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DESCRIPTION
REGULATION OF REPRESSOR GENES USING NUCLEIC ACID
MOLECULES
Background of the Invention
This invention relates to a novel method for the inhibition of repressor
genes.
Specifically, inhibition of these repressor genes allows for the increased
expression
of beneficially gene products. Increasing the expression of beneficial gene
products
may be useful as therapeutic treatments for a wide range of indications.
The following is a discussion of relevant art, none of which is admitted to be
prior art to the present invention.
RNA synthesis in a biological system involves a number of regulatory steps.
For instance in a eukaryotic cell, RNA is synthesized from DNA genes via a
process
termed transcription. Transcription of RNA is an exquisitely regulated
process.
Transcription may be positively regulated when the RNA synthesis is stimulated
or
negatively regulated when the RNA synthesis is inhibited. This level of RNA
synthesis regulation is facilitated by the interaction of one or more protein
factors
that generally exert their effect on transcription by interacting with
specific cis-
acting elements in the gene. While, positive regulation of gene expression is
far
more prevalent in eukaryotic cells, negative regulation plays an important
role for
many genes. These protein factors involved in negative regulation
("repressors")
generally bind to cis-acting elements, usually upstream to genes, and cause
the down
regulation of that gene's transcription into RNA ("repression"). Only when
these
repressors are released from their targets can unhindered gene expression take
place.
Repressors can also function via other mechanisms such as interacting with
protein
factors involved in transcription thereby blocking transcription (e.g. protein-
protein
interaction; modification). A number of genes have been identified in
eukaryotic
systems that encode repressors. A few non-limiting examples of these repressor
genes include:
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GATA Transcription Factors: Currently 5 factors make up the human GATA family
of transcription factors: hGATA-1 (also known as Eryfl, GF-1, or NF-E1)
(Trainor
et al., 1990, Nature 343, 92-96; Genbank Accession No. X17254); hGATA-2
(Dorfman et al., 1992, J. Biol. Chem. 167, 1279-1285; Genbank Accession No.
M77810); hGATA-3 (Joulin et al., 1991, EMBO J. 10, 1809-1816; Genbank
Accession No. X58072); hGATA-4 (Genbank Accession No. L34357); and hGATA-
6 (Huggon et al., 1997, Biochim. Biophys. Acta 1353, 98-102; Genbank Accession
No.X95701). The GATA element or binding region for the GATA protein is
present ~30bp upstream of the erythropoietin (Epo) gene. Transfection of QT6
cells
with hGATA-1, -2, and -3 have shown that all three factors were able to bind
to the
GATA element. In addition, all three factors were shown to down regulate the
expression of Erythropoietin in Hep3B cells (Imagawa et al, 1996, Acta
Haematol.
95, 248-256).
EAR3/COUP-TF-1: EAR3/COUP-TF-1 (Miyajima et al., 1988, Nucleic Acids
Research 16, 11057-11074; Genbank Accession No.X12795) has been shown to
bind to the promoter region of Erythropoietin gene and negatively regulate its
expression. This transcription factor appears to compete with hepatic nuclear
factor
4 (HNF-4) which is believed to positively regulate Epo expression (Galson et
al.,
1995, Mol. Cell Biol. 15, 2135-2144).
TR2 & TR2-11 Orphan Receptors: TR2 orphan receptor (Chang et al., 1989,
Biocherrt. Biophys. Res. Commun. 165, 735-741; Genbank Accession Co. M29959)
and TR2-11 orphan receptor (Chang et al., supra; Genbank Accession No. M29960)
are another set of transcription factors believed to negatively regulate Epo
expression. The isolated TR2 cDNA encodes for a 603 amino acid protein with a
mass of 67 kDa. This protein is believed to bind to a 3' enhancer region of
the Epo
gene and repress the expression of Epo (Lee et al., 1996, J. Biol. Chem. 271,
10405-
10412).
CCAAT Displacement Protein (CDP): CDP (Neufeld et al., 1992, Nature Genet. 1,
50-55; Genbank Accession No. M74099) is a 180-200 kDa protein that has been
shown to negatively regulate a number of genes including gamma-globin, NCAM,
and gp91-phox gene, neutrophil collagenase, neutrophil gelatinase, and
granulocyte
colony stimulating factor (G-CSF) (Khanna-Gupta et al., 1997, Blood 90, 2784-
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2795). Elevated levels of G-CSF would be beneficial for treatment during
myelosuppressive chemotherapy, AIDS, and chronic neutropenia.
Genesis: Also known as HNF-3/Forkhead, Genesis is a member of the winged helix
transcriptional regulatory family and is believed to function as a repressor
gene with
activity in embryonic differentiation in drosophilia (Sutton et a1.,1996, J.
Biol.
Chem. 271, 23126-23133). Studies in 32D cells indicate that protein products
of the
Genesis gene may inhibit G-CSF gene expression (Xu et al., 1997, Leukemia 12,
207-212). A human homolog of this gene may have the same effect in human cells
and is likely to regulate G-CSF gene expression.
Interferon re ug latory Factor-2 (IRF-2): IRF-2 (Itoh et al., 1989, Nucleic
Acids
Research 17, 8372; Genbank Accession No. X15949) is a member of the interferon
regulatory factors of which more than 10 members exist. IRF-2 is believed to
play a
role in the regulation of expression for interferon-beta, interferon-alpha,
and MHC
class I (Nguyen et. al., 1997, Cytokine & Growth Factor Reviews 8, 293-312).
The
DNA binding domain of IRF-2 is located within the N-terminus of the protein.
Imagawa et al., 1997, Blood 4, 1430-1439, describes the use an antisense
phosphorothioate oligodeoxynucleotide having the sequence
CGGGCGCCACCTCCATGGCCGGCCGGGCGG to inhibit hGATA-2
transcription factor expression in Hep3B cells.
Summary Of The Invention
The invention features novel nucleic acid-based techniques (e.g., enzymatic
nucleic acid molecules, antisense nucleic acids, 2-SA antisense chimeras,
triplex
DNA, antisense nucleic acids containing RNA cleaving chemical groups).
In one aspect, the invention features use of one or more of the nucleic acid
based techniques to inhibit the expression of repressor genes. Inhibition of
the
repressor gene can then result in the increased expression of genes repressed
by these
repressor genes.
By "repressor genes" is meant genes whose expression can directly or
indirectly down regulate or repress or suppress the expression of other genes.
By "inhibit" it is meant that the activity of repressor genes or level of
mRNAs or equivalent RNAs encoding repressor genes is reduced below that
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observed in the absence of the nucleic acid. In one embodiment, inhibition
with
ribozymes preferably is below that level observed in the presence of an
enzymatically attenuated nucleic acid molecule that is able to bind to the
same site
on the mRNA, but is unable to cleave that RNA. In another embodiment,
inhibition
with nucleic acid molecules, including enzymatic nucleic acid and antisense
molecules, is preferably greater than that observed in the presence of for
example, an
oligonucleotide with scrambled sequence or with mismatches. In another
embodiment, inhibition of repressor genes with the nucleic acid molecule of
the
instant invention is greater than in the presence of the nucleic acid molecule
than in
its absence.
By "antisense nucleic acid" it is meant a non-enzymatic nucleic acid
molecule that binds to target RNA by means of RNA-RNA or RNA-DNA or RNA-
PNA (protein nucleic acid; Egholm et al., 1993 Nature 365, 566) interactions
and
alters the activity of the target RNA (for a review see Stein and Cheng, 1993
Science
261, 1004).
By "2-SA antisense chimera" it is meant, an antisense oligonucleotide
containing a 5' phosphorylated 2'-S'-linked adenylate residues. These chimeras
bind
to target RNA in a sequence-specific manner and activate a cellular 2-SA-
dependent
ribonuclease which, in turn, cleaves the target RNA (Torrence et al., 1993
Proc.
Natl. Acad. Sci. USA 90, 1300).
By "triplex DNA" it is meant an oligonucleotide that can bind to a double-
stranded DNA in a sequence-specific manner to form a triple-strand helix.
Formation of such triple helix structure has been shown to inhibit
transcription of the
targeted gene (Duval-Valentin et al., 1992 Proc. Natl. Acad. Sci. USA 89,
504).
By "gene" it is meant a nucleic acid that encodes an RNA.
By "enzymatic nucleic acid" it is meant a nucleic acid molecule capable of
catalyzing reactions including, but not limited to, site-specific cleavage
and/or
ligation of other nucleic acid molecules, cleavage of peptide and amide bonds,
and
trans-splicing. Such a molecule with endonuclease activity may have
complementarity in a substrate binding region to a specified gene target, and
also has
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an enzymatic activity that specifically cleaves RNA or DNA in that target.
That is,
the nucleic acid molecule with endonuclease activity is able to
intramolecularly or
intermolecularly cleave RNA or DNA and thereby inactivate a target RNA or DNA
molecule. This complementarity functions to allow sufficient hybridization of
the
enzymatic RNA molecule to the target RNA or DNA to allow the cleavage to
occur.
100% complementarity is preferred, but complementarity as low as 50-75% may
also
be useful in this invention. The nucleic acids may be modified at the base,
sugar,
and/or phosphate groups. The term enzymatic nucleic acid is used
interchangeably
with phrases such as ribozymes, catalytic RNA, enzymatic RNA, catalytic DNA,
catalytic oligonucleotides, nucleozyme, DNAzyme, RNA enzyme, endoribonuclease,
endonuclease, minizyme, leadzyme, oligozyme or DNA enzyme. All of these
terminologies describe nucleic acid molecules with enzymatic activity. The
specific
enzymatic nucleic acid molecules described in the instant application are not
limiting
in the invention and those skilled in the art will recognize that all that is
important in
an enzymatic nucleic acid molecule of this invention is that it has a specific
substrate
binding site which is complementary to one or more of the target nucleic acid
regions, and that it have nucleotide sequences within or surrounding that
substrate
binding site which impart a nucleic acid cleaving activity to the molecule
(Cech et
al., U.S. Patent No. 4,987,071; Cech et al., 1988, JAMA).
By "enzymatic portion" or "catalytic domain" is meant that portion/region of
the ribozyme essential for cleavage of a nucleic acid substrate (for example
see
Figure 1 ).
By "substrate binding arm" or "substrate binding domain" is meant that
portion/region of a ribozyme which is complementary to (i.e., able to base-
pair with)
a portion of its substrate. Generally, such complementarity is 100%, but can
be less
if desired. For example, as few as 10 bases out of 14 may be base-paired. Such
arms
are shown generally in Figure 1 and 3. That is, these arms contain sequences
within a
ribozyme which are intended to bring ribozyme and target RNA together through
complementary base-pairing interactions. The ribozyme of the invention may
have
binding arms that are contiguous or non-contiguous and may be of varying
lengths.
The length of the binding arms) are preferably greater than or equal to four
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nucleotides; specifically preferably 12-100 nucleotides; more preferably 14-24
nucleotides long. If two binding arms are chosen, the design is such that the
length
of the binding arms are symmetrical (i.e., each of the binding arms is of the
same
length; e.g., five and five nucleotides, six and six nucleotides or seven and
seven
nucleotides long) or asymmetrical (i.e., the binding arms are of different
length; e.g.,
six and three nucleotides; three and six nucleotides long; four and five
nucleotides
long; four and six nucleotides long; four and seven nucleotides long; and the
like).
In one of the preferred embodiments of the inventions herein, the enzymatic
nucleic acid molecule is formed in a hammerhead or hairpin motif, but may also
be
formed in the motif of a hepatitis ~ virus, group I intron, group II intron or
RNase P
RNA (in association with an RNA guide sequence), Neurospora VS RNA,
DNAzymes, NCH cleaving motifs, or G-cleavers. Examples of such hammerhead
motifs are described by Dreyfus, supra, Rossi et al., 1992, AIDS Research and
Human Retroviruses 8, 183; of hairpin motifs by Hampel et al., EP0360257,
Hampel
and Tritz, 1989 Biochemistry 28, 4929, Feldstein et al., 1989, Gene 82, 53,
Haseloff
and Gerlach, 1989, Gene, 82, 43, and Hampel et al., 1990 Nucleic Acids Res.
