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NM_147147 Homo Sapiens blood vessel epicardial substance (BVES), transcript
variant E
NM_147148 Homo sapiens glutathione S-transferase M4 (GSTM4), transcript
variant 2, m
NM_147149 Homo sapiens glutathione S-transferase M4 (GSTM4), transcript
variant 3, m
NM_147150 Homo sapiens A kinase (PRKA) anchor protein 2 (AKAP2), transcript
variant
NM_147152 Homo sapiens intersectin 2 (ITSN2), transcript variant 2, mRNA
NM_147156 Homo sapiens transmembrane protein 23 (TMEM23), mRNA
NM_147157 Homo sapiens opioid receptor, sigma 1 (OPRS1 ), transcript variant
2, mRNA
NM_147158 Homo Sapiens opioid receptor, sigma 1 (OPRS1 ), transcript variant
3, mRNA
NM_147159 Homo sapiens opioid receptor, sigma 1 (OPRS1 ), transcript variant
4, mRNA
NM_147160 Homo sapiens opioid receptor, sigma 1 (OPRS1 ), transcript variant
5, mRNA
NM_147161 Homo sapiens thioesterase, adipose associated (THEA), transcript
variant 2,
NM_147162 Homo sapiens interleukin 1 1 receptor, alpha (1L11 RA), transcript
variant 2, n-
NM_147164 Homo sapiens ciliary neurotrophic factor receptor (CNTFR),
transcript variant
NM_147166 Homo sapiens A kinase (PRKA) anchor protein (yotiao) 9 (AKAP9),
transcrip
NM_147168 Homo sapiens chromosome 9 open reading frame 24 (C9orF24),
transcript vs
NM_147169 Homo sapiens chromosome 9 open reading frame 24 (C9orf24),
transcript v~
NM_147171 Homo sapiens A kinase (PRKA) anchor protein (yotiao) 9 (AKAP9),
transcrip
NM_147172 Homo Sapiens nudix (nucleoside diphosphate linked moiety X)-type
motif 2 (I
NM_147173 Homo sapiens nudix (nucleoside diphosphate linked moiety X)-type
motif 2 (I
NM_147174 Homo sapiens heparan sulfate 6-O-sulfotransferase 2 (HS6ST2), mRNA
NM_147175 Homo Sapiens heparan sulfate 6-O-sulfotransferase 2 (HS6ST2),
transcript v
NM_147180 Homo sapiens protein phosphatase 3 (formerly 2B), regulatory subunit
B, 191
NM_147181 Homo sapiens Kv channel interacting protein 4 (KCNIP4), transcript
variant 2
NM_147182 Homo sapiens Kv channel interacting protein 4 (KCNIP4), transcript
variant
NM_147183 Homo sapiens Kv channel interacting protein 4 (KCNIP4), transcript
variant 4
NM_147184 Homo Sapiens tumor protein p53 inducible protein 3 (TP5313),
transcript varia
NM_147185 Homo sapiens A kinase (PRKA) anchor protein (yotiao) 9 (AKAP9),
transcrip
NM_147187 Homo Sapiens tumor necrosis factor receptor superfamily, member 10b
(TNF
NM_147188 Homo Sapiens F-box protein 22 (FBX022), transcript variant 1, mRNA
NM_147189 Homo Sapiens hypothetical protein MGC39325 (MGC39325), mRNA
NM_147190 Homo sapiens LAG1 longevity assurance homolog 5 (S. cerevisiae)
(LASSS;
NM_147191 Homo sapiens matrix metalloproteinase 21 (MMP21), mRNA
NM_147192 Homo Sapiens diencephalon/mesencephalon homeobox 1 (DMBX1), transcri
NM_147193 Homo sapiens GLIS family zinc finger 1 (GLIS1 ), mRNA
NM_147194 Homo Sapiens hypothetical protein MGC35361 (MGC35361), mRNA
NM_147195 Homo sapiens FLJ35740 protein (FLJ35740), mRNA
NM_147196 Homo sapiens transmembrane inner ear (TMIE), mRNA
NM_147197 Homo sapiens WAP four-d isulfide core domain 11 (WFDC11 ), mRNA
NM_147198 Homo sapiens WAP four-disulfide core domain 9 (WFDC9), mRNA
NM_147199 Homo Sapiens G protein-coupled receptor MRGX1 (MRGX1), mRNA
NM_147200 Homo Sapiens chromosome 6 open reading frame 4 (C6orf4), transcript
vari~
NM_147202 Homo sapiens chromosome 9 open reading frame 25 (C9orF25), mRNA
NM_147203 Homo sapiens fibrinogen-li ke 1 (FGL1 ), transcript variant 2, mRNA
NM_147204 Homo sapiens transient receptor potential cation channel, subfamily
V, mem
NM_147223 Homo sapiens nuclear receptor coactivator 1 (NCOA1 ), transcript
variant 2, r
NM_147233 Homo sapiens nuclear receptor coactivator 1 (NCOA1 ), transcript
variant 3, r
NM_147686 Homo Sapiens chromosome 6 open reading frame 4 (C6orf4), transcript
varia
NM_147777 Homo sapiens sorting nexin 15 (SNX15), transcript variant B, mRNA
NM_147780 Homo Sapiens cathepsin B (CTSB), transcript variant 2, mRNA
NM_147781 Homo sapiens cathepsin E3 (CTSB), transcript variant 3, mRNA
NM_147782 Homo sapiens cathepsin B (CTSB), transcript variant 4, mRNA
NM_147783 Homo Sapiens cathepsin B (CTSB), transcript variant 5, mRNA
NM_148169 Homo Sapiens F-box protein 17 (FBX017), transcript variant 1, mRNA
NM_148170 Homo sapiens cathepsin C (CTSC), transcript variant 2, mRNA
NM_148171 Homo Sapiens ubiquitin associated protein 2 (UBAP2), transcript
variant 3, rr
NM 148172 Homo sapiens phosphatidylethanolamine N-methyltransferase (PEMT),
nucl~
NM 148173 Homo sapiens phosphatidylethanolamine N-methyltransferase (PEMT),
nuclE
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NM_148174 Homo sapiens ornithine decarboxylase antizyme inhibitor (OAZIN),
transcript
NM_148175 Homo sapiens peptidylprolyl isomerase (cyclophilin)-like 2 (PPIL2),
transcript
NM_148176 Homo sapiens peptidylprolyl isomerase (cyclophilin)-like 2 (PPIL2),
transcript
NM_148177 Homo sapiens F-box protein 32 (FBX032), transcript variant 2, mRNA
NM_148178 Homo sapiens chromosome 9 open reading frame 23 (C9orf23),
transcript v~
NM_148179 Homo Sapiens chromosome 9 open reading frame 23 (C9orf23),
transcript ve
NM_148414 Homo sapiens ataxin 2 related protein (A2LP), transcript variant C,
mRNA
NM_148415 Homo Sapiens ataxin 2 related protein (A2LP), transcript variant D,
mRNA
NM_148416 Homo sapiens ataxin 2 related protein (A2LP), transcript variant E,
mRNA
NM_148570 Homo sapiens mitochondria) ribosomal protein L27 (MRPL27), nuclear
gene
NM_148571 Homo sapiens mitochondria) ribosomal protein L27 (MRPL27), nuclear
gene
NM_148672 Homo sapiens chemokine (C-C motif) ligand 28 (CCL28), transcript
variant 2
NM_148674 Homo sapiens SMC1 structural maintenance of chromosomes 1-like 2
(yeast
NM_148675 Homo Sapiens Down syndrome critical region gene 9 (DSCR9), mRNA
NM_148676 Homo sapiens Down syndrome critical region gene 10 (DSCR10), mRNA
NM_148842 Homo sapiens Williams-Beuren syndrome chromosome region 16 (WBSCR1
NM_148886 Homo sapiens Smith-Magenis syndrome chromosome region, candidate 7
(~
NM_148887 Homo sapiens mitochondria) ribosomal protein L10 (MRPL10), nuclear
gene
NM_148888 Homo sapiens chemokine (C-C motif) ligand 25 (CCL25), transcript
variant 2
NM_148894 Homo sapiens family with sequence similarity 44, member A (FAM44A),
mRP
NM_148896 Homo Sapiens preproneuropeptide B (NPB), mRNA
NM_148897 Homo sapiens orphan short-chain dehydrogenase / reductase (SDR-O),
mRl
NM_148898 Homo sapiens forkhead box P2 (FOXP2), transcript variant 2, mRNA
NM_148899 Homo sapiens forkhead box P2 (FOXP2), transcript variant 3, mRNA
NM_148900 Homo Sapiens forkhead box P2 (FOXP2), transcript variant 4, mRNA
NM_148901 Homo sapiens tumor necrosis factor receptor superfamily, member 18
(TNFF
NM_148902 Homo sapiens tumor necrosis factor receptor superfamily, member 18
(TNFF
NM_148903 Homo sapiens GREB1 protein (GREB1 ), transcript variant c, mRNA
NM_148904 Homo sapiens oxysterol binding protein-like 9 (OSBPL9), transcript
variant 1
NM_148905 Homo sapiens oxysterol binding protein-like 9 (OSBPL9), transcript
variant 2
NM_148906 Homo sapiens oxysterol binding protein-like 9 (OSBPL9), transcript
variant 3
NM_148907 Homo sapiens oxysterol binding protein-like 9 (OSBPL9), transcript
variant 4
NM_148908 Homo sapiens oxysterol binding protein-like 9 (OSBPL9), transcript
variant 5
NM_148909 Homo Sapiens oxysterol binding protein-like 9 (OSBPL9), transcript
variant 7
NM_148910 Homo sapiens toll-interleukin 1 receptor (TIR) domain containing
adaptor pro
NM_148911 Homo sapiens CHRNA7 (cholinergic receptor, nicotinic, alpha
polypeptide 7,