18,
299; Chowrira & McSwiggen, US. Patent No. 5,631,359; of the hepatitis 8 virus
motif is described by Perrotta and Been, 1992 Biochemistry 31, 16; of the
RNase P
motif by Guerner-Takada et al., 1983 Cell 35, 849; Forster and Altman, 1990,
Science 249, 783; Li and Altman, 1996, Nucleic Acids Res. 24, 835; Neurospora
VS
RNA ribozyme motif is described by Collins (Saville and Collins, 1990 Cell 61,
685-696; Saville and Collins, 1991 Proc. Natl. Acad. Sci. USA 88, 8826-8830;
Collins and Olive, 1993 Biochemistry 32, 2795-2799; Guo and Collins, 1995,
EMBO. J. 14, 363); Group II introns are described by Griffin et al., 1995,
Chem.
Biol. 2, 761; Michels and Pyle, 1995, Biochemistry 34, 2965; Pyle et al.,
International PCT Publication No. WO 96/22689; of the Group I intron by Cech
et
al., U.S. Patent 4,987,071 and of DNAzymes by Usman et al., International PCT
Publication No. WO 95/11304; Chartrand et al., 1995, NAR 23, 4092; Breaker et
al.,
1995, Chem. Bio. 2, 655; Santoro et al., 1997, PNAS 94, 4262. NCH cleaving
motifs are described in Ludwig & Sproat, International PCT Publication No. WO
98/58058; and G-cleavers are described in Kore et al., 1998, Nucleic Acids
Research
26, 4116-4120. These specific motifs are not limiting in the invention and
those
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skilled in the art will recognize that all that is important in an enzymatic
nucleic acid
molecule of this invention is that it has a specific substrate binding site
which is
complementary to one or more of the target gene RNA regions, and that it have
nucleotide sequences within or surrounding that substrate binding site which
impart
an RNA cleaving activity to the molecule (Cech et al., U.S. Patent No.
4,987,071).
In preferred embodiments of the present invention, a nucleic acid molecule,
e.g., an antisense molecule, a triplex DNA, or a ribozyme, is 13 to 100
nucleotides in
length, e.g., in specific embodiments 35, 36, 37, or 38 nucleotides in length
(e.g., for
particular ribozymes). In particular embodiments, the nucleic acid molecule is
15-
100, 17-100, 20-100, 21-100, 23-100, 25-100, 27-100, 30-100, 32-100, 35-100,
40-
100, 50-100, 60-100, 70-100, or 80-100 nucleotides in length. Instead of 100
nucleotides being the upper limit on the length ranges specified above, the
upper
limit of the length range can be, for example, 30, 40, 50, 60, 70, or 80
nucleotides.
Thus, for any of the length ranges, the length range for particular
embodiments has
lower limit as specified, with an upper limit as specified which is greater
than the
lower limit. For example, in a particular embodiment, the length range can be
35-50
nucleotides in length. All such ranges are expressly included. Also in
particular
embodiments, a nucleic acid molecule can have a length which is any of the
lengths
specified above, for example, 21 nucleotides in length.
By "equivalent" RNA to repressor genes is meant to include those naturally
occurring RNA molecules having homology (partial or complete) to repressor
genes
or encoding for proteins with similar function as repressor genes in various
animals,
including human, rodent, primate, rabbit and pig. The equivalent RNA sequence
also includes in addition to the coding region, regions such as 5'-
untranslated region,
3'-untranslated region, introns, intron-exon junction and the like.
By "complementarity" is meant that a nucleic acid can form hydrogen bonds)
with another RNA 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 target or
complementary
sequence is sufficient to allow the relevant function of the nucleic acid to
proceed,
e.g., ribozyme cleavage, antisense or triple helix inhibition. Determination
of
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binding free energies for nucleic acid molecules is well-known in the 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. Am. Chem. Soc.
109:3783-3785. A percent complementarity indicates the percentage of
contiguous
residues in a nucleic acid molecule which can form hydrogen bonds (e.g.,
Watson-
Crick base pairing) with a second nucleic acid sequence (e.g., 5, 6, 7, 8, 9,
10 out of
being 50%, 60%, 70%, 80%, 90%, and 100% complementary). "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
10 acid sequence.
In preferred embodiments of the present invention, inhibition of expression of
repressor genes is related to treatment of a disease or conditions. By
"related" is
meant that the inhibition of repressor gene RNAs and thus reduction in the
respective levels of protein activity will relieve to some extent the symptoms
of the
1 S disease or condition.
In another preferred embodiment, the invention features nucleic acid based
techniques (e.g., enzymatic nucleic acid molecules (ribozymes), antisense
nucleic
acids, 2-SA antisense chimeras, triplex DNA, antisense nucleic acids
containing
RNA cleaving chemical groups) and methods for their use to down regulate or
inhibit the expression of genes capable of repressing interferon-alpha (IFN-
a).
Repressors of IFN-a include, but are not limited to, IRF-2 (Lopez et al.,
1997, J.
Biol Chem 272, 22788-22799).
In another preferred embodiment, the invention features nucleic acid
techniques (e.g., enzymatic nucleic acid molecules (ribozymes), antisense
nucleic
acids, 2-SA antisense chimeras, triplex DNA, antisense nucleic acids
containing
RNA cleaving chemical groups) and methods for their use to down regulate or
inhibit the expression of genes capable of repressing Granulocyte colony-
stimulating factor (G-CSF). These repressor genes include, but are not limited
to,
CCAAT displacement protein (CDP) (Khanna-Gupta et al, 1997, Blood 90, 2784-
2795) and Genesis (Xu et al, 1998, Leukemia, 12, 207-2012).
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In another preferred embodiment, the invention features the use of enzymatic
nucleic acids (e.g. ribozymes) that cleave the RNAs encoded by repressor genes
capable of repressing erythropoietin (Epo) expression. The list of genes
capable of
inhibiting Epo include, but are not limited to, TR2 Orphan Receptor (Lee et
al., The
Journal of Biological Chemistry, 271, 10405-10412), EAR3/COUP-TF-1 (Galson et
al., 1995, Molecular and Cellular Biology, 15, 2135-2144), and GATA
Transcription Factors (Imagawa et al., 1997, Blood, 89, 1430-1439). The
inhibition
of one or more of these repressing factors would increase cellular production
of Epo
which would be beneficial for applications including but not limited to:
adjuvant
therapy for chemotherapy and treatment during renal dialysis.
In preferred embodiments, the ribozymes of the present invention have
binding arms that are complementary to the target sequences in Tables III-VII
(i.e.,
Tables III, IV, V, VI, and VII). Examples of such ribozymes are also shown in
Tables III-VIII. Table III displays target sequences and ribozymes targeting
GATA
transcription factors (1,2,3,4,6). Table IV displays target sequences and
ribozymes
targeting TR2 & TR2-11 Orphan Receptors, table V displays target sequences and
ribozymes for EAR3/COUP-TF-1, table VI displays target sequences and ribozymes
for IRF-2, and table VII displays target sequences and ribozymes for CDP.
Examples of such ribozymes consist essentially of sequences defined in these
Tables.
In yet another embodiment, the invention features antisense nucleic acid
molecules and 2-SA chimera including sequences complementary to the target
sequences shown in tables III-VII. Such nucleic acid molecules can include
sequences as shown for the binding arms of the ribozymes in Tables III-VII
(i.e., the
left-most and right-most sequence portions in the columns headed "RZ."
Similarly,
triplex molecules can be provided targeted to the corresponding DNA target
regions,
and containing the DNA equivalent of a target sequence or a sequence
complementary to the specified target (substrate) sequence. Typically,
antisense
molecules will be complementary to a target sequence along a single contiguous
sequence of the antisense molecule. However, in certain embodiments, an
antisense
molecule may bind to substrate such that the substrate molecule forms a loop,
and/or
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an antisense molecule may bind such that the antisense molecule forms a loop.
Thus, the antisense molecule may be complementary to two (or even more) non
contiguous substrate sequences or two (or even more) non-contiguous sequence
portions of an antisense molecule may be complementary to a target sequence or
S both.
By "consists essentially of in connection with ribozyme sequences is meant
that the active ribozyme contains an enzymatic center, or core, equivalent to
those in
the examples, and binding arms able to bind RNA such that cleavage at the
target
site occurs. Other sequences may be present which do not significantly
interfere
with such cleavage. Thus, a core region may, for example, include one or more
loop
or stem-loop structures which do not prevent enzymatic activity. "X" in the
sequences in Tables III-VII can be such a loop.
Thus, in one aspect, the invention features ribozymes that inhibit repressor
gene expression. These chemically or enzymatically synthesized ribozyme
molecules
1 S contain substrate binding domains that bind to accessible regions of their
target
RNAs. The ribozymes also contain domains that catalyze the cleavage of target
RNA. The enzymatic nucleic acid molecules are preferably ribozymes of the
hammerhead or hammerhead-like motif (Kore et al., 1998, Nucleic Acids Research
26, 4116-4120; Ludwig & Sproat, International PCT Publication No. WO 98/58058
) or hairpin motif. Alternatively, the ribozymes are DNAzymes. Chemically
synthesized ribozyme molecules also include ribozymes assembled together from
various fragments of nucleic acid using a chemical or an enzymatic ligation
method.
Upon binding, the ribozymes cleave the target RNAs, preventing translation and
protein accumulation. The expression of genes repressed by repressor genes
("repressed genes") may be elevated in the absence of or under reduced level
of
repressor genes. This elevated level of the repressed gene may be beneficial
to the
cell and target organism. In a preferred embodiment, ribozymes are added
directly,
or can be complexed with cationic lipids, packaged within liposomes, or
otherwise
delivered to target cells. The nucleic acid or nucleic acid complexes can be
locally
administered to relevant tissues ex vivo, or in vivo through injection,
infusion pump
or stmt, with or without their incorporation in biopolymers. In another
preferred
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embodiment, the ribozyme is administered to the site of TR2 Orphan Receptor,
TR2-11 Orphan Receptor, EAR3/COUP-TF-1, and GATA transcription factors,
CDP, or IRF-2 expression (e.g. liver cells, cancer cells) in an appropriate
liposomal
vehicle.
In another aspect of the invention, ribozymes that cleave target molecules and
TR2 Orphan Receptor, TR2-11 Orphan Receptor, EAR3/COUP-TF-1, and GATA
transcription factors, CDP, or IRF-2 activity are expressed from transcription
units
inserted into DNA or RNA vectors. The recombinant vectors are preferably DNA
plasmids or viral vectors. Ribozyme expressing viral vectors could be
constructed
based on, but not limited to, adeno-associated virus, retrovirus, adenovirus,
or
alphavirus. Preferably, the recombinant vectors capable of expressing the
ribozymes
are delivered as described above, and persist in target cells. Alternatively,
viral
vectors may be used that provide for transient expression of ribozymes. Such
vectors
might be repeatedly administered as necessary. Once expressed, the ribozymes
cleave the target RNA. Delivery of ribozyme expressing vectors could be
systemic,
such as by intravenous or intramuscular administration, by administration to
target
cells ex-planted from the patient followed by reintroduction into the patient,
or by
any other means that would allow for introduction into the desired target cell
(for a
review see Couture and Stinchcomb, 1996, TIG., 12, 510). In another aspect of
the
invention, ribozymes that cleave target molecules and inhibit cell
proliferation are
expressed from transcription units inserted into DNA, RNA, or viral vectors.
Preferably, the recombinant vectors capable of expressing the ribozymes are
locally
delivered as described above, and transiently persist in smooth muscle cells.
However, other mammalian cell vectors that direct the expression of RNA may be
used for this purpose.
By "patient" is meant an organism which is a donor or recipient of explanted
cells or the cells themselves. "Patient" also refers to an organism to which
enzymatic nucleic acid molecules can be administered. Preferably, a patient is
a
mammal or mammalian cells. More preferably, a patient is a human or human
cells.
By "vectors" is meant any nucleic acid- and/or viral-based technique used to
deliver a desired nucleic acid.
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In another aspect, the nucleic acid molecule of the present invention is
administered individually or in combination or in conjunction with other
drugs, can
be used to treat diseases or conditions. For example, to treat a disease or
condition
associated with cancer, the patient may be treated, or other appropriate cells
may be
treated, as is evident to those skilled in the art.
By "comprising" is meant including, but not limited to, whatever follows the
word "comprising". Thus, use of the term "comprising" indicates that the
listed
elements are required or mandatory, but that other elements are optional and
may or
may not be present. By "consisting of is meant including, and limited to,
whatever
follows the phrase "consisting of'. Thus, the phrase "consisting of indicates
that
the listed elements are required or mandatory, and that no other elements may
be
present. By "consisting essentially of is meant including any elements listed
after
the phrase, and limited to other elements that do not interfere with or
contribute to
the activity or action specified in the disclosure for the listed elements.
Thus, the
phrase "consisting essentially of indicates that the listed elements are
required or
mandatory, but that other elements are optional and may or may not be present
depending upon whether or not they affect the activity or action of the listed
elements.
Other features and advantages of the invention will be apparent from the
following description of the preferred embodiments thereof, and from the
claims.
Description Of The Preferred Embodiments
The drawings will first briefly be described.
Figure 1 shows the secondary structure model for seven different classes of
enzymatic nucleic acid molecules. Arrow indicates the site of cleavage. -------
-- indicate
the target sequence. Lines interspersed with dots are meant to indicate
tertiary
interactions. - is meant to indicate base-paired interaction. Group I Intron:
P1-P9.0
represent various stem-loop structures (Cech et al., 1994, Nature Struc. Bio.,
1, 273).
RNase P (M1RNA): EGS represents external guide sequence (Forster et al., 1990,
Science, 249, 783; Pace et al., 1990, J. Biol. Chem., 265, 3587). Group II
Intron: 5'SS
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means 5' splice site; 3'SS means 3'-splice site; IBS means intron binding
site; EBS
means exon binding site (Pyle et al., 1994, Biochemistry, 33, 2716). VS RNA: I-
VI are
meant to indicate six stem-loop structures; shaded regions are meant to
indicate tertiary
interaction (Collins, International PCT Publication No. WO 96/19577). HDV
Ribozyme: : I-IV are meant to indicate four stem-loop structures (Been et al.,
US Patent
No. 5,625,047). Hammerhead Ribozyme: : I-III are meant to indicate three stem-
loop
structures; stems I-III can be of any length and may be symmetrical or
asymmetrical
(Usman et al., 1996, Curr. Op. Struct. Bio., 1, 527). Hairpin Ribozyme: Helix
1, 4 and 5
can be of any length; Helix 2 is between 3 and 8 base-pairs long; Y is a
pyrimidine; Helix
2 (H2) is provided with a least 4 base pairs (i.e., n is 1, 2, 3 or 4) and
helix 5 can be
optionally provided of length 2 or more bases (preferably 3 - 20 bases, i.e.,
m is from 1 -
or more). Helix 2 and helix 5 may be covalently linked by one or more bases
(i.e., r is
>_ 1 base). Helix 1, 4 or 5 may also be extended by 2 or more base pairs
(e.g., 4 - 20 base
pairs) to stabilize the ribozyme structure, and preferably is a protein
binding site. In each
15 instance, each N and N' independently is any normal or modified base and
each dash
represents a potential base-pairing interaction. These nucleotides may be
modified at the
sugar, base or phosphate. Complete base-pairing is not required in the
helices, but is
preferred. Helix 1 and 4 can be of any size (i.e., o and p is each
independently from 0 to
any number, e.g., 20) as long as some base-pairing is maintained. Essential
bases are
20 shown as specific bases in the structure, but those in the art will
recognize that one or
more may be modified chemically (abasic, base, sugar and/or phosphate
modifications)
or replaced with another base without significant effect. Helix 4 can be
formed from two
separate molecules, i.e., without a connecting loop. The connecting loop when
present
may be a ribonucleotide with or without modifications to its base, sugar or
phosphate.
"q" >_ is 2 bases. The connecting loop can also be replaced with a non-
nucleotide linker
molecule. H refers to bases A, U, or C. Y refers to pyrimidine bases. " "
refers to a
covalent bond. (Burke et al., 1996, Nucleic Acids & Mol. Biol., 10, 129;
Chowrira et al.,
US Patent No. 5,631,359).
Figure 2 is an example of the secondary structure of a hammerhead ribozyme
targeting hGATA-2 which has the sequence contained in Seq. LD. No. 281.
CA 02364577 2001-10-03
WO 00/61729 14 PCT/US00/09721
Figure 3 is a schematic diagram indicating the mechanism of action by the
nucleic acid molecules of the present invention. The regulation of
transcription
initiation can occur by one or more transcription factors working together.
When
more than one factor is involved the transcription factors can be present as
homodimers or heterodimers. In some cases, the formation of heterodimers would
result in repression of transcription, while homodimers would form inactive
transcription complexes. By blocking the expression of one subunit of the
heterodimer, the equilibrium would shift towards formation of more homodimers
resulting in a reduced formation of active repressors and enhanced
transcription.
Figure 4 is a graph demonstrating increased erythropoietin synthesis in
Hep3B cells following cobalt induction and administration of ribozymes
targeting
GATA transcription factor 2, TR2 orphan receptor and EAR3/COUP-TR1 compared
to the irrelevant controls (IR1 and IR2).
Figure 5 is a graph demonstrating increased erythropoietin synthesis in
Hep3B cells without cobalt induction and administration of ribozymes targeting
GATA transcription factor 2, TR2 orphan receptor and EAR3/COUP-TRl compared
to the irrelevant controls (IR1 and IR2).
Figure 6 is a bar graph demonstrating increased Epo expression compared to
irrelevant controls in Hep3B cells following continuous delivery of ribozymes
targeting hGATA-2 transcription factor RNA.
Figure 7 is a bar graph demonstrating increased Epo expression compared to
irrelevant controls in Hep3B cells following continuous delivery of ribozymes
targeting EAR3/Coup-TRl RNA.
Figure 8 is a bar graph demonstrating increased Epo expression compared to
irrelevant controls in Hep3B cells following pulsed delivery of ribozymes
targeting
hGATA-2 transcription factor RNA.
Figure 9 is a bar graph demonstrating increased Epo expression compared to
irrelevant controls in Hep3B cells following pulsed delivery of ribozymes
targeting
EAR3/Coup-TRl RNA.
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WO 00/61729 15 PCT/US00/09721
Eukaryotic Gene Repression
For the transcription of genes, a number of transcription factors are required
for
gene expression and its modulation. The most prevalent type of regulator genes
within eukaryotes appear to be those that function to aid RNA polymerase in
the
initiation of gene expression, however, many examples exist of genes under
negative
control. This important class of factors is known as negative regulators or
repressors.
These trans-acting protein factors (repressor proteins) generally modulate the
rates of
transcription by binding to a specific site on a gene. The binding site is
typically a
cis-element upstream to the target gene, often within the promoter and is in
many
cases less than 10 nucleotides in length. Genes under negative control are
those that
are generally constitutively expressed unless turned off by repressor
protein(s).
In certain situations, the expression of repressed genes become highly
desirable. Therefore stimulating the expression of repressed genes by
inhibiting the
expression of repressor genes would have a beneficial effect in treating a
variety of
diseases. A number of proteins and/or peptides exist which would have such
beneficial effects on cells or patients. Several non-limiting examples are
described
below. Those of ordinary skill in the art will recognize that other genes
exist which
an organism would benefit from their increased expression.
Er~poietin: Erythropoetin is a 30.4 kDA glycoprotein hormone which is
produced in the kidney and fetal liver as a response hypoxia (Galson et al.,
supra).
The hormone regulates erythrocyte production and functions as a survival
factor for
the precursors of erythrocytes in bone marrow (Maxwell & Radcliffe, 1998,
Curr.
Opin. in Hematol. 5, 166-170). It is believed that a hemoglobin like sensor
which is
present within cells producing Epo, acts as a receptor for oxygen molecules
(Goldberg et al., 1988, Science 242, 1412-1415). When the level of oxygen
falls
below tightly regulated parameter, Erythropoietin synthesis is induced.
A number of indications may be treated using Epo. For example, patients with
renal disease may develop anemia which is defined as an absence of
erythrocytes
within blood. Treatment with recombinant Epo can significantly enhance the
production of these red blood cells (Maxwell & Radcliffe, supra). By
inhibiting the
CA 02364577 2001-10-03
WO 00/61729 16 PCT/US00/09721
production of Epo repressors, the kidneys or liver and other parts of the body
may be
induced to synthesize erythropoietin to counter anemia. Another application of
the
present invention is as an adjuvant for chemotherapy. During chemotherapy, the
patient may lose a large quantity of red blood cells. By inhibiting a
repressor gene
S for erythropoietin, the Epo protein could be expressed in elevated
quantities in the
kidneys or liver which would in turn stimulate the production of more
erythrocytes.
Granulocyte Colony Stimulating Factor (G-CSF): Granulocyte colony
stimulating factor (G-CSF) is a hematopoietic growth factor that regulates the
production and function of neutrophils from committed progenitor cells. It is
produced in vivo by monocytes, fibroblasts and endothelial cells. Recombinant
G-
CSF is given clinically to decrease neutropenia associated with chemotherapy
as
well as treatment for congenital diseases such as severe chronic neutropenia .
An
alternative to exogenous addition of G-CSF would be to produce more endogenous
G-CSF, thus potentially avoiding the limitations and complications associated
with
injection of therapeutic proteins. There are several potential molecular
targets that
may act as indirect or direct repressors of G-CSF production or activity. CDP
or
CCAAT displacement protein is a known transcription repressor that binds to a
negative regulatory element to block gene expression. It has extensive
homology to
the Drosophila cut protein. Reports indicate that CDP binds to the Lactoferrin
gene
and suppresses basal promoter activity. Overexpression of CDP blocks G-CSF -
induced neutrophil maturation in cultured myeloid stem cells (Blood 90, 2784-
95,
1997). Another potential target is Genesis, a transcriptional repressor which
blocks
granulocytic differentiation of myeloid cells (Leukemia 12, 207-212, 1998).
Genesis
is a member of the "winged-helix" transcription factor regulatory family. 32D
myeloid cells that are over-expressing Genesis fail to mature when stimulated
with
G-CSF. Genesis is expressed almost exclusively in embryonic stem cells and
embryonal carcinoma cells. Both CDP and Genesis appear to be involved in the
regulation of development and down-regulation of these could relieve a
blockage in
stem cell maturation.
Interferon-alpha: Interferon exhibits multiple biological effects through the
induction of over 30 genes encoding proteins that have antiviral,
antiproliferative,
immunomodulatory and cytokine stimulation functions. Alpha interferon (IFN-A)
is
CA 02364577 2001-10-03
WO 00/61729 17 PCT/US00/09721
a critical immune system modulator. IFN-A is encoded by a large family of
structurally related genes. Interferon therapy is used for cell proliferation
disorders
(cancer) and viral infection (HBV, HCV). Interferon-alpha differential gene
expression is accomplished by a complex interaction between cis-acting DNA
regulatory regions and the corresponding trans-acting factors. One potential
limitation for expression of the interferon-alpha genes is the repressor
transcription
factor IRF-2 (JBC 272, 22788-99, 1997). There are also other negative
regulatory
regions for which the trans-acting repressors have not yet been identified,
but which
could be additional targets inhibition by nucleic acid molecules of the
present
invention. Inhibiting expression of this transcriptional repressor could allow
increased levels of endogenous interferon-alpha to be produced. There are also
other
negative regulatory regions for which the trans-acting repressors have not yet
been
identified, but which could be additional targets for inhibition by nucleic
acid
molecules of the present invention. An advantage of this approach would be the
avoidance of the production of antibodies to exogenous interferon as well as
the
avoidance of the autoimmune complications often seen with exogenous interferon-
alpha administration.