NM_148912 Homo sapiens Williams Beuren syndrome chromosome region 21 (WBSCR~
NM_148913 Homo sapiens Williams Beuren syndrome chromosome region 21 (WBSCR~
NM_148914 Homo Sapiens Williams Beuren syndrome chromosome region 21 (WBSCR~
NM_148915 Homo sapiens Williams Beuren syndrome chromosome region 21 (WBSCR~
NM_148916 Homo sapiens Williams Beuren syndrome chromosome region 21 (WBSCR~
NM_148918 Homo sapiens serine hydroxymethyltransferase 1 (soluble) (SHMT1),
transcr
NM_148919 Homo sapiens proteasome (prosome, macropain) subunit, beta type, 8
(large
NM_148920 Homo sapiens phosphatidylinositol glycan, class Q (PIGQ), transcript
variant
NM_148921 Homo Sapiens epsin 2 (EPN2), transcript variant 1, mRNA
NM_148923 Homo sapiens cytochrome b-5 (CYBS), mRNA
NM_148936 Homo sapiens Williams Beuren syndrome chromosome region 20C (WBSCF
NM_148954 Homo sapiens proteasome (prosome, macropain) subunit, beta type, 9
(large
NM_148955 Homo Sapiens sorting nexin 1 (SNX1 ), transcript variant 2, mRNA
NM_148956 Homo sapiens Williams Beuren syndrome chromosome region 20A (WBSCF
NM_148957 Homo sapiens tumor necrosis factor receptor superfamily, member 19
(TNFF
NM_148959 Homo sapiens HUS1 checkpoint homolog b (S. pombe) (HUS1 B), mRNA
NM_148960 Homo Sapiens claudin 19 (CLDN19), mRNA
NM_148961 Homo Sapiens otospiralin (OTOS), mRNA
NM_148962 Homo Sapiens oxoeicosanoid (OXE) receptor 1 (OXER1 ), mRNA
NM 148963 Homo Sapiens G protein-coupled receptor, family C, group 6, member A
(GP
NM 148964 Homo Sapiens cathepsin E (CTSE), transcript variant 2, mRNA
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NM_148965 Homo Sapiens tumor necrosis factor receptor superFamily, member 25
(TNFF
NM_148966 Homo Sapiens tumor necrosis factor receptor superfamily, member 25
(TNFF
NM_148967 Homo sapiens tumor necrosis factor receptor superfamily, member 25
(TNFF
NM_148968 Homo Sapiens tumor necrosis factor receptor superfamily, member 25
(TNFF
NM_148969 Homo sapiens tumor necrosis factor receptor superfamily, member 25
(TNFF
NM_148970 Homo Sapiens tumor necrosis factor receptor supertamily, member 25
(TNFF
NM_148971 Homo sapiens tumor necrosis factor receptor superfamily, member 25
(TNFF
NM_148972 Homo Sapiens tumor necrosis factor receptor superfamily, member 25
(TNFF
NM_148973 Homo sapiens tumor necrosis factor receptor superfamily, member 25
(TNFF
NM_148974 Homo sapiens tumor necrosis factor receptor superfamily, member 25
(TNFF
NM_148975 Homo sapiens membrane-spanning 4-domains, subfamily A, member 4 (MS~
NM_148976 Homo sapiens proteasome (prosome, macropain) subunit, alpha type, 1
(PSI
NM_148977 Homo sapiens pantothenate kinase 1 (PANK1 ), transcript variant
alpha, mRP
NM_148978 Homo Sapiens pantothenate kinase 1 (PANK1), transcript variant beta,
mRN~
NM_148979 Homo sapiens cathepsin H (CTSH), transcript variant 2, mRNA
NM_148980 Homo sapiens Williams Beuren syndrome chromosome region 20C (WBSCF
NM_149379 Homo sapiens Williams Beuren syndrome chromosome region 20C (WBSCF
NM_152132 Homo sapiens proteasome (prosome, macropain) subunit, alpha type, 3
(PSI
NM_152133 Homo sapiens T-cell activation GTPase activating protein (TAGAP),
transcriK
NM_152219 Homo sapiens gap junction protein, chi 1, 31.9kDa (connexin 31.9)
(GJC1), r
NM_152221 Homo sapiens casein kinase 1 , epsilon (CSNK1 E), transcript variant
1, mRN
NM_152222 Homo Sapiens tumor necrosis factor receptor superfamily, member 19-
like ('f
NM_152223 Homo sapiens protein phosphatase, EF hand calcium-binding domain 1
(PPI
NM_152224 Homo Sapiens protein phosphatase, EF hand calcium-binding domain 1
(PPI
NM_152225 Homo sapiens protein phosphatase, EF hand calcium-binding domain 1
(PPI
NM_152226 Homo sapiens protein phosphatase, EF hand calcium-binding domain 1
(PPI
NM_152227 Homo Sapiens sorting nexin 5 (SNXS), transcript variant 1, mRNA
NM_152230 Homo sapiens inositol polyphosphate multikinase (IPMK), mRNA
NM_152232 Homo sapiens taste receptor, type 1, member 2 (TAS1R2), mRNA
NM_152233 Homo sapiens sorting nexin 6 (SNX6), transcript variant 2, mRNA
NM_152235 Homo sapiens splicing factor, arginine/serine-rich 8 (suppressor-of-
white-apr
NM_152236 Homo sapiens growth arrest-specific 2 like 1 (GAS2L1 ), transcript
variant 2, i
NM_152237 Homo sapiens growth arrest-specific 2 like 1 (GAS2L1 ), transcript
variant 3, i
NM_152238 Homo sapiens sorting nexin 7 (SNX7), transcript variant 2, mRNA
NM_152240 Homo sapiens p53 target zinc finger protein (WIG1 ), transcript
variant 2, mR
NM_152243 Homo sapiens CDC42 effector protein (Rho GTPase binding) 1
(CDC42EP1;
NM_152244 Homo sapiens sorting nexin 11 (SNX11), transcript variant 1, mRNA
NM_152245 Homo sapiens carnitine palmitoyltransferase 1 B (muscle) (CPT1 B),
nuclear c
NM_152246 Homo sapiens carnitine palmitoyltransferase 1 B (muscle) (CPT1 B),
nuclear c
NM_152247 Homo sapiens carnitine palmitoyltransferase 1 B (muscle) (CPT1 B),
nuclear c
NM_152250 Homo sapiens defensin, beta 105 (DEFB105), mRNA
NM_152251 Homo sapiens defensin, beta 106 (DEFB106), mRNA
NM_152253 Homo sapiens choline kinase beta (CHKB), transcript variant 2, mRNA
NM_152255 Homo sapiens proteasome (prosome, macropain) subunit, alpha type, 7
(PSI
NM_152257 Homo sapiens KIAA0889 protein (KIAA0889), mRNA
NM_152259 Homo sapiens leucine-rich repeat kinase 1 (MGC45866), mRNA
NM_152260 Homo sapiens chromosome 15 open reading frame 19 (C15orf19), mRNA
NM_152261 Homo sapiens hypothetical protein MGC17943 (MGC17943), mRNA
NM_152262 Homo sapiens zinc finger protein 439 (ZNF439), mRNA
NM_152263 Homo sapiens tropomyosin 3 (TPM3), mRNA
NM_152264 Homo sapiens solute carrier family 39 (zinc transporter), member 13
(SLC39
NM_152266 Homo sapiens hypothetical protein MGC32020 (MGC32020), mRNA
NM_152267 Homo sapiens hypothetical protein FLJ38628 (FLJ38628), mRNA
NM_152268 Homo sapiens similar to tRNA synthetase class II (DKFZp727A071 ),
mRNA
NM_152269 Homo sapiens hypothetical protein FLJ38663 (FLJ38663), mRNA
NM 152270 Homo sapiens hypothetical protein FLJ34922 (FLJ34922), mRNA
NM 152271 Homo sapiens hypothetical protein FLJ23749 (FLJ23749), mRNA
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NM_152272 Homo sapiens hypothetical protein MGC29816 (MGC29816), mRNA
NM_152274 Homo sapiens hypothetical protein MGC29729 (MGC29729), mRNA
NM_152275 Homo sapiens hypothetical protein FLJ13946 (FLJ13946), mRNA
NM_152277 Homo sapiens dendritic cell-derived ubiquitin-like protein (DC-UbP),
mRNA
NM_152278 Homo sapiens hypothetical protein MGC23947 (MGC23947), mRNA
NM_152279 Homo sapiens zinc finger protein 585B (ZNF585B), mRNA
NM_152280 Homo sapiens synaptotagmin XI (SYT11), mRNA
NM_152281 Homo sapiens NTKL-binding protein 1 (FLJ11752), mRNA
NM_152282 Homo sapiens hypothetical protein FLJ23751 (FLJ23751), mRNA
NM_152283 Homo sapiens zinc finger protein 62 homolog (mouse) (ZFP62), mRNA
NM_152284 Homo sapiens Snf7 homologue associated with Alix 3 (Shax3), mRNA
NM_152285 Homo sapiens arrestin domain containing 1 (ARRDC1), mRNA
NM_152286 Homo sapiens chromosome 9 open reading frame 111 (C9orf111 ), mRNA
NM_152287 Homo sapiens zinc finger protein 276 homolog (mouse) (ZFP276), mRNA
NM_152288 Homo sapiens hypothetical protein MGC13024 (MGC13024), mRNA
NM_152289 Homo sapiens zinc finger protein 561 (ZNF561 ), mRNA
NM_152290 Homo sapiens hypothetical protein MGC35194 (MGC35194), mRNA
NM_152291 Homo sapiens mucin 7, salivary (MUC7), mRNA
NM_152292 Homo sapiens RNA (guanine-9-) methyltransferase domain containing 2
(RC
NM_152295 Homo sapiens threonyl-tRNA synthetase (TARS), mRNA
NM_152296 Homo Sapiens ATPase, Na+/K+ transporting, alpha 3 polypeptide
(ATP1A3),
NM_152298 Homo sapiens nuclear autoantigenic sperm protein (histone-binding)