Mechanism of action of Nucleic Acid Molecules of the Invention
Antisense: Antisense molecules may be modified or unmodified RNA, DNA,
or mixed polymer oligonucleotides and primarily function by specifically
binding to
matching sequences resulting in inhibition of peptide synthesis (Wu-Pong, Nov
1994, BioPharm, 20-33). The antisense oligonucleotide binds to target RNA by
Watson Crick base-pairing and blocks gene expression by preventing ribosomal
translation of the bound sequences either by steric blocking or by activating
RNase
H enzyme. Antisense molecules may also alter protein synthesis by interfering
with
RNA processing or transport from the nucleus into the cytoplasm (Mukhopadhyay
&
Roth, 1996, Crit. Rev. in Oncogenesis 7, 151-190).
In addition, binding of single stranded DNA to RNA may result in nuclease
degradation of the heteroduplex (Wu-Pong, supra; Crooke, supra). To date, the
only
backbone modified DNA chemistry which will act as substrates for RNase H are
CA 02364577 2001-10-03
WO 00/61729 18 PCT/US00/09721
phosphorothioates and phosphorodithioates. Recently it has been reported that
2'-
arabino and 2'-fluoro arabino- containing oligos can also activate RNase H
activity.
A number of antisense molecules have been described that utilize novel
configurations of chemically modified nucleotides, secondary structure, and/or
RNase H substrate domains (Woolf et al., International PCT Publication No. WO
98/13526; Thompson et al., USSN 60/082,404 which was filed on April 20, 1998;
Hartmann et al., USSN 60/101,174 which was filed on September 21, 1998) all of
these are incorporated by reference herein in their entirety.
Triplex Forming Oli~onucleotides (TFO): Single stranded DNA may be
designed to bind to genomic DNA in a sequence specific manner. TFOs are
comprised of pyrimidine-rich oligonucleotides which bind DNA helices through
Hoogsteen Base-pairing (Wu-Pong, supra)The resulting triple helix composed of
the
DNA sense, DNA antisense, and TFO disrupts RNA synthesis by RNA polymerase.
The TFO mechanism may result in gene expression or cell death since binding
may
be irreversible (Mukhopadhyay & Roth, supra)
2-SA Antisense Chimera: The 2-SA system is an interferon mediated
mechanism for RNA degradation found in higher vertebrates (Mitra et al., 1996,
Proc Nat Acad Sci USA 93, 6780-6785). Two types of enzymes, 2-SA synthetase
and RNase L, are required for RNA cleavage. The 2-5A synthetases require
double
stranded RNA to form 2'-5' oligoadenylates (2-SA). 2-SA then acts as an
allosteric
effector for utilizing RNase L which has the ability to cleave single stranded
RNA.
The ability to form 2-5A structures with double stranded RNA makes this system
particularly useful for inhibition of viral replication.
(2'-5') oligoadenylate structures may be covalently linked to antisense
molecules to form chimeric oligonucleotides capable of RNA cleavage (Torrence,
supra). These molecules putatively bind and activate a 2-SA dependent RNase,
the
oligonucleotide/enzyme complex then binds to a target RNA molecule which can
then be cleaved by the RNase enzyme.
Enzymatic Nucleic Acid: Seven basic varieties of naturally-occurring
enzymatic RNAs are known presently. In addition, several in vitro selection
(evolution) strategies (Orgel, 1979, Proc. R. Soc. London, B 205, 435) have
been
CA 02364577 2001-10-03
WO 00/61729 19 PCT/US00/09721
used to evolve new nucleic acid catalysts capable of catalyzing cleavage and
ligation
of phosphodiester linkages (Joyce, 1989, Gene, 82, 83-87; Beaudry et al.,
1992,
Science 257, 635-641; Joyce, 1992, Scientific American 267, 90-97; Breaker et
al.,
1994, TIBTECH 12, 268; Bartel et al.,1993, Science 261:1411-1418; Szostak,
1993,
TIBS 17, 89-93; Kumar et al., 1995, FASEB J., 9, 1183; Breaker, 1996, Curr.
Op.
Biotech., 7, 442; Santoro et al., 1997, Proc. Natl. Acad. Sci., 94, 4262; Tang
et al.,
1997, RNA 3, 914; Nakamaye & Eckstein, 1994, supra; Long & Uhlenbeck, 1994,
supra; Ishizaka et al., 1995, supra; Vaish et al., 1997, Biochemistry 36,
6495; all of
these are incorporated by reference herein). Each can catalyze a series of
reactions
including the hydrolysis of phosphodiester bonds in traps (and thus can cleave
other
RNA molecules) under physiological conditions. Table I summarizes some of the
characteristics of some of these ribozymes. In general, enzymatic nucleic
acids act
by first binding to a target RNA. Such binding occurs through the target
binding
portion of an enzymatic nucleic acid which is held in close proximity to an
enzymatic portion of the molecule that acts to cleave the target RNA. Thus,
the
enzymatic nucleic acid first recognizes and then binds a target RNA through
complementary base-pairing, and once bound to the correct site, acts
enzymatically
to cut the target RNA. Strategic cleavage of such a target RNA will destroy
its
ability to direct synthesis of an encoded protein. After an enzymatic nucleic
acid has
bound and cleaved its RNA target, it is released from that RNA to search for
another
target and can repeatedly bind and cleave new targets.
The enzymatic nature of a ribozyme has significant advantages, such as the
concentration of ribozyme necessary to affect a therapeutic treatment is
lower. This
advantage reflects the ability of the ribozyme to act enzymatically. Thus, a
single
ribozyme molecule is able to cleave many molecules of target RNA. In addition,
the
ribozyme is a highly specific inhibitor, with the specificity of inhibition
depending
not only on the base-pairing mechanism of binding to the target RNA, but also
on
the mechanism of target RNA cleavage. Single mismatches, or base-
substitutions,
near the site of cleavage can be chosen to completely eliminate catalytic
activity of a
ribozyme.
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WO 00/61729 20 PCT/US00/09721
Nucleic acid molecules having an endonuclease enzymatic activity are able to
repeatedly cleave other separate RNA molecules in a nucleotide base sequence-
specific manner. Such enzymatic nucleic acid molecules can be targeted to
virtually
any RNA transcript, and efficient cleavage achieved in vitro (Zaug et al.,
324,
Nature 429 1986 ; Uhlenbeck, 1987 Nature 328, 596; Kim et al., 84 Proc. Natl.
Acad. Sci. USA 8788, 1987; Dreyfus, 1988, Einstein Quart. J. Bio. Med., 6, 92;
Haseloff and Gerlach, 334 Nature 585, 1988; Cech, 260 JAMA 3030, 1988; and
Jefferies et al., 17 Nucleic Acids Research 1371, 1989; Santoro et al., 1997
supra).
Because of their sequence-specificity, traps-cleaving ribozymes show promise
as therapeutic agents for human disease (Usman & McSwiggen, 1995 Ann. Rep.
Med. Chem. 30, 285-294; Christoffersen and Marr, 1995 J. Med. Chem. 38, 2023-
2037). Ribozymes can be designed to cleave specific RNA targets within the
background of cellular RNA. Such a cleavage event renders the RNA non-
functional and abrogates protein expression from that RNA. In this manner,
synthesis of a protein associated with a disease state can be selectively
inhibited.
Synthesis 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.,
antisense
oligonucleotides, hammerhead or the hairpin ribozymes) are preferably used for
exogenous delivery. The simple structure of these molecules increases the
ability of
the nucleic acid to invade targeted regions of RNA structure. Exemplary
molecules
of the instant invention were chemically synthesized, and others can similarly
be
synthesized. Oligodeoxyribonucleotides were synthesized using standard
protocols
as described in Caruthers et al., 1992, Methods in Enzymology 211,3-19, and is
incorporated by reference.
The method of synthesis used for normal RNA including certain
enzymatic nucleic acid molecules follows the procedure as described in Usman
et
CA 02364577 2001-10-03
WO 00/61729 21 PCT/US00/09721
al., 1987 J. Am. Chem. Soc., 109, 7845; Scaringe et al., 1990 Nucleic Acids
Res.,
18, 5433; and Wincott et al., 1995 Nucleic Acids Res. 23, 2677-2684 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 were conducted on a 394 Applied Biosystems, Inc. synthesizer
using
a 0.2 ~mol scale protocol with a 7.75 min coupling step for alkylsilyl
protected
nucleotides and a 2.5 min coupling step for 2'-O-methylated nucleotides. Table
II
outlines the amounts and the contact times of the reagents used in the
synthesis
cycle. Alternatively, syntheses at the 0.2 ~mol 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 15-fold excess (31 ~L of 0.1 M = 3.1
~mol) of
phosphoramidite and a 38.7-fold excess of S-ethyl tetrazole (31 ~L of 0.25 M =
7.75
~mol) relative to polymer-bound 5'-hydroxyl was used in each coupling cycle.
Average coupling yields on the 394 Applied Biosystems, Inc. synthesizer,
determined by colorimetric quantitation of the trityl fractions, were 97.5-
99%. Other
oligonucleotide synthesis reagents for the 394 Applied Biosystems, Inc.
synthesizer;
detritylation solution was 3% TCA in methylene chloride (ABI); capping was
performed with 16% N methyl imidazole in THF (ABI) and 10% acetic
anhydride/10% 2,6-lutidine in THF (ABI); oxidation solution was 16.9 mM I2, 49
mM pyridine, 9% water in THF (PERSEPTIVETM). Burdick & Jackson Synthesis
Grade acetonitrile was used directly from the reagent bottle. S-Ethyltetrazole
solution (0.25 M in acetonitrile) was made up from the solid obtained from
American International Chemical, Inc.
Deprotection of the RNA was performed using either a two-pot or one-pot
protocol. For the two-pot protocol, the polymer-bound trityl-on
oligoribonucleotide
was 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 was removed from the polymer support. The support was washed three
times with 1.0 mL of EtOH:MeCN:H20/3:1:1, vortexed and the supernatant was
then added to the first supernatant. The combined supernatants, containing the
oligoribonucleotide, were dried to a white powder. The base deprotected
oligoribonucleotide was resuspended in anhydrous TEA/HF/NMP solution (300 ~L
CA 02364577 2001-10-03
WO 00/61729 22 PCT/US00/09721
of a solution of 1.5 mL N-methylpyrrolidinone, 750 ~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
was quenched with 1.5 M NH,~HC03.
Alternatively, for the one-pot protocol, the polymer-bound trityl-on
oligoribonucleotide was 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 min.
The vial was brought to r.t. TEA~3HF (0.1 mL) was added and the vial was
heated at
65 °C for 15 min. The sample was cooled at -20 °C and then
quenched with 1.5 M
NH,~HCO ~.
For purification of the trityl-on oligomers, the quenched NH;~HCO~ solution
was loaded onto a C-18 containing cartridge that had been prewashed with
acetonitrile followed by 50 mM TEAA. After washing the loaded cartridge with
water, the RNA was detritylated with 0.5% TFA for 13 min. The cartridge was
then
washed again with water, salt exchanged with 1 M NaCI and washed with water
again. The oligonucleotide was then eluted with 30% acetonitrile.
Inactive hammerhead ribozymes or binding attenuated control (BAC)
oligonucleotides) were synthesized by substituting a U for GS and a U for A14
(numbering from Hertel, K. J., et al., 1992, Nucleic Acids Res., 20; 3252).
The average stepwise coupling yields were >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, all that is
important is
the ratio of chemicals used in the reaction.
Alternatively, the nucleic acid molecules of the present invention can
be synthesized separately and joined together 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 Research 19, 4247)
Administration of Nucleic Acid Molecules
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WO 00/61729 23 PCT/US00/09721
Methods for the delivery of nucleic acid molecules is described in Akhtar et
al.,
1992, Trends Cell Bio., 2, 139; and Delivery Strategies for Antisense
Oligonucleotide
Therapeutics, ed. Akhtar, 1995 which are both incorporated herein by
reference.