(NASP)
NM_152299 Homo sapiens hypothetical protein 384D8 6 (384D8-2), mRNA
NM_152300 Homo sapiens DEAD (Asp-Glu-Ala-Asp) box polypeptide 52 (DDX52),
transc
NM_152301 Homo Sapiens PP784 protein (PP784), transcript variant 1, mRNA
NM_152302 Homo sapiens chromosome 20 open reading frame 158 (C20orf158), mRNA
NM_152303 Homo Sapiens zinc finger protein 554 (ZNF554), mRNA
NM_152304 Homo sapiens hypothetical protein MGC45806 (MGC45806), mRNA
NM_152305 Homo Sapiens x 010 protein (MDS010), mRNA
NM_152306 Homo sapiens ubiquitin-like, containing PHD and RING finger domains,
2 (U1
NM_152307 Homo sapiens hypothetical protein FLJ40452 (FLJ40452), mRNA
NM_152308 Homo sapiens hypothetical protein MGC24665 (MGC24665), mRNA
NM_152309 Homo sapiens phosphoinositide-3-kinase adaptor protein 1 (PIK3AP1 ),
mRN
NM_152310 Homo sapiens elongation of very long chain fatty acids (FEN1/Elo2,
SUR4/EI
NM_152311 Homo Sapiens hypothetical protein MGC32871 (MGC32871), mRNA
NM_152312 Homo sapiens glycosyltransferase-like 1 B (GYLTL1 B), mRNA
NM_152313 Homo sapiens solute carrier family 36 (proton/amino acid symporter),
memb~
NM_152314 Homo sapiens hypothetical protein MGC34830 (MGC34830), mRNA
NM_152315 Homo sapiens hypothetical protein MGC34290 (MGC34290), mRNA
NM_152316 Homo sapiens hypothetical protein FLJ38968 (FLJ38968), mRNA
NM_152317 Homo sapiens DEP domain containing 4 (DEPDC4), mRNA
NM_152318 Homo sapiens hypothetical protein MGC40397 (MGC40397), mRNA
NM_152319 Homo sapiens hypothetical protein MGC35033 (MGC35033), mRNA
NM_152320 Homo sapiens hypothetical protein FLJ31295 (FLJ31295), mRNA
NM_152321 Homo sapiens hypothetical protein FLJ32115 (FLJ32115), mRNA
NM_152322 Homo sapiens BTB (POZ) domain containing 11 (BTBD11), mRNA
NM_152323 Homo Sapiens Spi-C transcription factor (Spi-1/PU.1 related) (SPIC),
mRNA
NM_152324 Homo sapiens hypothetical protein MGC35169 (MGC35169), mRNA
NM_152325 Homo sapiens hypothetical protein MGC40178 (MGC40178), mRNA
NM_152326 Homo sapiens ankyrin repeat domain 9 (ANKRD9), mRNA
NM_152327 Homo sapiens adenylate kinase 7 (AK7), mRNA
NM_152328 Homo sapiens adenylosuccinate synthase like 1 (ADSSL1 ), transcript
variant
NM_152329 Homo sapiens peptidylprolyl isomerase (cyclophilin) like 5 (PPILS),
transcript
NM_152330 Homo sapiens chromosome 14 open reading frame 31 (C14orf31), mRNA
NM_152331 Homo sapiens peroxisomal acyl-CoA thioesterase 2B (PTE2B), mRNA
NM 152332 Homo sapiens membrane targeting (tandem) C2 domain containing 1
(MTAC
NM 152333 Homo sapiens solute carrier family 25, member 29 (SLC25A29), mRNA
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NM_152334 Homo sapiens FLJ25005 protein (FLJ25005), mRNA
NM_152335 Homo sapiens chromosome 15 open reading frame 27 (C15orf27), mRNA
NM_152336 Homo sapiens hypothetical protein FLJ32310 (FLJ32310), mRNA
NM_152337 Homo sapiens hypothetical protein FLJ32702 (FLJ32702), mRNA
NM_152338 Homo sapiens zymogen granule protein 16 (ZG16), mRNA
NM_152339 Homo sapiens hypothetical protein MGC26885 (MGC26885), mRNA
NM_152340 Homo sapiens hypothetical protein FLJ39075 (FLJ39075), mRNA
NM_152341 Homo sapiens progestin and adipoQ receptor family member IV (PAQR4),
m
NM_152342 Homo Sapiens chromodomain protein, Y-like 2 (CDYL2), mRNA
NM_152343 Homo sapiens hypothetical protein FLJ25414 (FLJ25414), mRNA
NM_152344 Homo sapiens hypothetical protein FLJ30656 (FLJ30656), mRNA
NM_152345 Homo sapiens hypothetical protein FLJ25555 (FLJ25555), mRNA
NM_152346 Homo sapiens hypothetical protein MGC34680 (MGC34680), mRNA
NM_152347 Homo sapiens hypothetical protein FLJ40342 (FLJ40342), mRNA
NM_152348 Homo sapiens hypothetical protein FLJ33817 (FLJ33817), mRNA
NM_152349 Homo sapiens hypothetical protein MGC45562 (MGC45562), mRNA
NM_152350 Homo sapiens hypothetical protein MGC40157 (MGC40157), mRNA
NM_152351 Homo sapiens solute carrier family 5 (sodium/glucose cotransporter),
membf
NM_152352 Homo sapiens chromosome 18 open reading frame 19 (C18orf19), mRNA
NM_152353 Homo sapiens hypothetical protein MGC33839 (MGC33839), mRNA
NM_152354 Homo sapiens zinc finger protein 285 (ZNF285), mRNA
NM_152355 Homo Sapiens zinc finger protein 441 (ZNF441 ), mRNA
NM_152356 Homo sapiens zinc finger protein 491 (ZNF491 ), mRNA
NM_152357 Homo sapiens zinc finger protein 440 (ZNF440), mRNA
NM_152358 Homo sapiens hypothetical protein MGC33947 (MGC33947), mRNA
NM_152359 Homo sapiens carnitine palmitoyltransferase 1C (CPT1C), mRNA
NM_152360 Homo sapiens zinc finger protein 573 (ZNF573), mRNA
NM_152361 Homo sapiens hypothetical protein FLJ38944 (FLJ38944), mRNA
NM_152362 Homo Sapiens hypothetical protein MGC17791 (MGC17791 ), mRNA
NM_152363 Homo sapiens hypothetical protein FLJ39369 (FLJ39369), mRNA
NM_152365 Homo sapiens hypothetical protein FLJ34633 (FLJ34633), mRNA
NM_152366 Homo sapiens hypothetical protein MGC33338 (MGC33338), mRNA
NM_152367 Homo sapiens hypothetical protein FLJ38716 (FLJ38716), mRNA
NM_152369 Homo Sapiens hypothetical protein MGC45474 (MGC45474), mRNA
NM_152371 Homo sapiens hypothetical protein MGC26818 (MGC26818), mRNA
NM_152372 Homo sapiens myomesin family, member 3 (MYOM3), mRNA
NM_152373 Homo Sapiens hypothetical protein MGC27466 (MGC27466), mRNA
NM_152374 Homo sapiens hypothetical protein FLJ38984 (FLJ38984), mRNA
NM_152375 Homo sapiens hypothetical protein FLJ38753 (FLJ38753), mRNA
NM_152376 Homo sapiens UBX domain containing 3 (UBXD3), mRNA
NM_152377 Homo Sapiens hypothetical protein MGC34837 (MGC34837), mRNA
NM_152378 Homo sapiens hypothetical protein FLJ31052 (FLJ31052), mRNA
NM_152379 Homo Sapiens hypothetical protein DKFZp547B1713 (DKFZp547B1713), mF
NM_152382 Homo sapiens hypothetical protein FLJ37953 (FLJ37953), mRNA
NM_152383 Homo sapiens hypothetical protein MGC42174 (MGC42174), mRNA
NM_152384 Homo sapiens Bardet-Biedl syndrome 5 (BBSS), mRNA
NM_152385 Homo sapiens hypothetical protein FLJ31438 (FLJ31438), mRNA
NM_152386 Homo sapiens sphingosine-1-phosphate phosphotase 2 (SGPP2), mRNA
NM_152387 Homo sapiens hypothetical protein FLJ31322 (FLJ31322), mRNA
NM_152388 Homo Sapiens amyotrophic lateral sclerosis 2 Quvenile) chromosome
region,
NM_152389 Homo sapiens hypothetical protein MGC35338 (MGC35338), mRNA
NM_152390 Homo sapiens hypothetical protein MGC33926 (MGC33926), mRNA
NM_152391 Homo sapiens chromosome 2 open reading frame 22 (C2orF22), mRNA
NM_152392 Homo sapiens AHA1, activator of heat shock 90kDa protein ATPase
homolol
NM_152393 Homo sapiens ketch repeat and BTB (POZ) domain containing 5
(KBTBDS),
NM 152394 Homo sapiens hypothetical protein MGC39662 (MGC39662), mRNA
NM 152395 Homo sapiens hypothetical protein FLJ31265 (FLJ31265), mRNA
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NM_152396 Homo sapiens hypothetical protein MGC24132 (MGC24132), mRNA
NM_152397 Homo sapiens hypothetical protein MGC39725 (MGC39725), mRNA
NM_152398 Homo sapiens hypothetical protein MGC45416 (MGC45416), mRNA
NM_152399 Homo sapiens hypothetical protein FLJ30834 (FLJ30834), mRNA
NM_152400 Homo sapiens hypothetical protein FLJ39370 (FLJ39370), mRNA
NM_152401 Homo sapiens phosducin-like 2 (PDCL2), mRNA
NM_152402 Homo Sapiens translocation associated membrane protein 1-like 1
(TRAM1 L
NM_152403 Homo sapiens hypothetical protein FLJ39155 (FLJ39155), transcript
variant '
NM_152404 Homo Sapiens hypothetical protein FLJ34658 (FLJ34658), mRNA
NM_152405 Homo sapiens junction-mediating and regulatory protein (JMY), mRNA
NM_152407 Homo sapiens GrpE-like 2, mitochondria) (E, coli) (GRPEL2), mRNA
NM_152408 Homo sapiens hypothetical protein FLJ35779 (FLJ35779), mRNA
NM_152409 Homo sapiens hypothetical protein FLJ3T562 (FLJ37562), mRNA '