Sullivan et al., PCT WO 94/02595, further describes the general methods for
delivery of
enzymatic RNA molecules . These protocols may be utilized for the delivery of
virtually
any nucleic acid molecule. Nucleic acid molecules may be administered to cells
by a
variety of methods known to those familiar to the art, including, but not
restricted to,
encapsulation in liposomes, by iontophoresis, or by incorporation into other
vehicles,
such as hydrogels, cyclodextrins, biodegradable nanocapsules, and bioadhesive
microspheres. For some indications, nucleic acid molecules may be directly
delivered ex
vivo to cells or tissues with or without the aforementioned vehicles.
Alternatively, the
nucleic acid/vehicle combination is locally delivered by direct injection or
by use of a
catheter, infusion pump or stmt. Other routes of delivery include, but are not
limited to,
intravascular, intramuscular, subcutaneous or joint injection, aerosol
inhalation, oral
(tablet or pill form), topical, systemic, ocular, intraperitoneal and/or
intrathecal delivery.
More detailed descriptions of nucleic acid delivery and administration are
provided in
Sullivan et al., supra and Draper et al., PCT W093/23569 which have been
incorporated
by reference herein.
The molecules of the instant invention can be used as pharmaceutical agents.
Pharmaceutical agents prevent, inhibit the occurrence, or treat (alleviate a
symptom
to some extent, preferably all of the symptoms) of a disease state in a
patient.
The negatively charged polynucleotides of the invention can be administered
(e.g., RNA, DNA or protein) and introduced into a patient 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 may also be formulated and used as tablets, capsules or
elixirs for
oral administration; suppositories for rectal administration; sterile
solutions;
suspensions for injectable administration; and the like.
The present invention also includes pharmaceutically acceptable formulations
of the compounds described. These formulations include salts of the above
CA 02364577 2001-10-03
WO 00/61729 24 PCT/US00/09721
compounds, e.g., acid addition salts, for example, salts of hydrochloric,
hydrobromic, acetic acid, and benzene sulfonic acid.
A pharmacological composition or formulation refers to a composition or
formulation in a form suitable for administration, e.g., systemic
administration, into
a cell or patient, preferably 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 to reach a target cell (i.e., a
cell to which
the negatively charged polymer is desired to be delivered to). 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 which prevent the composition or formulation from exerting its effect.
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 which lead to systemic absorption include,
without limitations: intravenous, subcutaneous, intraperitoneal, inhalation,
oral,
intrapulmonary and intramuscular. Each of these administration routes expose
the
desired negatively charged polymers, e.g., nucleic acids, 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 which can facilitate the association of
drug
with the surface of cells, such as, lymphocytes and macrophages is also
useful. This
approach may 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 the cancer cells.
The invention also features the use of a composition comprising surface-
modified liposomes containing poly (ethylene glycol) lipids (PEG-modified, or
long-
circulating liposomes or stealth liposomes). These formulations offer an
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
CA 02364577 2001-10-03
WO 00/61729 25 PCT/US00/09721
RES), thereby enabling longer blood circulation times and enhanced tissue
exposure
for the encapsulated drug (Lasic et al. Chem. Rev. 1995, 95, 2601-2627;
Ishiwata et
al., Chem. 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
al.,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. Chem. 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; all of these are incorporated by reference
herein).
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. All of these references are incorporated by reference herein.
The present invention also includes compositions prepared for storage or
administration which include a pharmaceutically effective amount of the
desired
compounds in a pharmaceutically acceptable Garner or diluent. Acceptable
Garners
or diluents for therapeutic use are well known in the pharmaceutical art, and
are
described, for example, in Remington's Pharmaceutical Sciences, Mack
Publishing
Co. (A.R. Gennaro edit. 1985) hereby incorporated by reference herein. For
example, preservatives, stabilizers, dyes and flavoring agents may be
provided. Id.
at 1449. These include sodium benzoate, sorbic acid and esters ofp-
hydroxybenzoic
acid. In addition, antioxidants and suspending agents may be used. Id.
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 which those skilled in
the
CA 02364577 2001-10-03
WO 00/61729 26 PCT/US00/09721
medical arts will recognize. Generally, an amount between 0.1 mg/kg and 100
mg/kg body weight/day of active ingredients is administered dependent upon
potency of the negatively charged polymer.
The nucleic acid molecules of the present invention may also be administered
to a patient in combination with other therapeutic compounds to increase the
overall
therapeutic effect. The use of multiple compounds to treat an indication may
increase the beneficial effects while reducing the presence of side effects.
Alternatively, the nucleic acid molecules of the instant invention (e.g.
ribozyme and antisense molecules) 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., 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. Virol, 66, 1432-41; Weerasinghe et al., 1991
J.
Virol, 65, 5531-4; Ojwang et al., 1992 Proc. Natl. Acad. Sci. USA 89, 10802-6;
Chen et al., 1992 Nucleic Acids Res., 20, 4581-9; Sarver et al., 1990 Science
247,
1222-1225; Thompson et al., 1995 Nucleic Acids Res. 23, 2259; Good et al.,
1997,
Gene Therapy, 4, 45; all of the references are hereby incorporated in their
totality by
reference herein). 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 ribozyme (Draper et al., PCT WO 93/23569, and Sullivan et al., PCT WO
94/02595; Ohkawa et al., 1992 Nucleic Acids Symp. 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. Chem. 269, 25856; all of the
references are
hereby incorporated in their totality by reference herein).
In another aspect of the invention, enzymatic nucleic acid molecules that
cleave target molecules are expressed from transcription units (see for
example
Couture et al., 1996, TIG., 12, 510) inserted into DNA or RNA vectors. The
recombinant vectors are preferably DNA plasmids or viral vectors. Ribozyme
expressing viral vectors could be constructed based on, but not limited to,
adeno-
associated virus, retrovirus, adenovirus, or alphavirus. Preferably, the
recombinant
CA 02364577 2001-10-03
WO 00/61729 2~ PCT/US00/09721
vectors capable of expressing the ribozymes are delivered as described above,
and
persist in target cells. Alternatively, viral vectors may be used that provide
for
transient expression of ribozymes. Such vectors might be repeatedly
administered as
necessary. Once expressed, the ribozymes cleave the target RNA. The active
ribozyme contains an enzymatic center or core equivalent to those in the
examples,
and binding arms able to bind target nucleic acid molecules such that cleavage
at
the target site occurs. Other sequences may be present which do not interfere
with
such cleavage. Delivery of ribozyme expressing vectors could be systemic, such
as
by intravenous or intramuscular administration, by administration to target
cells ex-
planted from the patient followed by reintroduction into the patient, 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 nucleic
acid sequence encoding at least one of the nucleic acid molecules (ribozyme,
antisense) of the instant invention is disclosed. The nucleic acid sequence
encoding
the nucleic acid molecule of the instant invention is operably linked in a
manner
which allows expression of that nucleic acid molecule.
In another aspect the invention features, the expression vector comprises: 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);
c) a gene encoding at least one of the nucleic acid molecule of the instant
invention;
and wherein said gene is operably linked to said initiation region and said
termination region, in a manner which allows expression and/or delivery of
said
nucleic acid molecule. The vector may optionally include an open reading frame
(ORF) for a protein operably linked on the 5' side or the 3'-side of the gene
encoding
the nucleic acid molecule of the invention; and/or an intron (intervening
sequences).
Transcription of the ribozyme or antisense sequences are driven from a
promoter for eukaryotic RNA polymerise I (pol I), RNA polymerise II (pol II),
or
RNA polymerise III (pol III). Transcripts from pol II or pol III promoters
will be
expressed at high levels in all cells; the levels of a given pol II promoter
in a given
cell type will depend on the nature of the gene regulatory sequences
(enhancers,
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WO 00/61729 28 PCT/US00/09721
silencers, etc.) present nearby. Prokaryotic RNA polymerase promoters are also
used, providing that the prokaryotic RNA polymerase 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 Enzymol., 217, 47-66; Zhou et al., 1990 Mol. Cell. Biol., 10, 4529-
37).
Several investigators have demonstrated that ribozymes expressed from such
promoters can function in mammalian cells (e.g. Kashani-Sabet et al., 1992
Antisense 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, Science, 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
ribozymes in cells (Thompson et al., supra; Couture and Stinchcomb, 1996,
supra;
Noonberg et al., 1994, Nucleic Acid Res., 22, 2830; Noonberg et al., US Patent
No.
5,624,803; Good et al., 1997, Gene Ther. 4, 45; Beigelman et al.,
International PCT
Publication No. WO 96/18736; all of these publications are incorporated by
reference herein. The above 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 yet another aspect the invention features an expression vector comprising
nucleic acid sequence encoding at least one of the nucleic acid molecule of
the
invention, in a manner which allows expression of that nucleic acid molecule.
The
expression vector comprises in one embodiment; a) a transcription initiation
region;
b) a transcription termination region; c) a gene encoding at least one said
nucleic
acid molecule; and wherein said gene is operably linked to said initiation
region and
said termination region, in a manner which allows expression and/or delivery
of said
nucleic acid molecule. In another preferred embodiment the expression vector
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WO 00/61729 29 PCT/US00/09721
comprises: a) a transcription initiation region; b) a transcription
termination region;
c) an open reading frame; d) a gene encoding at least one said nucleic acid
molecule,
wherein said gene is operably linked to the 3'-end of said open reading frame;
and
wherein said gene is operably linked to said initiation region, said open
reading
frame and said termination region, in a manner which allows expression and/or
delivery of said nucleic acid molecule. In yet another embodiment the
expression
vector comprises: a) a transcription initiation region; b) a transcription
termination
region; c) an intron; d) a gene encoding at least one said nucleic acid
molecule; and
wherein said gene is operably linked to said initiation region, said intron
and said
termination region, in a manner which allows expression and/or delivery of
said
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 frame; e) a gene encoding at least one said nucleic acid
molecule,
wherein said gene is operably linked to the 3'-end of said open reading frame;
and
wherein said gene is operably linked to said initiation region, said intron,
said open
reading frame and said termination region, in a manner which allows expression
and/or delivery of said nucleic acid molecule.
In another aspect, the invention features a method of increasing the level of
target protein in a cell comprising the step of contacting the cell with
nucleic acid
molecules capable of specifically inhibiting the expression of a repressor
protein that
represses the expression of the target protein under conditions suitable for
increasing
the level of target protein in the cell.
In another aspect, this invention features a method of increasing the level of
target protein in a cell comprising the step of isolating cells from a
patient,
introducing the nucleic acid molecule (synthetic or vector) capable of
inhibiting the
expression of a repressor of target protein, introducing the cells into same
or a
different patient under conditions for the increased expression of the target
protein.
Optimizing Ribozyme Activity
Catalytic activity of the ribozymes described in the instant invention can be
optimized as described by Draper et al., supra. The details will not be
repeated here,
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WO 00/61729 30 PCT/US00/09721
but include altering the length of the ribozyme binding arms, or chemically
synthesizing ribozymes with modifications (base, sugar and/or phosphate) that
prevent their degradation by serum ribonucleases and/or enhance their
enzymatic
activity (see e.g., Eckstein et al., International Publication No. WO
92/07065;
Perrault et al., 1990 Nature 344, 565; Pieken et al., 1991 Science 253, 314;
Usman
and Cedergren, 1992 Trends in Biochem. Sci. 17, 334; Usman et al.,
International
Publication No. WO 93/15187; and Rossi et al., International Publication No.
WO 91/03162; Sproat, US Patent No. 5,334,711; and Burgin et al., supra; all of
these describe various chemical modifications that can be made to the base,
phosphate and/or sugar moieties of enzymatic RNA molecules). Modifications
which enhance their efficacy in cells, and removal of bases from stem loop
structures
to shorten RNA synthesis times and reduce chemical requirements are desired.
(All
these publications are hereby incorporated by reference herein).