NM_152410 Homo Sapiens PARK2 co-regulated (PACRG), mRNA
NM_152411 Homo sapiens hypothetical protein DKFZp7621137 (DKFZp7621137), mRNA
NM_152412 Homo Sapiens zinc finger protein 572 (ZNF572), mRNA
NM_152413 Homo sapiens hypothetical protein MGC33309 (MGC33309), mRNA
NM_152414 Homo sapiens basic helix-loop-helix domain containing, class B, 5
(BHLHBS'
NM_152415 Homo sapiens hepatocellular carcinoma related protein 1 (FLJ32642),
mRN~
NM_152416 Homo sapiens hypothetical protein MGC40214 (MGC40214), mRNA
NM_152417 Homo sapiens hypothetical protein FLJ32370 (FLJ32370), mRNA
NM_152418 Homo Sapiens hypothetical protein FLJ35775 (FLJ35775), mRNA
NM_152420 Homo Sapiens chromosome 9 open reading frame 41 (C9orf41), mRNA
NM_152421 Homo sapiens hypothetical protein MGC20262 (MGC20262), mRNA
NM_152422 Homo sapiens protein tyrosine phosphatase domain containing 1
(PTPDC1),
NM_152423 Homo sapiens hypothetical protein FLJ33516 (FLJ33516), mRNA
NM_152424 Homo sapiens hypothetical protein FLJ39827 (FLJ39827), mRNA
NM_152425 Homo Sapiens hypothetical protein FLJ40249 (FLJ40249), mRNA
NM_152427 Homo sapiens cofilin pseudogene 1 (CFLP1), mRNA
NM_152428 Homo sapiens FERM and PDZ domain containing 2 (FRMPD2), mRNA
NM_152429 Homo sapiens chromosome 10 open reading frame 13 (C10orf13), mRNA
NM_152430 Homo sapiens hypothetical protein MGC24137 (MGC24137), mRNA
NM_152431 Homo sapiens piwi-like 4 (Drosophila) (PIWIL4), mRNA
NM_152433 Homo sapiens ketch repeat and BTB (POZ) domain containing 3
(KBTBD3),
NM_152434 Homo sapiens CWF19-like 2, cell cycle control (S. pombe) (CWF19L2),
mRP
NM_152435 Homo sapiens hypothetical protein MGC35366 (MGC35366), mRNA
NM_152436 Homo Sapiens hypothetical protein MGC39497 (MGC39497), mRNA
NM_152437 Homo sapiens hypothetical protein DKFZp7618128 (DKFZp761 B128), mRN~
NM_152439 Homo Sapiens vitelliform macular dystrophy 2-like 3 (VMD2L3), mRNA
NM_152440 Homo sapiens hypothetical protein FLJ32549 (FLJ32549), mRNA
NM_152441 Homo Sapiens F-box and leucine-rich repeat protein 14 (FBXL14), mRNA
NM_152442 Homo sapiens RAD9 homolog B (S. cerevisiae) (RAD9B), mRNA
NM_152443 Homo Sapiens retinol dehydrogenase 12 (all-trans and 9-cis) (RDH12),
mRN
NM_152444 Homo sapiens zinc binding alcohol dehydrogenase, domain containing 1
(ZA
NM_152445 Homo sapiens chromosome 14 open reading frame 44 (C14orf44), mRNA
NM_152447 Homo sapiens leucine rich repeat and fibronectin type III domain
containing
NM_152448 Homo sapiens hypothetical protein MGC33951 (MGC33951), mRNA
NM_152449 Homo Sapiens hypothetical protein FLJ33008 (FLJ33008), mRNA
NM_152450 Homo sapiens hypothetical protein MGC26690 (MGC26690), mRNA
NM_152451 Homo sapiens GRINL1A complex upstream protein (Gup1), mRNA
NM_152453 Homo sapiens hypothetical protein MGC35118 (MGC35118), mRNA
NM_152454 Homo sapiens hypothetical protein FLJ31461 (FLJ31461), mRNA
NM_152455 Homo sapiens hypothetical protein FLJ35867 (FLJ35867), mRNA
NM_152456 Homo sapiens hypothetical protein MGC34647 (MGC34647), mRNA
NM_152457 Homo sapiens zinc finger protein 597 (ZN F597), mRNA
NM 152458 Homo sapiens hypothetical protein FLJ32130 (FLJ32130), mRNA
NM 152459 Homo sapiens hypothetical protein MGC45438 (MGC45438), mRNA
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NM_152460 Homo sapiens hypothetical protein FLJ31882 (FLJ31882), mRNA
NM_152461 Homo sapiens ER to nucleus signalling 1 (ERN1 ), transcript variant
2, mRNp
NM_152462 Homo sapiens transmembrane protein 21A (TMEM21A), mRNA
NM_152463 Homo sapiens essential meiotic endonuclease 1 homolog 1 (S. pombe)
(EMI
NM_152464 Homo sapiens chromosome 17 open reading frame 32 (C17orf32), mRNA
NM_152465 Homo sapiens hypothetical protein MGC39650 (MGC39650), mRNA
NM_152466 Homo sapiens hypothetical protein FLJ25168 (FLJ25168), mRNA
NM_152467 Homo sapiens ketch-like 10 (Drosophila) (KLHL10), mRNA
NM_152468 Homo sapiens epidermodysplasia verruciformis 2 (EVER2), mRNA
NM_152470 Homo sapiens chromosome 18 open reading frame 23 (C18orf23), mRNA
NM_152472 Homo Sapiens zinc finger protein 578 (ZNF578), mRNA
NM_152473 Homo sapiens hypothetical protein FLJ32214 (FLJ32214), mRNA
NM_152474 Homo sapiens chromosome 19 open reading frame 18 (C19orf18), mRNA
NM_152475 Homo sapiens hypothetical protein MGC34079 (MGC34079), mRNA
NM_152476 Homo Sapiens zinc finger protein 560 (ZNF560), mRNA
NM_152477 Homo sapiens zinc finger protein 565 (ZNF565), mRNA
NM_152478 Homo sapiens zinc finger protein 583 (ZNF583), mRNA
NM_152479 Homo sapiens hypothetical protein MGC33962 (MGC33962), mRNA
NM_152480 Homo sapiens chromosome 19 open reading frame 23 (C19orf23), mRNA
NM_152481 Homo sapiens hypothetical protein FLJ25660 (FLJ25660), mRNA
NM_152482 Homo sapiens chromosome 19 open reading frame 25 (C19orf25), mRNA
NM_152483 Homo sapiens hypothetical protein FLJ25328 (FLJ25328), mRNA
NM_152484 Homo Sapiens zinc finger protein 569 (ZNF569), mRNA
NM_152485 Homo sapiens hypothetical protein FLJ25078 (FLJ25078), mRNA
NM_152486 Homo sapiens sterile alpha motif domain containing 11 (SAMD11), mRNA
NM_152487 Homo Sapiens hypothetical protein FLJ31842 (FLJ31842), mRNA
NM_152488 Homo sapiens hypothetical protein FLJ32833 (FLJ32833), mRNA
NM_152489 Homo Sapiens hypothetical protein MGC35130 (MGC35130), mRNA
NM_152490 Homo sapiens beta 1,3-N-acetylgalactosaminyltransferase-II
(MGC39558), n
NM_152491 Homo sapiens hypothetical protein FLJ32569 (FLJ32569), mRNA
NM_152492 Homo sapiens hypothetical protein FLJ32825 (FLJ32825), mRNA
NM_152493 Homo sapiens FLJ25476 protein (FLJ25476), mRNA
NM_152494 Homo sapiens hypothetical protein FLJ32785 (FLJ32785), mRNA
NM_152495 Homo sapiens hypothetical protein FLJ38993 (FLJ38993), mRNA
NM_152496 Homo sapiens hypothetical protein FLJ31434 (FLJ31434), mRNA
NM_152497 Homo Sapiens hypothetical protein FLJ32206 (FLJ32206), mRNA
NM_152498 Homo sapiens hypothetical protein FLJ32000 (FLJ32000), mRNA
NM_152499 Homo sapiens hypothetical protein MGC45441 (MGC45441), mRNA
NM_152500 Homo Sapiens hypothetical protein FLJ33084 (FLJ33084), mRNA
NM_152501 Homo sapiens interferon-inducible protein X (IFIX), transcript
variant a1, mRl
NM_152503 Homo sapiens chromosome 20 open reading frame 132 (C20orf132),
transcr
NM_152504 Homo sapiens hypothetical protein FLJ25067 (FLJ25067), mRNA
NM_152505 Homo sapiens chromosome 21 open reading frame 13 (C21orf13), mRNA
NM_152506 Homo sapiens chromosome 21 open reading frame 129 (C21 orf129), mRNA
NM_152507 Homo Sapiens chromosome 21 open reading frame 128 (C21orf128), mRNA
NM_152509 Homo sapiens hypothetical protein FLJ31568 (FLJ31568), mRNA
NM_152510 Homo Sapiens hypothetical protein MGC26710 (MGC26710), mRNA
NM_152511 Homo sapiens dual specificity phosphatase 18 (DUSP18), mRNA
NM_152512 Homo sapiens hypothetical protein FLJ25421 (FLJ25421), mRNA
NM_152515 Homo sapiens hypothetical protein FLJ40629 (FLJ40629), mRNA
NM_152516 Homo sapiens copper metabolism (Murr1) domain containing 1 (COMMD1),
NM_152517 Homo sapiens hypothetical protein FLJ30990 (FLJ30990), mRNA
NM_152519 Homo sapiens hypothetical protein FLJ23861 (FLJ23861), mRNA
NM_152520 Homo sapiens zinc finger protein 533 (ZNF533), mRNA
NM_152522 Homo sapiens ADP-ribosylation-like factor 6-interacting protein 6
(MGC3386~
NM 152523 Homo sapiens hypothetical protein FLJ40432 (FLJ40432), mRNA
NM 152524 Homo sapiens shugoshin-like 2 (S. pombe) (SGOL2), mRNA
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NM_152525 Homo sapiens hypothetical protein FLJ25351 (FLJ25351 ), mRNA
NM_152526 Homo sapiens amyotrophic lateral sclerosis 2 (juvenile) chromosome
region,
NM_152527 Homo sapiens solute carrier family 16 (monocarboxylic acid
transporters), m.
NM_152528 Homo sapiens WD repeat and SAM domain containing 1 (WDSAM1), mRNA
NM_152529 Homo sapiens G protein-coupled receptor 155 (GPR155), mRNA
NM_152531 Homo Sapiens hypothetical protein FLJ35155 (FLJ35155), mRNA
NM_152533 Homo sapiens hypothetical protein MGC34728 (MGC34728), mRNA
NM_152534 Homo sapiens hypothetical protein FLJ32685 (FLJ32685), mRNA
NM_152536 Homo sapiens FYVE, RhoGEF and PH domain containing 5 (FGDS), mRNA
NM_152538 Homo sapiens immunoglobulin superfamily, member 11 (IGSF11), mRNA
NM_152539 Homo sapiens hypothetical protein FLJ32859 (FLJ32859), mRNA
NM_152540 Homo sapiens sect family domain containing 2 (SCFD2), mRNA
NM_152542 Homo sapiens hypothetical protein DKFZp7616058 (DKFZp761G058), mRN
NM_152543 Homo sapiens hypothetical protein FLJ25371 (FLJ25371), mRNA
NM_152544 Homo sapiens hypothetical protein FLJ35725 (FLJ35725), mRNA
NM_152545 Homo Sapiens RasGEF domain family, member 1 B (RASGEF1 B), mRNA
NM_152546 Homo sapiens hypothetical protein FLJ25286 (FLJ25286), mRNA
NM_152547 Homo sapiens butyrophilin-like 9 (BTNL9), mRNA
NM_152548 Homo sapiens hypothetical protein FLJ25333 (FLJ25333), mRNA
NM_152549 Homo sapiens hypothetical protein MGC39633 (MGC39633), mRNA
NM 152550 Homo sapiens SH3 domain containing ring finger 2 (SH3RF2), mRNA
NM 152551 Homo sapiens chromosome 6 open reading frame 151 (C6orf151), mRNA
NM_152552 Homo sapiens sterile alpha motif domain containing 3 (SAMD3), mRNA
NM_152553 Homo sapiens IBR domain containing 1 (IBRDC1 ), mRNA
NM_152554 Homo sapiens chromosome 6 open reading frame 195 (C6orf195), mRNA
NM_152556 Homo sapiens hypothetical protein FLJ31818 (FLJ31818), mRNA
NM_152557 Homo Sapiens hypothetical protein FLJ31413 (FLJ31413), mRNA
NM_152558 Homo sapiens KIAA1023 protein (KIAA1023), mRNA
NM_152559 Homo sapiens Williams Beuren syndrome chromosome region 27 (WBSCR~
NM_152562 Homo sapiens cell division cycle associated 2 (CDCA2), mRNA
NM_152563 Homo sapiens hypothetical protein FLJ10661 (FLJ10661), mRNA
NM_152564 Homo Sapiens Cohen syndrome 1 (COH1), transcript variant 1, mRNA
NM_152565 Homo sapiens ATPase, H+ transporting, lysosomal 38kDa, VO subunit d
isofi
NM_152568 Homo Sapiens hypothetical protein FLJ25169 (FLJ25169), mRNA
NM_152569 Homo sapiens chromosome 9 open reading frame 66 (C9orF66), mRNA
NM_152570 Homo Sapiens hypothetical protein FLJ31810 (FLJ31810), mRNA
NM_152571 Homo sapiens hypothetical protein FLJ36779 (FLJ36779), mRNA
NM_152572 Homo sapiens chromosome 9 open reading frame 98 (C9orF98), mRNA
NM_152573 Homo sapiens RAS and EF hand domain containing (RASEF), mRNA
NM_152574 Homo sapiens chromosome 9 open reading frame 52 (C9orf52), mRNA
NM_152577 Homo Sapiens hypothetical protein FLJ25735 (FLJ25735), mRNA
NM_152578 Homo Sapiens fragile X mental retardation 1 neighbor (FMR1 NB), mRNA
NM_152579 Homo sapiens hypothetical protein FLJ38564 (FLJ38564), mRNA
NM_152581 Homo Sapiens motile sperm domain containing 2 (MOSPD2), mRNA
NM_152582 Homo sapiens hypothetical protein MGC27005 (MGC27005), mRNA
NM_152583 Homo sapiens hypothetical protein MGC40053 (MGC40053), mRNA
NM_152584 Homo sapiens heat shock transcription factor, Y-linked 1 (HSFY1 ),
transcript
NM_152585 Homo sapiens RNA binding motif protein, Y-linked, family 1
(MGC33094), m(
NM_152586 Homo sapiens ubiquitin specific protease 54 (USP54), mRNA
NM_152587 Homo sapiens hypothetical protein MGC33948 (MGC33948), mRNA
NM_152588 Homo sapiens hypothetical protein DKFZp762A217 (DKFZp762A217), mRN~
NM_152589 Homo sapiens hypothetical protein FLJ35821 (FLJ35821), mRNA
NM_152590 Homo sapiens hypothetical protein FLJ36004 (FLJ36004), mRNA
NM_152591 Homo sapiens hypothetical protein FLJ35843 (FLJ35843), mRNA
NM_152592 Homo sapiens chromosome 14 open reading frame 49 (C14orf49), mRNA
NM_152594 Homo sapiens sprouty-related, EVH1 domain containing 1 (SPRED1),
mRN~
NM_152595 Homo Sapiens piggyBac transposable element derived 4 (PGBD4), mRNA
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NM_152596 Homo sapiens hypothetical protein MGC33637 (MGC33637), mRNA
NM_152597 Homo sapiens fibrous sheath interacting protein 1 (FSIP1), mRNA
NM_152598 Homo sapiens hypothetical protein FLJ35757 (FLJ35757), mRNA
NM_152599 Homo Sapiens hypothetical protein FLJ35773 (FLJ35773), mRNA
NM_152600 Homo sapiens zinc finger protein 579 (ZNF579), mRNA
NM_152601 Homo sapiens hypothetical protein FLJ38281 (FLJ38281), mRNA
NM_152602 Homo sapiens zinc finger protein 433 (ZNF433), mRNA
NM_152603 Homo sapiens zinc finger protein 567 (ZNF567), mRNA
NM_152604 Homo sapiens zinc finger protein 383 (ZNF383), mRNA
NM_152605 Homo sapiens hypothetical protein FLJ37549 (FLJ37549), mRNA
NM_152606 Homo sapiens zinc finger protein 540 (ZNF540), mRNA
NM_152607 Homo sapiens hypothetical protein FLJ40201 (FLJ40201), mRNA
NM_152608 Homo Sapiens hypothetical protein FLJ35382 (FLJ35382), mRNA
NM_152609 Homo sapiens hypothetical protein FLJ32001 (FLJ32001), mRNA
NM_152610 Homo sapiens hypothetical protein FLJ35728 (FLJ35728), mRNA
NM_152611 Homo sapiens chromosome 20 open reading frame 75 (C20orf75), mRNA
NM_152612 Homo sapiens hypothetical protein FLJ36046 (FLJ36046), mRNA
NM_152613 Homo sapiens hypothetical protein MGC26816 (MGC26816), mRNA
NM_152614 Homo sapiens hypothetical protein MGC35154 (MGC35154), mRNA
NM_152615 Homo sapiens hypothetical protein FLJ40597 (FLJ40597), mRNA
NM_152616 Homo sapiens tripartite motif-containing 42 (TRIM42), mRNA
NM_152617 Homo sapiens hypothetical protein FLJ35794 (FLJ35794), mRNA
NM_152618 Homo sapiens hypothetical protein FLJ35630 (FLJ35630), mRNA
NM_152619 Homo sapiens hypothetical protein MGC45428 (MGC45428), mRNA
NM_152620 Homo sapiens ring finger protein 129 (RNF129), mRNA
NM_152621 Homo sapiens hypothetical protein MGC26963 (MGC26963), mRNA
NM_152622 Homo sapiens hypothetical protein FLJ35954 (FLJ35954), mRNA
NM_152623 Homo sapiens CDC20-like protein (FLJ37927), mRNA
NM_152624 Homo sapiens decapping enzyme hDcp2 (DCP2), mRNA
NM_152625 Homo sapiens zinc finger protein 366 (ZNF366), mRNA
NM_152626 Homo sapiens zinc finger protein 92 (HTF~ 2) (ZNF92), mRNA
NM_152628 Homo Sapiens hypothetical protein MGC39715 (MGC39715), mRNA
NM_152629 Homo sapiens GLIS family zinc finger 3 (GLIS3), mRNA
NM_152630 Homo sapiens hypothetical protein MGC26999 (MGC26999), mRNA
NM_152631 Homo sapiens hypothetical protein FLJ35782 (FLJ35782), mRNA
NM_152632 Homo Sapiens chromosome X open reading frame 22 (CXorf22), mRNA
NM_152633 Homo sapiens hypothetical protein FLJ34064 (FLJ34064), mRNA
NM_152635 Homo Sapiens oncoprotein induced transcript 3 (01T3), mRNA
NM_152636 Homo Sapiens hypothetical protein FLJ33979 (FLJ33979), mRNA
NM_152637 Homo sapiens hypothetical protein MGC17301 (MGC17301), mRNA
NM_152638 Homo sapiens hypothetical protein MGC26598 (MGC26598), mRNA
NM_152640 Homo sapiens decapping enzyme hDcp1 b (DCP1 B), mRNA
NM_152643 Homo sapiens kinase non-catalytic C-lobe domain (KIND) containing 1
(KND
NM_152644 Homo sapiens family with sequence similarity 24, member B (FAM24B),
mRP
NM_152647 Homo sapiens hypothetical protein FLJ32800 (FLJ32800), mRNA
NM_152649 Homo sapiens hypothetical protein FLJ34389 (FLJ34389), mRNA
NM_152652 Homo sapiens zinc finger protein 553 (ZNF553), mRNA
NM_152653 Homo sapiens ubiquitin-conjugating enzyme E2E 2 (UBC4/5 homolog,
yeast
NM_152654 Homo sapiens hypothetical protein FLJ38607 (FLJ38607), mRNA
NM_152655 Homo sapiens zinc finger protein 585A (ZNF585A), transcript variant