There are several examples in the art describing sugar, base and phosphate
modifications that can be introduced into enzymatic nucleic acid molecules
without
significantly effecting catalysis and with significant enhancement in their
nuclease
stability and efficacy. Ribozymes are modified to enhance stability and/or
enhance
catalytic activity by modification with nuclease resistant groups, for
example, 2'-
amino, 2'-C-allyl, 2'-fluoro, 2'-O-methyl, 2'-H, nucleotide base modifications
(for a
review see Usman and Cedergren, 1992 TIBS 17, 34; Usman et al., 1994 Nucleic
Acids Symp. Ser. 31, 163; Burgin et al., 1996 Biochemistry 35, 14090). Sugar
modification of enzymatic 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, US Patent No.
5,334,711 and Beigelman et al., 1995 J. Biol. Chem. 270, 25702; 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
ribozymes without inhibiting catalysis, and are incorporated by reference
herein. In
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WO 00/61729 31 PCT/US00/09721
view of such teachings, similar modifications can be used as described herein
to
modify the nucleic acid catalysts of the instant invention.
Nucleic acid catalysts having chemical modifications which maintain or
enhance enzymatic activity are provided. Such nucleic acid is also generally
more
resistant to nucleases than unmodified nucleic acid. Thus, in a cell and/or in
vivo the
activity may not be significantly lowered. As exemplified herein such
ribozymes are
useful in a cell and/or in vivo even if activity over all is reduced 10 fold
(Burgin et
al., 1996, Biochemistry, 35, 14090). Such ribozymes herein are said to
"maintain"
the enzymatic activity on all RNA ribozyme.
Therapeutic ribozymes delivered exogenously must optimally be stable within
cells until translation of the target RNA has been inhibited long enough to
reduce
the levels of the undesirable protein. This period of time varies between
hours to
days depending upon the disease state. Clearly, ribozymes must be resistant to
nucleases in order to function as effective intracellular therapeutic agents.
Improvements in the chemical synthesis of RNA (Wincott et al., 1995 Nucleic
Acids
Res. 23, 2677; incorporated by reference herein) have expanded the ability to
modify
ribozymes by introducing nucleotide modifications to enhance their nuclease
stability as described above.
By "enhanced enzymatic activity" is meant to include activity measured in
cells and/or in vivo where the activity is a reflection of both catalytic
activity and
ribozyme stability. In this invention, the product of these properties is
increased or
not significantly (less that 10 fold) decreased in vivo compared to an all RNA
ribozyme.
In yet another preferred embodiment, nucleic acid catalysts having chemical
modifications which maintain or enhance enzymatic activity is provided. Such
nucleic acid is also generally more resistant to nucleases than unmodified
nucleic
acid. Thus, in a cell and/or in vivo the activity may not be significantly
lowered. As
exemplified herein such ribozymes are useful in a cell and/or in vivo even if
activity
over all is reduced 10 fold (Burgin et al., 1996, Biochemistry, 35, 14090).
Such
ribozymes herein are said to "maintain" the enzymatic activity on all RNA
ribozyme.
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WO 00/61729 32 PCT/US00/09721
Use of these molecules will lead to better treatment of the disease
progression
by affording the possibility of combination therapies (e.g., multiple
ribozymes
targeted to different genes, ribozymes coupled with known small molecule
inhibitors, or intermittent treatment with combinations of ribozymes
(including
different ribozyme motifs) and/or other chemical or biological molecules). The
treatment of patients with nucleic acid molecules may also include
combinations of
different types of nucleic acid molecules. Therapies may be devised which
include a
mixture of ribozymes (including different ribozyme motifs), antisense and/or 2-
SA
chimera molecules to one or more targets to alleviate symptoms of a disease.
Animal Models
In order to evaluate the therapeutic potential nucleic acid targeting
repressors
of Epo synthesis, two animals models of chronic anemia exist. These models
are: 1 )
chemotherapy-induced anemia in mice and 2.) chronic renal failure-induced
anemia
in mice. Both of these murine models closely mimic the pathophysiology of the
corresponding disease in human patients.
(1) Chemotherany-Induced Anemia in C57/B16 Mice: The primary goal
of these studies is to evaluate the effectiveness of nucleic acid therapy
targeted at
increasing the body's ability to produce red blood cells and thus counteract
chemotherapy-induced severe anemia.
Many drugs used to treat cancer patients (cytotoxic compounds) adversely
effect the bone marrow and markedly reduce the number of circulating red blood
cells. This is primarily due to a decrease in the hormone erythropoietin (Epo)
which
stimulates the production of red blood cells. Many types of chemotherapy also
induce hemolytic anemia. The severe anemia that occurs with many forms of
chemotherapy has a marked impact on the patients' quality of life (exercising,
performing job duties, etc.) and normal daily activities are difficult to
perform.
Nucleic acid molecules targeting repressors of Epo are evaluated for their
ability to improve severe loss of circulating red blood cells (anemia)
associated with
chemotherapy in C57B1/6 mice which is an indication of enhanced Epo
production.
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WO 00/61729 33 PCT/LJS00/09721
Experimental Procedure: All studies are performed on pathogen-free, 20
258 female C57B1/6 mice. Mice are housed in a pathogen-free environment and
allowed food and water ad lib. For induction of anemia, all animals receive an
intraperitoneal injection of 3.5 mg/kg Cisplatin (CDDP), in a 200 ~L volume
(Day
0).
For all blood sample collection, animals are euthanized by COZ asphyxiation.
Baseline blood samples are obtained via cardiac puncture for hematological and
biochemical analyses prior to initiating chemotherapy (Day-0). Blood samples
obtained via cardiac puncture, body weights and spleen weights from groups of
10
CDDP-treated animals are obtained beginning on Day-1 and three times weekly
for
27 days. Acute renal failure with marked uremia (elevation of BUN) and anemia
is
apparent within 1 day post-single dose chemotherapy. Hematocrits are measured,
in
triplicate, using a Clay Adams microhematocrit centrifuge on a pooled whole
blood
sample (in EDTA) from each group of 10 animals at each termination. In
addition, a
complete blood cell count is obtained from whole blood. The remaining sample
is
spun down and plasma samples are saved at -70°C for later determination
of plasma
erythropoietin levels.
Plasma Epo levels A determined by a commercially available ELISA (R&D
Systems, Minneapolis, MN) using the manufacturer's protocol.
Compound Efficacy Studies Four groups of animals are tested per drug: Group 1
receives active nucleic acid molecules (e.g. ribozyme), Group 2 receives
scrambled
attenuated control nucleic acid molecules as therapy and Group 3 receives
vehicle as
therapy. Group 4 serves as a positive therapeutic control and receives
recombinant
human erythropoietin (rhu-Epo; 2500 U/kg, thrice weekly). There are 10 animals
per group per time point and up to three doses of nucleic acid molecules per
group
for groups 1 and 2. There are 13 time points (Days 0, 1, 3, 5, 8, 10, 12, 15,
17, 19,
22, 24, 26) in each study. Ten animals per group per time point per dose are
euthanized and blood samples collected and tested as described above. Test
agents
may be delivered via an ALZETTM osmotic pump (Alza Scientific Products)
subcutaneously or intravenously, subcutaneous bolus, direct i.p. injection or
intravenously via the tail vein.
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WO 00/61729 34 PCT/US00/09721
(2) Chronic Renal Failure-Induced Anemia in C57/B16 Mice (Zhang et al.,
1996, Nephron 72: 654-661): The primary goal of these studies is to evaluate
the
effectiveness of nucleic acid therapy targeted at increasing the body's
ability to
produce red blood cells and thus counteract chronic renal failure-induced
severe
anemia.
Chronic renal failure (CRF) is a functional clinical diagnosis characterized
by
a progressive and irreversible decline in the kidneys' ability to filter the
blood
(glomerular filtration rate; GFR). This condition is associated with a number
a
primary diseases including, but not limited to, glomerulonephritis,
cardiovascular
disease and hypertension, diabetes, kidney infections and urinary tract
disease. CRF
afflicts more than 370,000 patients in the U.S. alone. Most of these patients'
disease
will progress to end stage renal disease (ESRD) and will require renal
replacement
therapy (hemodialysis, peritoneal dialysis, kidney transplant) to survive.
Both the
loss of functional kidney tissue and the dialysis procedure cause a severe
reduction
in the red blood cell count of these patients. This primarily due to a
decrease in the
hormone erythropoietin (Epo) which stimulates the production of red blood
cells.
The severe chronic anemia has a marked impact on the patients' quality of life
(exercising, performing job duties, etc.) and normal daily activities are
difficult to
perform.
Experimental Procedure: All studies are performed on pathogen-free,
female 20-25g C57B1/6. Mice are housed in a pathogen-free environment and
allowed food and water ad lib. To establish CRF in these animals, two surgical
procedures are required separated by a two week recovery period.
For the first surgical procedure, animals are anesthetized with a ketamine/
xylazine cocktail (1.2 mg/kg and .14 mg/kg) and a right lateral laparotomy is
performed. The entire surface of the right kidney, excluding a 2 mm rim around
the
hilum, is electrocoagulated using a disposable vasectomy cautery
(2250°F). The
kidney is returned to the renal fossa and wounds are aseptically closed with 4-
0 silk
suture and surgical clips Animals are allowed to recover for two weeks before
the
second surgical procedure is performed. For the second procedure, animals are
anesthetized with a ketamine/ xylazine cocktail (1.2 mg/kg and .14 mg/kg) and
a left
lateral laparotomy is performed. The left kidney is removed and the wound
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WO 00/61729 35 PCT/US00/09721
aseptically closed with 4-0 silk suture. All animals receive penicillin G
(Durapen -
30,000 U, IM) following each surgical procedure.
For all blood sample collections, animals are euthanized by COZ
asphyxiation. Blood samples, body weights and spleen weights are obtained from
groups of 8 animals each weekly beginning at week 1 post-second surgery for
evaluation of disease progression up until week 14 post-Nx. A group of 8
normal
animals are euthanized and blood samples obtained for control hematology and
biochemistry determinations. Therefore, there are 12 euthanization time points
including the control group. From reports in the literature, CRF with marked
uremia
(persistent elevation of BUN) and anemia will be present within 8 weeks post-
Nx.
At necropsy, blood samples will be obtained via cardiac puncture for clinical
chemistry (BUN and creatinine) and hematology (WBC, Diff., platelet count)
tests
are performed by an external laboratory (IDEXX, Inc.).
Compound Efficacy Studies: There are four groups of animals per drug
tested: Group 1 receives active nucleic acid molecules of the invention (e.g.
ribozyme), Group 2 receives scrambled attenuated nucleic acid as therapy and
Group
3 receives vehicle as therapy. Group 4 serves as a positive therapeutic
control and
receives recombinant human erythropoietin (rhu-Epo; 250 U/kg; thrice weekly).
There are 8 animals per group and up to three doses of nucleic acid per group
for
groups 1 and 2.
Test agents may be delivered via an ALZETTM osmotic pump (Alza
Scientific Products) subcutaneously or intravenously, subcutaneous bolus,
direct i.p.
injection or intravenously via the tail vein.
(3) Chemotherapy-Induced Myelosuppression in C57/Bl6 Mice (Misaki et
al., 1998, British Journal of Cancer 77:884-889) : The primary goal of these
studies
is to evaluate the effectiveness of therapy targeted at increasing the body's
ability to
produce white blood cells and thus counteract chemotherapy-induced
neutropenia.
The ability of these nucleic acid molecules to improve severe loss of
circulating white blood cells (neutropenia) associated with chemotherapy in
Balb/c
mice is tested . A protocol modified from that of Misaki, et al. (1998) is
utilized.
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Experimental Procedure: All studies are performed on pathogen-free, 25-30g
female Balb/c mice. Mice are housed in a pathogen-free environment and allowed
food and water ad lib. For induction of myelosuppression, all animals receive
an
intraperitoneal injection of 200 mg/kg Cyclophosphamide (CPA), in a 200 pL
volume (Day-0).