1, mRN
NM_152657 Homo sapiens gametogenetin (GGN), transcript variant 1, mRNA
NM_152658 Homo Sapiens THAP domain containing 8 (THAPB), mRNA
NM_152660 Homo sapiens hypothetical protein MGC34648 (MGC34648), mRNA
NM_152662 Homo sapiens hypothetical protein FLJ23867 (FLJ23867), mRNA
NM_152663 Homo sapiens Ral GEF with PH domain and SH3 binding motif 2 (RALGPS2
NM 152665 Homo sapiens hypothetical protein FLJ40873 (FLJ40873), mRNA
NM 152666 Homo sapiens hypothetical protein FLJ40773 (FLJ40773), mRNA
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NM_152667 Homo Sapiens chromosome 20 open reading frame 147 (C20orf147), mRNA
NM_152670 Homo sapiens hypothetical protein FLJ25369 (FLJ25369), mRNA
NM_152671 Homo sapiens phosphatidylinositol-3-phosphate/phosphatidylinositol 5-
kinas
NM_152672 Homo sapiens organic solute transporter alpha (OSTalpha), mRNA
NM_152673 Homo sapiens mucin 20 (MUC20), mRNA
NM_152675 Homo sapiens hypothetical protein FLJ23754 (FLJ23754), mRNA
NM_152676 Homo sapiens F-box protein 15 (FBX015), mRNA
NM_152677 Homo sapiens zinc finger protein 494 (ZNF494), mRNA
NM_152678 Homo sapiens hypothetical protein FLJ34969 (FLJ34969), mRNA
NM_152679 Homo sapiens solute carrier family 10 (sodium/bile acid
cotransporter family)
NM_152680 Homo sapiens hypothetical protein FLJ32028 (FLJ32028), mRNA
NM_152681 Homo sapiens hypothetical protein FLJ38482 (FLJ38482), mRNA
NM_152682 Homo sapiens hypothetical protein MGC10198 (MGC10198), mRNA
NM_152683 Homo sapiens hypothetical protein FLJ33167 (FLJ33167), mRNA
NM_152684 Homo sapiens hypothetical protein FLJ39653 (FLJ39653), mRNA
NM_152685 Homo sapiens solute carrier family 23 (nucleobase transporters),
member 1
NM_152686 Homo sapiens hypothetical protein MGC29463 (MGC29463), mRNA
NM_152687 Homo sapiens hypothetical protein FLJ33641 (FLJ33641), mRNA
NM_152688 Homo sapiens KH domain containing, RNA binding, signal transduction
assn
NM_152689 Homo sapiens hypothetical protein MGC9712 (MGC9712), mRNA
NM_152690 Homo sapiens dolichyl-phosphate mannosyltransferase polypeptide 2,
reguh
NM_152692 Homo sapiens core 1 UDP-galactose:N-acetylgalactosamine-alpha-R beta
1.
NM_152693 Homo sapiens hypothetical protein MGC34827 (MGC34827), mRNA
NM_152694 Homo sapiens zinc finger, CCHC domain containing 5 (ZCCHCS), mRNA
NM_152695 Homo sapiens hypothetical protein FLJ23614 (FLJ23614), mRNA
NM_152696 Homo sapiens homeodomain interacting protein kinase 1 (HIPK1),
transcript
NM_152697 Homo Sapiens hypothetical protein MGC34032 (MGC34032), mRNA
NM_152698 Homo sapiens hypothetical protein FLJ38377 (FLJ38377), mRNA
NM_152699 Homo Sapiens SUM01/sentrin specific protease 5 (SENPS), mRNA
NM_152700 Homo sapiens hypothetical protein MGC26597 (MGC26597), mRNA
NM_152701 Homo sapiens ATP binding cassette gene, sub-family A (ABC1 ), member
13
NM_152702 Homo Sapiens chromosome 9 open reading frame 94 (C9orf94), mRNA
NM_152704 Homo sapiens hypothetical protein FLJ25477 (FLJ25477), transcript
variant '
NM_152705 Homo sapiens hypothetical protein MGC9850 (MGC9850), mRNA
NM_152706 Homo sapiens hypothetical protein MGC26647 (MGC26647), mRNA
NM_152707 Homo sapiens solute carrier family 25 (mitochondrial carrier; Graves
disease
NM_152710 Homo sapiens chromosome 10 open reading frame 27 (C10orf27), mRNA
NM_152713 Homo sapiens integral membrane protein 1 (ITM1), mRNA
NM_152715 Homo sapiens hypothetical protein MGC10233 (MGC10233), mRNA
NM_152716 Homo sapiens hypothetical protein FLJ36874 (FLJ36874), mRNA
NM_152717 Homo sapiens hypothetical protein MGC35295 (MGC35295), mRNA
NM_152718 Homo sapiens hypothetical protein FLJ32009 (FLJ32009), mRNA
NM_152719 Homo sapiens testis-specific leucine zipper protein nurit (NURIT),
mRNA
NM_152720 Homo sapiens NIMA (never in mitosis gene a)-related kinase 3 (NEK3),
tran.
NM_152721 Homo sapiens docking protein 5-like (DOKSL), mRNA
NM_152722 Homo sapiens hypothetical protein FLJ25530 (FLJ25530), mRNA
NM_152723 Homo sapiens hypothetical protein FLJ38159 (FLJ38159), mRNA
NM_152724 Homo sapiens Ras suppressor protein 1 (RSU1), transcript variant 2,
mRNA
NM_152725 Homo Sapiens solute carrier family 39 (zinc transporter), member 12
(SLC39
NM_152726 Homo sapiens Smhs2 homolog (rat) (FLJ34588), mRNA
NM_152727 Homo sapiens copine II (CPNE2), mRNA
NM_152728 Homo sapiens chromosome 18 open reading frame 20 (C18orf20), mRNA
NM_152729 Homo sapiens 5'-nucleotidase, cytosolic II-like 1 (NT5C2L1), mRNA
NM_152730 Homo sapiens chromosome 6 open reading frame 170 (C6orf170), mRNA
NM_152731 Homo Sapiens chromosome 6 open reading frame 65 (C6orf65), mRNA
NM 152732 Homo Sapiens chromosome 6 open reading frame 206 (C6orf206), mRNA
NM 152733 Homo Sapiens BTB (POZ) domain containing 9 (BTBD9), mRNA
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NM_152734 Homo sapiens chromosome 6 open reading frame 89 (C6orf89), mRNA
NM_152735 Homo sapiens zinc finger and BTB domain containing 9 (ZBTB9), mRNA
NM_152736 Homo sapiens zinc finger protein 187 (ZNF187), mRNA
NM 152737 Homo sapiens hypothetical protein MGC33993 (MGC33993), mRNA
NM 152738 Homo Sapiens hypothetical protein MGC40222 (MGC40222), mRNA
NM_152739 Homo sapiens homeo box A9 (HOXA9), transcript variant 1, mRNA
NM_152740 Homo sapiens 3-hydroxyisobutyrate dehydrogenase (HI BADH), mRNA
NM_152742 Homo sapiens glypican 2 (cerebroglycan) (GPC2), mRNA
NM_152743 Homo Sapiens chromosome 7 open reading frame 27 (C7orf27), mRNA
NM_152744 Homo sapiens sidekick homolog 1 (chicken) (SDK1), mRNA
NM_152745 Homo sapiens neurexophilin 1 (NXPH1), mRNA
NM_152747 Homo sapiens hypothetical protein DKFZp58611420 (DKFZp58611420), mR~
NM_152748 Homo sapiens hypothetical protein FLJ31340 (FLJ31340), mRNA
NM_152749 Homo sapiens hypothetical protein MGC33190 (MGC33190), mRNA
NM_152750 Homo Sapiens hypothetical protein FLJ23834 (FLJ23834), mRNA
NM_152751 Homo sapiens chromosome 10 open reading frame 30 (C10orf30), mRNA
NM_152753 Homo sapiens signal peptide, CUB domain, EGF-like 3 (SCUBE3), mRNA
NM_152754 Homo sapiens sema domain, immunoglobulin domain (Ig), short basic
doma
NM_152755 Homo Sapiens hypothetical protein MGC40499 (MGC40499), mRNA
NM_152757 Homo Sapiens hypothetical protein FLJ30313 (FLJ30313), mRNA
NM_152758 Homo sapiens YTH domain family 3 (YTHDF3), mRNA
NM_152759 Homo sapiens hypothetical protein MGC35140 (MGC35140), mRNA
NM_152760 Homo Sapiens hypothetical protein FLJ30934 (FLJ30934), mRNA
NM_152761 Homo sapiens hypothetical protein FLJ25444 (FLJ25444), mRNA
NM_152762 Homo Sapiens testis specific, 10 interacting protein (TSGA101P),
mRNA
NM_152763 Homo sapiens hypothetical protein MGC26989 (MGC28989), mRNA
NM_152764 Homo sapiens hypothetical protein MGC35212 (MGC35212), mRNA
NM_152765 Homo sapiens hypothetical protein MGC33510 (MGC33510), mRNA
NM_152766 Homo sapiens hypothetical protein MGC40107 (MGC40107), mRNA
NM_152769 Homo Sapiens chromosome 19 open reading frame 26 (C19orf26), mRNA
NM_152770 Homo sapiens hypothetical protein MGC35043 (MGC35043), mRNA
NM_152771 Homo sapiens chromosome 19 open reading frame 34 (C19orf34), mRNA
NM_152772 Homo Sapiens hypothetical protein MGC40368 (MGC40368), mRNA
NM_152773 Homo sapiens hypothetical protein MGC33212 (MGC33212), mRNA
NM_152774 Homo Sapiens hypothetical protein MGC42090 (MGC42090), mRNA
NM_152775 Homo Sapiens hypothetical protein MGC33607 (MGC33607), mRNA
NM_152776 Homo sapiens hypothetical protein MGC40579 (MGC40579), mRNA
NM_152777 Homo sapiens chromosome 14 open reading frame 48 (C14orf48), mRNA
NM_152778 Homo sapiens hypothetical protein MGC33302 (MGC33302), mRNA
NM_152779 Homo sapiens hypothetical protein MGC26856 (MGC26856), mRNA
NM_152780 Homo sapiens hypothetical protein FLJ14503 (FLJ14503), mRNA
NM_152781 Homo sapiens hypothetical protein FLJ32830 (FLJ32830), mRNA
NM_152782 Homo sapiens hypothetical protein MGC33329 (MGC33329), mRNA
NM_152783 Homo sapiens hypothetical protein MGC25181 (MGC25181), mRNA
NM_152784 Homo sapiens hypothetical protein MGC39581 (MGC39581), mRNA
NM_152785 Homo sapiens germinal center expressed transcript 2 (GCET2), mRNA
NM_152786 Homo sapiens chromosome 9 open reading frame 43 (C9orf43), mRNA
NM_152787 Homo sapiens TAK1-binding protein 3 (TAB3), transcript variant 1,
mRNA
NM_152788 Homo sapiens E2a-Pbx1-associated protein (EB-1), transcript variant
1, mRP
NM_152789 Homo sapiens hypothetical protein MGC40405 (MGC40405), mRNA
NM_152791 Homo sapiens zinc finger protein 555 (ZNF555), mRNA
NM_152792 Homo sapiens hypothetical protein FLJ25084 (FLJ25084), mRNA
NM_152793 Homo sapiens hypothetical protein EIIs1 (EIIs1), mRNA
NM_152794 Homo sapiens hypoxia inducible factor 3, alpha subunit (HIF3A),
transcript v:
NM_152795 Homo sapiens hypoxia inducible factor 3, alpha subunit (HIF3A),
transcript v~
NM 152796 Homo sapiens hypoxia inducible factor 3, alpha subunit (HIF3A),
transcript v~
NM 152826 Homo sapiens sorting nexin 1 (SNX1 ), transcript variant 3, mRNA
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NM_152827 Homo sapiens sorting nexin 3 (SNX3), transcript variant 2, mRNA
NM_152828 Homo Sapiens sorting nexin 3 (SNX3), transcript variant 3, mRNA
NM_152829 Homo sapiens testis derived transcript (3 LIM domains) (TES),
transcript vari
NM_152830 Homo sapiens angiotensin I converting enzyme (peptidyl-dipeptidase
A) 1 (A
NM_152831 Homo sapiens angiotensin I converting enzyme (peptidyl-dipeptidase
A) 1 (A
NM_152832 Homo sapiens Mouse Mammary Turmor Virus Receptor homolog 1 (MTVR1 )
NM_152834 Homo sapiens transmembrane protein 18 (TMEM18), mRNA
NM_152835 Homo Sapiens casein kinase (LOC149420), mRNA
NM_152836 Homo sapiens sorting nexin 16 (SNX16), transcript variant 2, mRNA
NM_152837 Homo sapiens sorting nexin 16 (SNX16), transcript variant 3, mRNA
NM_152838 Homo sapiens RNA binding motif protein 12 (RBM12), transcript
variant 2, m
NM_152840 Homo sapiens Hermansky-Pudlak syndrome 4 (HPS4), transcript variant
3, r
NM_152841 Homo sapiens Hermansky-Pudlak syndrome 4 (HPS4), transcript variant
2, r
NM_152842 Homo sapiens Hermansky-Pudlak syndrome 4 (HPS4), transcript variant
5, r
NM_152843 Homo sapiens Hermansky-Pudlak syndrome 4 (HPS4), transcript variant
4, r
NM_152850 Homo sapiens phosphatidylinositol glycan, class O (PIGO), transcript
variant
NM_152851 Homo sapiens membrane-spanning 4-domains, subfamily A, member 6A (M;
NM_152852 Homo sapiens membrane-spanning 4-domains, subfamily A, member 6A (M1
NM_152854 Homo sapiens tumor necrosis factor receptor superfamily, member 5
(TNFR:
NM_152855 Homo sapiens immunoglobulin lambda-like polypeptide 1 (IGLL1),
transcript
NM_152856 Homo sapiens RNA binding motif protein 10 (RBM10), transcript
variant 2, m
NM_152857 Homo sapiens Wilms tumor 1 associated protein (WTAP), transcript
variant:
NM_152858 Homo Sapiens Wilms tumor 1 associated protein (WTAP), transcript
variant
NM_152860 Homo sapiens Sp7 transcription factor (SP7), mRNA
NM_152862 Homo sapiens actin related protein 2/3 complex, subunit 2, 34kDa
(ARPC2),
NM_152864 Homo sapiens chromosome 20 open reading frame 58 (C20orf58), mRNA
NM_152866 Homo sapiens membrane-spanning 4-domains, subfamily A, member 1 (MS~
NM_152867 Homo sapiens membrane-spanning 4-domains, subfamily A, member 1 (MS~
NM_152868 Homo sapiens potassium inwardly-rectifying channel, subfamily J,
member 4
NM_152869 Homo sapiens regucalcin (senescence marker protein-30) (RGN),
transcript'
NM_152870 Homo sapiens abhydrolase domain containing 1 (ABHD1 ), transcript
variant
NM_152871 Homo sapiens tumor necrosis factor receptor superfamily, member 6
(TNFR;
NM_152872 Homo Sapiens tumor necrosis factor receptor supertamily, member 6
(TNFR:
NM_152873 Homo sapiens tumor necrosis factor receptor superfamily, member 6
(TNFR;
NM_152874 Homo Sapiens tumor necrosis factor receptor superfamily, member 6
(TNFR:
NM_152875 Homo sapiens tumor necrosis factor receptor superfamily, member 6
(TNFRt
NM_152876 Homo Sapiens tumor necrosis factor receptor supertamily, member 6
(TNFR:
NM_152877 Homo sapiens tumor necrosis factor receptor superfamily, member 6
(TNFR;
NM_152878 Homo sapiens v-maf musculoaponeurotic fibrosarcoma oncogene homolog
F
NM_152879 Homo sapiens diacylglycerol kinase, delta 130kDa (DGKD), transcript
variant
NM_152880 Homo sapiens PTK7 protein tyrosine kinase 7 (PTK7), transcript
variant PTK
NM_152881 Homo sapiens PTK7 protein tyrosine kinase 7 (PTK7), transcript
variant PTK
NM_152882 Homo sapiens PTK7 protein tyrosine kinase 7 (PTK7), transcript
variant PTK
NM_152883 Homo sapiens PTK7 protein tyrosine kinase 7 (PTK7), transcript
variant PTK
NM_152888 Homo Sapiens collagen, type XXII, alpha 1 (COL22A1), mRNA
NM_152889 Homo sapiens carbohydrate (chondroitin 4) sulfotransferase 13
(CHST13), rr
NM_152890 Homo Sapiens collagen, type XXIV, alpha 1 (COL24A1), mRNA
NM_152891 Homo sapiens protease, serine, 33 (PRSS33), mRNA
NM_152892 Homo sapiens hypothetical protein DKFZp434K1815 (DKFZp434K1815), mF
NM_152896 Homo sapiens ubiquitin-like, containing PHD and RING finger domains,
2 (U1
NM_152897 Homo Sapiens chromosome 20 open reading frame 161 (C20orf161),
transcr
NM_152898 Homo sapiens Fer3-like (Drosophila) (FERD3L), mRNA
NM_152899 Homo sapiens interleukin 4 induced 1 (1L411), transcript variant 1,
mRNA
NM_152900 Homo Sapiens membrane-associated guanylate kinase-related (MAGI-3)
(M/
NM_152901 Homo Sapiens pyrin-domain containing protein 1 (PYC1), mRNA
NM 152902 Homo sapiens putative MAPK activating protein (MGC3794), mRNA
NM 152903 Homo Sapiens ketch repeat and BTB (POZ) domain containing 6
(KBTBD6),
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NM_152904 Homo sapiens sperm antigen HCMOGT-1 (HCMOGT-1), mRNA
NM_152905 Homo sapiens neural precursor cell expressed, developmentally down-
reguh
NM_152906 Homo sapiens hypothetical protein DKFZp761 P1121 (DKFZp761 P1121 ),
mF
NM_152908 Homo sapiens hypothetical protein FLJ31196 (FLJ31196), mRNA
NM_152909 Homo sapiens zinc finger protein 548 (ZNF548), mRNA
NM_152910 Homo sapiens diacylglycerol kinase, eta (DGKH), transcript variant
1, mRNA
NM_152911 Homo sapiens polyamine oxidase (exo-N4-amino) (PAOX), transcript
variant
NM_152912 Homo Sapiens mitochondrial translational initiation factor 3
(MTIF3), mRNA
NM_152913 Homo sapiens hypothetical protein DKFZp761 L1417 (DKFZp761 L1417),
mR
NM_152914 Homo sapiens transcript expressed during hematopoiesis 2 (MGC33894),
ml
NM_152916 Homo sapiens egf-like module containing, mucin-like, hormone
receptor-like
NM_152917 Homo sapiens egf like module containing, mucin-like, hormone
receptor-like
NM_152918 Homo sapiens egf-like module containing, mucin-like, hormone
receptor-like
NM_152919 Homo sapiens egf-like module containing, mucin-like, hormone
receptor-like
NM_152920 Homo Sapiens egf-like module containing, mucin-like, hormone
receptor-like
NM_152921 Homo sapiens egf-like module containing, mucin-like, hormone