There are 16 time points for blood sampling. Samples are obtained to
evaluate plasma G-CSF levels and CBCs. A single vehicle control group and a
rhuG-CSF group is used for all ribozyme formulation testing protocols. Body
and
spleen weights are recorded.
For all blood sample collections, animals are euthanized by COZ
asphyxiation. Baseline blood samples are obtained via cardiac puncture for
hematological analyses prior to initiating chemotherapy (Day-0). One group of
ten
animals is euthanized pre- CPA, 4 days post-CPA( at Gam, at 12 noon and at
6pm)
and daily thereafter. Two mls of whole blood is sent to mEXX veterinary
laboratory
for a complete blood cell count. The remaining samples are spun down and
plasma
samples are saved at -70°C for later determination of plasma G-CSF
levels. Plasma
G-CSF levels are determined in-house by a commercially available ELISA.
Remaining plasma samples are frozen for future analyses.
Compound Efficacy Studies: There are four groups of animals per drug
tested: Group 1 receives active nucleic acid molecules of the invention (e.g.
ribozyme), Group 2 receives scrambled attenuated nucleic acid as therapy and
Group
3 receives vehicle as therapy. Group 4 serves as a positive therapeutic
control and
receives recombinant human rhu-G-CSF (5 pg/kg, daily). There are 10 animals
per
group per time point and up to three doses of ribozyme per group for groups 1
and 2.
On day 0 animals receive cyclophosphamide (CPA; 200 mg/kg, IP). On day 4,
nucleic acid therapy is initiated. Therapy is continued daily until Day 16.
There are
16 time points (Days 0-17) in each study. Ten animals per group per time point
per
dose are euthanized and blood samples collected. One group of ten animals is
euthanized pre- CPA, 4 days post-CPA, at 6 and at 12 hrs. after nucleic acid
dosing
and daily thereafter. Two mls of whole blood are sent to IDEXX veterinary
laboratory for a complete blood cell count. The remaining sample is spun down
and
plasma samples are saved at -70°C for later determination of plasma
erythropoietin
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WO 00/61729 3~ PCT/US00109721
levels. Plasma G-CSF levels is determined in-house by a commercially available
ELISA. Remaining plasma samples are frozen for future analyses. Test agents
may
be delivered via an ALZETTM osmotic pump (Alza Scientific Products)
subcutaneously or intravenously, subcutaneous bolus, direct i.p. injection or
intravenously via the tail vein.
(4) Chronic, Relapsing Experimental Autoimmune Encephalitis in Rats:
Multiple sclerosis is a disorder of unknown cause that has a number of
symptoms
(weakness, numbness, lack of coordination, headaches) which are caused by
destruction of the protective tissue (myelin) surrounding the spinal cord.
Many
studies have been published which support both a possible immune system
problem
and/or an infectious agent. It is a chronic debilitating disease with a
clinical course
from onset to death of approximately 35 years. There are no spontaneous animal
models of MS but an autoimmune disorder which resembles MS can be induced in
rodents. This is accomplished by either injection under the skin of a crude
brain
mixture or purified proteins obtained from the brain. The goal of this model
is to
evaluate the effectiveness of therapy with nucleic acid targeted against the
interferon-_ repressor in improving the symptoms with this disease in an
animal
model.
Experimental Procedure: All studies are performed on pathogen-free, male
Dark Agouti (DA) rats 7-9 weeks of age obtained from Harlan, Inc. Rats are
housed
in a pathogen-free environment and allowed food and water ad lib for one week
prior to initiation of the study. All animals are immunized with syngeneic
spinal
cord (SSC) in incomplete Freund's adjuvant (IFA). For the preparation of the
spinal
cord emulsion, cords from donor DA rats are removed and minced thoroughly. One
part spinal cord to one part IFA (v/W) is used to prepare emulsion. The
appropriate
dose of emulsion is determined in the pilot study. 0.2 ml of homogenate (SSC
and
IFA) is injected into the dorsal base of the tail root on day 0. All animals
receive 75
mg/kg of syngeneic spinal cord. The primary endpoint of these studies is a
clinical
score. The clinical scoring system is as follows:
0.0 = Normal
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WO 00/61729 38 PCT/US00/09721
0.5 = Partial loss of tail tone
1.0 = Complete loss of tail tone
2.0 = Hindlimb weakness or dragging one
hindlimb
3.0 = Paralysis of both hindlimbs
4.0 = Paralysis of both hindlimbs and weakness
in forelimbs
5.0 = Moribund
Histopathologic evidence of demyelination is a secondary endpoint. Clinical
scores and body weights are determined daily for 21 days and EOD thereafter
until
day 90. At the termination of this study (90 days post-immunization), animals
are
euthanized. At necropsy, brain and spinal cord are removed, fixed in 10%
buffered
formalin and submitted for histopathologic analyses. The experimental method
(dose
of SSC) which provides the greatest reproducibility and the pathophysiology
that
most closely mimics the human clinical disease is then chosen for use in the
compound efficacy studies.
Compound Efficacy Studies: This study evaluates the efficacy of nucleic acid
molecules targeted against the interferon-alpha repressor gene on severity of
clinical
score and on histopathological changes in the spinal cord and brain of these
animals.
There are two main groups of animals per drug tested: one prophylactic
treatment
(beginning three days post-immunization) and one therapeutic treatment
(following
the first paralytic episode- at approximately day 15 post-immunization). Each
main
group has four subgroups: Group 1 receives vehicle as therapy, Group 2
receives
scrambled attenuated nucleic acid control as therapy, Group 3 receives active
nucleic
acid (e.g. ribozyme) and Group 4 receives recombinant human interferon-a (8
M.U.,
SC, per animal, EOD for 90 days). Nucleic acid molecules are administered at
30
mg/kg, EOD, SC for 90 days. There are 10 animals per subgroup and up to three
doses per subgroup for dose/response studies.
Test agents may be delivered via an ALZETTM osmotic pump (Alza
Scientific Products) subcutaneously or intravenously, subcutaneous bolus,
direct i.p.
injection or intravenously via the tail vein.
(6) Bl6 melanoma in C57/Bl6 Mice (Nishimura et al., 1985, Clin Exp
Metastasis 3, 295-304): The primary goal of these studies is to evaluate the
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effectiveness of nucleic acid therapy targeted increasing the body's ability
to produce
interferon-alpha and thus augment the immune response and inhibit cell
proliferation. Two syngeneic melanoma cell lines, B 16/B16 and B 16/F 10, are
utilized.
Experimental Procedure: All studies are performed on pathogen-free, 25-
30g female C57B16 mice. Mice are housed in a pathogen-free environment and
allowed food and water ad lib.
B16/B16: On Day 0, animals are injected with B16/B16 cells (5x105), SC in
100 q.l normal saline, mid-dorsal, in the scapular region. Primary tumor
volume are
measured using microcalipers. triplicate length and width measurements are
obtained from each tumor three days per week. Tumor volumes are calculated
from
tumor length and width measurements according to the equation:
Tumor volume = 0.5ab2 where
a=longest axis of the tumor
b=shortest axis of the tumor
In one set of animals (Group I), primary tumors are allowed to grow for up to
days. Therapeutic endpoints in this group are primary tumor volume, metastases
and survival. In the second set of animals (Group II), once B 16BL6 tumor
growth
reaches 500 mm3, the primary tumors are removed. Therapeutic endpoints in this
20 group are metastases and survival. Metastatic growth in the lungs is
observed at
death or at day 25 (final day of experiment). Metastasis is observed in the
lungs at
the end of the experiment by weighing the lungs and by counting the
macrometastases under 25X magnification. If no macrometastases are present,
the
lungs are perfusion fixed in formalin for subsequent sectioning and
histological
25 examination of micrometastases and survival time is recorded.
Compound Efficacy Studies: There are four subgroups of animals for Groups I
and II
per drug tested: Subgroup A receives active nucleic acid molecules of the
present
invention, Subgroup B receives scrambled attenuated nucleic acid control as
therapy, and Subgroup C receives vehicle as therapy. Subgroup D serves as a
positive therapeutic control and receives recombinant human IFN-alpha A/D (8
M.U., SC, per animal, EOD for 30 days). There are 15 animals per group and up
to
three doses of nucleic acid per group for groups A and B. Therapy begins on
day-3
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and is continued daily until Day 25. At necropsy, blood samples are obtained
via
cardiac puncture, spun down and plasma samples are saved at -70°C for
future
analyses.
Test agents may be delivered via an ALZETTM osmotic pump (Alza
Scientific Products) subcutaneously or intravenously, subcutaneous bolus,
direct i.p.
injection or intravenously via the tail vein.
B 16/F 10: On Day 0, animals are inj ected with B 16/F 10 (Sx 104 ) IV in 100
~l
normal saline. Therapeutic endpoints in this group are metastases and
survival.
Metastatic growth in the lungs is observed at death or at day 25 (final day of
experiment). Metastasis is observed in the lungs at the end of the experiment
by
weighing the lungs and by counting the macrometastases under 25X
magnification.
If no macrometastases are present the lungs are perfusion fixed in formalin
for
subsequent sectioning and histological examination of micrometastases and
survival
time is recorded.
Compound Efficacy Studies: There are four groups of animals per drug tested:
Group
1 receives active nucleic acid molecules (e.g. ribozymes), Group 2 receives
scrambled attenuated nucleic acid control as therapy, and Group 3
receivesvehicle as
therapy. Group 4 serves as a positive therapeutic control and receives
recombinant
human IFN-alpha A/D (8 M.U., SC, per animal, EOD for 30 days). There are 1 S
animals per group and up to three doses of nucleic acid molecules per group
for
groups 1 and 2. Therapy begins on day-3 and is continued daily until Day 25.
At
necropsy, blood samples are obtained via cardiac puncture, spun down and
plasma
samples are saved at -70°C for future analyses.
Test agents may be delivered via an ALZETTM osmotic pump (Alza
Scientific Products) subcutaneously or intravenously, subcutaneous bolus,
direct i.p.
injection or intravenously via the tail vein.
(7) Colorectal Carcinoma (COLON-26) in Balb/c Mice (Sanada et al., 1990,
Acta Med Okayama 44, 217-222, Ramani et al., 1989, Int J Cancer 43, 140-146,
1989): The primary goal of these studies is to evaluate the effectiveness of
nucleic
acid therapy targeted increasing the body's ability to produce interferon-
alpha and
thus augment the immune response and inhibit cell proliferation.The study
evaluates
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nucleic acid molecules targeting repressors of IFN-alpha on their ability to
improve
survival and reduce metastases in Balb/c mice with COLON-26 carcinoma.
Experimental Procedure: All studies are performed on pathogen-free, 18-20g
female
Balb/c mice. Mice are housed in a pathogen-free environment and allowed food
and
water ad lib. On Day 0, animals are injected with COLON-26 cells (1x106) in
100 ~1
normal saline into the splenic capsule.
On day-5 following tumor cell inoculation, the primary tumors are removed.
Therapeutic endpoints are metastases and survival. Metastatic growth in the
lungs
and in the liver is observed at death or at day 40 (final day of experiment).
Metastasis is observed in the lungs and liver at the end of the experiment by
weighing the organs and by counting the macrometastases under 25X
magnification.
If no macrometastases are present in these tissues, the organs are perfusion
fixed in
formalin for subsequent sectioning and histological examination of
micrometastases
and survival time is recorded.
Compound Efficacy Studies There are four groups of animals per drug tested:
Group 1 receives active nucleic acid molecules of the invention
(e.g.ribozymes),
Group 2 receives scrambled attenuated nucleic acid control as therapy, and
Group 3
receives vehicle as therapy. Group 4 serves as a positive therapeutic control
and
receives recombinant human IFN-alpha A/D (8 M.U., SC, per animal, EOD for 30
days). There are 15 animals per group and up to three doses of nucleic acid
molecules per group for groups 1 and 2. Therapy begins on day-3 and is
continued
daily until Day 40. At necropsy, blood samples are obtained via cardiac
puncture,
spun down and plasma samples are saved at -70°C for future analyses.