receptor-like
NM_152924 Homo Sapiens abhydrolase domain containing 2 (ABHD2), transcript
variant
NM_152925 Homo sapiens copine I (CPNE1), transcript variant 1, mRNA
NM_152926 Homo sapiens copine I (CPNE1 ), transcript variant 2, mRNA
NM_152927 Homo sapiens copine I (CPNE1 ), transcript variant 4, mRNA
NM_152928 Homo Sapiens copine I (CPNE1 ), transcript variant 5, mRNA
NM_152929 Homo sapiens copine I (CPNE1 ), transcript variant 6, mRNA
NM_152930 Homo sapiens copine I (CPNE1 ), transcript variant 7, mRNA
NM_152931 Homo sapiens copine I (CPNE1 ), transcript variant 8, mRNA
NM_152932 Homo sapiens glycosyltransferase AD-017 (AD-017), transcript variant
1, mF
NM_152933 Homo Sapiens protein phosphatase, EF hand calcium-binding domain 2
(PPI
NM_152934 Homo sapiens protein phosphatase, EF hand calcium-binding domain 2
(PPI
NM_152939 Homo sapiens egf-like module containing, mucin-like, hormone
receptor-like
NM_152942 Homo Sapiens tumor necrosis factor receptor superfamily, member 8
(TNFR;
NM_152943 Homo sapiens zinc finger protein 268 (ZNF268), transcript variant B,
mRNA
NM_152945 Homo sapiens developmentally regulated RNA-binding protein 1 (DRB1),
mF
NM_152988 Homo Sapiens SPPL2b (SPPL2B), mRNA
NM_152989 Homo Sapiens SRY (sex determining region Y)-box 5 (SOXS), transcript
varis
NM_152990 Homo sapiens peroxisomal, testis specific 1 (PXT1), mRNA
NM_152991 Homo sapiens embryonic ectoderm development (EED), transcript
variant 2,
NM_152992 Homo sapiens POM (POM121 homolog, rat) and ZP3 fusion (POMZP3), tran
NM_152994 Homo sapiens smooth muscle myosin heavy chain 11 isoforrn SM1-like
(LO(
NM_152995 Homo sapiens ovarian zinc finger protein (HOZFP), mRNA
NM_152996 Homo sapiens sialyltransferase 7 ((alpha-N-acetylneuraminyl-2,3-beta-
galaci
NM_152997 Homo sapiens chromosome 4 open reading frame 7 (C4orf7), mRNA
NM_152998 Homo sapiens enhancer of zeste homolog 2 (Drosophila) (EZH2),
transcript
NM_152999 Homo sapiens six transmembrane epithelial antigen of prostate 2
(STEAP2),
NM_153000 Homo Sapiens adenomatosis polyposis coli down-regulated ~ (APCDD1),
mF
NM_153001 Homo sapiens proteasome (prosome, macropain) 26S subunit, ATPase, 4
(F
NM_153002 Homo sapiens G protein-coupled receptor 156 (GPR156), mRNA
NM_153003 Homo sapiens orofacial cleft 1 candidate 1 (OFCC1), mRNA
NM_153005 Homo sapiens RIO kinase 1 (yeast) (RIOK1), transcript variant 2,
mRNA
NM_153006 Homo sapiens N-acetylglutamate synthase (NAGS), mRNA
NM_153007 Homo sapiens outer dense fiber of sperm tails 4 (ODF4), mRNA
NM_153008 Homo sapiens hypothetical protein FLJ30277 (FLJ30277), m RNA
NM_153010 Homo sapiens chromosome 18 open reading frame 16 (C18orf16), mRNA
NM_153011 Homo sapiens hypothetical protein FLJ30594 (FLJ30594), m RNA
NM_153012 Homo sapiens tumor necrosis factor (ligand) superFamily, member 12
(TNFS
NM_153013 Homo Sapiens hypothetical protein FLJ30596 (FLJ30596), mRNA
NM_153014 Homo sapiens hypothetical protein FLJ30634 (FLJ30634), mRNA
NM 153015 Homo sapiens hypothetical protein FLJ30668 (FLJ30668), mRNA
NM 153018 Homo sapiens hypothetical protein FLJ30726 (FLJ30726), mRNA
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NM_153019 Homo Sapiens transmembrane protease, serine 6 (TMPRSS6), mRNA
NM_153020 Homo Sapiens RNA binding motif protein 24 (RBM24), mRNA
NM_153022 Homo sapiens hypothetical protein FLJ31166 (FLJ31166), mRNA
NM_153023 Homo Sapiens spermatogenesis associated 13 (SPATA13), mRNA
NM_153024 Homo sapiens seven transmembrane helix receptor (FLJ31393), mRNA
NM_153025 Homo Sapiens hypothetical protein FLJ31606 (FLJ31606), mRNA
NM_153026 Homo Sapiens prickle-like 1 (Drosophila) (PRICKLED, mRNA
NM_153027 Homo sapiens hypothetical protein FLJ31659 (FLJ31659), mRNA
NM_153028 Homo sapiens zinc finger protein 75a (ZNF75A), mRNA
NM_153029 Homo sapiens Nedd4 binding protein 1 (N4BP1), mRNA
NM_153031 Homo sapiens hypothetical protein FLJ32063 (FLJ32063), mRNA
NM_153032 Homo Sapiens hypothetical protein FLJ32065 (FLJ32065), mRNA
NM_153033 Homo sapiens potassium channel tetramerisation domain containing 7
(KCT
NM_153034 Homo sapiens zinc finger protein 488 (ZNF488), mRNA
NM_153035 Homo sapiens hypothetical protein FLJ32112 (FLJ321.12), mRNA
NM_153036 Homo sapiens chromosome 6 open reading frame 78 (C6orf78), mRNA
NM_153038 Homo sapiens hypothetical protein FLJ32447 (FLJ32447), mRNA
NM_153040 Homo sapiens hypothetical protein FLJ32831 (FLJ32831 ), mRNA
NM_153041 Homo Sapiens hypothetical protein FLJ32955 (FLJ32955), mRNA
NM_153043 Homo sapiens hypothetical protein FLJ37078 (FLJ37078), mRNA
NM_153044 Homo Sapiens hypothetical protein FLJ35801 (FLJ35801 ), mRNA
NM_153045 Homo sapiens chromosome 9 open reading frame 91 (C9orF91), mRNA
NM_153046 Homo sapiens tudor domain containing 9 (TDRD9), mRNA
NM_153047 Homo sapiens FYN oncogene related to SRC, FGR, YES (FYN), transcript
w
NM_153048 Homo sapiens FYN oncogene related to SRC, FGR, YES (FYN), transcript
v;
NM_153050 Homo sapiens myotubularin related protein 3 (MTMR3), transcript
variant 1, t
NM_153051 Homo sapiens myotubularin related protein 3 (MTMR3), transcript
variant 2, i
NM_153181 Homo sapiens neuropilin (NRP) and tolloid (TLL)-like 1 (NET01 ),
transcript v
NM_153182 Homo sapiens MYC induced nuclear antigen (MINA), transcript variant
3, mF
NM_153183 Homo sapiens nudix (nucleoside diphosphate linked moiety X)-type
motif 10
NM_153184 Homo sapiens immunoglobulin superfamily, member 4D (IGSF4D), mRNA
NM_153186 Homo sapiens ankyrin repeat domain 15 (ANKRD15), transcript variant
2, ml
NM_153187 Homo sapiens solute carrier family 22 (organic cation transporter),
member 1
NM_153188 Homo sapiens transportin 1 (TNP01 ), transcript variant 2, mRNA
NM_153189 Homo sapiens sperm adhesion molecule 1 (PH-20 hyaluronidase, zona
pellu
NM_153191 Homo Sapiens solute carrier family 22 (organic cation transporter),
member
NM_153200 Homo sapiens endothelial differentiation-related factor 1 (EDF1 ),
transcript v.
NM_153201 Homo sapiens heat shock 70kDa protein 8 (HSPAB), transcript variant
2, mR
NM_153202 Homo sapiens a disintegrin and metalloproteinase domain 33 (ADAM33),
tra
NM_153204 Homo sapiens chromosome 21 open reading frame 90 (C21orf90), mRNA
NM_153206 Homo sapiens adhesion molecule AMICA (AMICA), mRNA
NM_153207 Homo sapiens AE binding protein 2 (AEBP2), mRNA
NM_153208 Homo sapiens hypothetical protein MGC35048 (MGC35048), mRNA
NM_153209 Homo sapiens hypothetical protein FLJ37300 (FLJ37300), mRNA
NM_153211 Homo Sapiens chromosome 18 open reading frame 17 (C18orF17), mRNA
NM_153212 Homo sapiens gap junction protein, beta 4 (connexin 30.3) (GJB4),
mRNA
NM_153213 Homo sapiens Rho guanine nucleotide exchange factor (GEF) 19
(ARHGEF~
NM_153214 Homo sapiens hypothetical protein FLJ37440 (FLJ37440), mRNA
NM_153215 Homo Sapiens hypothetical protein FLJ38608 (FLJ38608), mRNA
NM_153216 Homo sapiens hypothetical protein FLJ25680 (FLJ25680), mRNA
NM_153217 Homo Sapiens hypothetical protein MGC13034 (MGC13034), mRNA
NM_153218 Homo Sapiens hypothetical protein FLJ38725 (FLJ38725), mRNA
NM_153219 Homo Sapiens zinc finger protein 524 (ZNF524), mRNA
NM_153220 Homo sapiens hypothetical protein MGC35440 (MGC35440), mRNA
NM_153221 Homo Sapiens cartilage intermediate layer protein 2 (CILP2), mRNA
NM 153223 Homo sapiens hypothetical protein FLJ36090 (FLJ36090), mRNA
NM 153225 Homo sapiens RPE-spondin (RPESP), mRNA
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