Test agents may be delivered via an ALZETTM osmotic pump (Alza Scientific
Products) subcutaneously or intravenously, subcutaneous bolus, direct i.p.
injection
or intravenously via the tail vein.
Examples
The following are non-limiting examples showing the selection, isolation,
synthesis and activity of enzymatic nucleic acids of the instant invention.
The following examples demonstrate the selection of ribozymes that cleave
TR2 Orphan Receptor, EAR3/COUP-TF-1, GATA transcription factors, IRF-2,
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Genesis, and CDP. The methods described herein represent a scheme by which
ribozymes may be derived that cleave other RNA targets expressed from
repressor
genes. Those of ordinary skill in the art will recognize that other ribozymes
with
motifs other than hammerhead may also be devised in a similar fashion and are
S within the scope of the invention.
Example 1: Identification of Potential Ribozyme Cleavage Sites in GATA
Transcription Factor 2 (hGATA-2)
The sequences of human GATA transcription factor 2 (HUMGATA2A,
Genbank Accession No. M77810 (Dorfman et al., 1997, J. Biol. Chem, 267, 1279-
1285) were screened for accessible sites using a computer folding algorithm.
Regions of the RNA that did not form secondary folding structures and
contained
potential hammerhead cleavage sites were identified. The sequences of these
cleavage sites are shown in Table III.
Example 2: Selection of Ribozyme Cleavage Sites in Human GATA transcription
1 S factor
To test whether the sites predicted by the computer-based RNA folding
algorithm corresponded to accessible sites in GATA transcription factor, 70
hammerhead sites were selected for analysis. Ribozyme target sites were chosen
by
analyzing genomic sequences of hGATA-2 (Dorfman, supra) and prioritizing the
sites on the basis of folding. Hammerhead ribozymes were designed that could
bind
each target (see Figure 1 ) and were individually analyzed by computer folding
(Christoffersen et al., 1994 J. Mol. Struc. Theochem, 311, 273; Jaeger et al.,
1989,
Proc. Natl. Acad. Sci. USA, 86, 7706) to assess whether the ribozyme sequences
fold
into the appropriate secondary structure. Those ribozymes with unfavorable
intramolecular interactions between the binding arms and the catalytic core
were
eliminated from consideration. As noted below, varying binding arm lengths can
be
chosen to optimize activity. Generally, at least 5 bases on each arm are able
to bind
to, or otherwise interact with, the target RNA. An example of a ribozyme
targeted
to hGATA-2 is shown in figure 2.
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Example 3: Chemical Synthesis and Purification of Ribozymes for Efficient
Cleavage of GATA Transcription Factor 2 RNA
Ribozymes of the hammerhead and/or hammerhead like motifs were
designed to anneal to various sites in the RNA message. The binding arms are
complementary to the target site sequences described above. The ribozymes were
chemically synthesized. The method of synthesis used followed the procedure
for
normal RNA synthesis as described in Usman et al., (1987 J. Am. Chem. Soc.,
109,
7845), Scaringe et al., (1990 Nucleic Acids Res., 18, 5433) and Wincott et
al., supra,
and made use of common nucleic acid protecting and coupling groups, such as
dimethoxytrityl at the 5'-end, and phosphoramidites at the 3'-end. The average
stepwise coupling yields were >98%.
Inactive ribozymes were synthesized by substituting a U for GS and a U for
A14 (numbering from Hertel et al., 1992 Nucleic Acids Res., 20, 3252). Hairpin
ribozymes are synthesized in two parts and annealed to reconstruct the active
ribozyme (Chowrira and Burke, 1992 Nucleic Acids Res., 20, 2835-2840).
Ribozymes are also synthesized from DNA templates using bacteriophage T7 RNA
polymerase (Milligan and Uhlenbeck, 1989, Methods Enzymol. 180, 51 ).
Ribozymes
were modified 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 review
see
Usman and Cedergren, 1992 TIBS 17, 34). Ribozymes were purified by gel
electrophoresis using general methods or were purified by high pressure liquid
chromatography (HPLC; See Wincott et al., supra; the totality of which is
hereby
incorporated herein by reference) and were resuspended in water. The sequences
of
the chemically synthesized ribozymes used in this study are shown below in
Table
III-VI.
Example 4: Ribozyme Cleavage of hGATA-2 RNA Target in vitro
Ribozymes targeted to the human hGATA-2 RNA are designed and
synthesized as described above. These ribozymes can be tested for cleavage
activity
in vitro, for example using the following procedure. The target sequences and
the
nucleotide location within the hGATA-2 mRNA are given in Table III.
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Cleavage Reactions: Full-length or partially full-length, internally-labeled
target RNA for ribozyme cleavage assay is prepared by in vitro transcription
in the
presence of [a-32p] CTP, passed over a G 50 Sephadex column by spin
chromatography and used as substrate RNA without further purification.
Alternately, substrates are 5'-32P-end labeled using T4 polynucleotide kinase
enzyme. Assays are performed by pre-warming a 2X concentration of purified
ribozyme in ribozyme cleavage buffer (50 mM Tris-HCI, pH 7.5 at 37°C,
10 mM
MgCl2) and the cleavage reaction was initiated by adding the 2X ribozyme mix
to an
equal volume of substrate RNA (maximum of 1-5 nM) that was also pre-warmed in
°
cleavage buffer. As an initial screen, assays are carned out for 1 hour at 37
C using
a final concentration of either 40 nM or 1 mM ribozyme, i. e., ribozyme
excess. The
reaction is quenched by the addition of an equal volume of 95% formamide, 20
mM
EDTA, 0.05% bromophenol blue and 0.05% xylene cyanol after which the sample is
°
heated to 95 C for 2 minutes, quick chilled and loaded onto a denaturing
polyacrylamide gel. Substrate RNA and the specific RNA cleavage products
generated by ribozyme cleavage are visualized on an autoradiograph of the gel.
The
percentage of cleavage is determined by PHOSPHOR IMAGER~ quantitation of
bands representing the intact substrate and the cleavage products.
Example 5: Increased Expression of Erythropoietin by Inhibition of Repressors
of
Erythropoietin
Transcriptional repressors of the erythropoetin gene were targeted with
ribozymes in order to increase Epo levels. Ribozymes were synthesized
targeting
hGATA-2, TR-2, and EAR3/Coup-TF1. Ribozyme screening was performed by
complexing with lipid, delivering to the appropriate cell line, and monitoring
for Epo
production. The ability of these ribozymes to increase Epo expression in both
induced (with CoCl2) and non-induced cells was also tested. Erythropoietin
(Epo) is
produced in the adult kidney and fetal liver in response to hypoxia and CoCl2.
Two
human hepatoma cell lines, Hep G2 and Hep 3B, exhibit regulated expression of
Epo in response to hypoxia and CoCl2. Ribozymes were tested under non-induced
and induced conditions to determine if Epo levels could be increased under one
or
both conditions.
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Hep3B cells were plated at 1.8 x 104 cells per well in a 96 well plate.
Ribozymes were then transfected into cells using cationic lipids 24 hours
after
seeding the plates. Two concentrations of each ribozyme (100 and 400 nm) were
tested using 5 or 7.5 pg/ml of cationic lipid. The sequences for the ribozymes
and
the irrelevant controls (IR1 & IR2) are given in table VIII. Cells were then
induced
to express Erythropoietin by applying cell culture media containing CoCl2 (50
nM).
After 24 hours, 100 ml of media was removed from the plate well and added into
a
plate for an ELISA assay. The remaining media is aspirated off and the cells
were
frozen at -70°C until tested by CYQUANTTM assay using the
manufacturer's
protocol. The ELISA for quantification of erythropoietin was performed using
QUANTIKINE IVDTM kit sold by R&D Systems (Minneapolis, MN) by using the
manufacturers protocol. The data indicates that a number of ribozymes were
able to
cause elevated expression of Epo in these cells compared to the inactive
controls.
Results are shown in Figures 4 and 5 for cobalt-induced and without cobalt
induction respectively.
Example 6: Elevated Expression of Erythropoietin Over Time Using Ribozymes
Tar etin~Epo Repressors
Hep3B cells were prepared as described in example 5. Ribozymes (RPI No. 14260
(targeting hGATA-2) & 144521 (targeting EAR3/COUP-TR1; table VIII) at a
concentration of 100nm were transfected into Hep3B cells using 5 p.g/ml of
cationic
lipid. Epo expression in these cells was measured at 36 and 48 hours for
continuous
delivery and at 12, 24, and 36 hours for pulsed delivery using an ELISA assay
from
example 5. The data was compared to two irrelevant and an untreated control
(Unt) .
The sequences for the ribozymes and the irrelevant controls (IR-1 & IR-2) are
given
in table VIII. The ribozyme was either delivered continuously during the
incubation
period or added for just 4 hours and then replaced with fresh media (pulsed
delivery). The data is shown in figures 6-9 which demonstrate that either
continuous
or pulsed delivery of ribozymes targeting hGATA-2 or EAR3/Coup-TR1 will result
in elevated expression of Epo in Hep3B cells compared to irrelevant and
untreated
controls.
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Diagnostic uses
Nucleic acid molecules of this invention may be used as diagnostic tools to
examine genetic drift and mutations within diseased cells or to detect the
presence of
specific RNA in a cell. For instance, the close relationship between ribozyme
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 ribozymes described in this invention,
one
may map nucleotide changes which are important to RNA structure and function
in
vitro, as well as in cells and tissues. Cleavage of target RNAs with ribozymes
may
be used to inhibit gene expression and define the role (essentially) of
specified gene
products in the progression of disease. In this manner, other genetic targets
may be
defined as important mediators of the disease. Other in vitro uses of
ribozymes of
this invention are well known in the art, and include detection of the
presence of
mRNAs associated with related conditions. Such RNA is detected by determining
the presence of a cleavage product after treatment with a ribozyme using
standard
methodology.
In a specific example, ribozymes which can cleave only wild-type or mutant
forms of the target RNA are used for the assay. The first ribozyme is used to
identify wild-type RNA present in the sample and the second ribozyme will be
used
to identify mutant RNA in the sample. As reaction controls, synthetic
substrates of
both wild-type and mutant RNA will be cleaved by both ribozymes to demonstrate
the relative ribozyme efficiencies in the reactions and the absence of
cleavage of the
"non-targeted" RNA species. The cleavage products from the synthetic
substrates
will also serve to generate size markers for the analysis of wild-type and
mutant
RNAs in the sample population. Thus each analysis will require two ribozymes,
two substrates and one unknown sample which will be combined into six
reactions.
The presence of cleavage products will be determined using an RNase protection
assay so that full-length and cleavage fragments of each RNA can be analyzed
in one
lane of a polyacrylamide gel. It is not absolutely required 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
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is implicated in the development of the phenotype is adequate to establish
risk. If
probes of comparable specific activity are used for both transcripts, then a
qualitative comparison of RNA levels will be adequate and will decrease the
cost of
the initial diagnosis. Higher mutant form to wild-type ratios will be
correlated with
S higher risk whether RNA levels are compared qualitatively or quantitatively.
Additional Uses
Potential usefulness of sequence-specific enzymatic nucleic acid molecules
of the instant invention might have many of the same applications for the
study of
RNA that DNA restriction endonucleases have for the study of DNA (Nathans et
al.,
1975 Ann. Rev. Biochem. 44:273). For example, the pattern of restriction
fragments
could be used to establish sequence relationships between two related RNAs,
and
large RNAs could be specifically cleaved to fragments of a size more useful
for
study. The ability to engineer sequence specificity of the ribozyme is ideal
for
cleavage of RNAs of unknown sequence.
The nucleic acid molecules of the present invention may also be used for
small and large scale synthesis of proteins. Nucleic acids such as enzymatic
nucleic
acids and antisense molecules may be administered into cells in culture to
initiate in
vitro synthesis of such repressed proteins as erythropoietin, G-CSF, or
interferon-
alpha. The method involves the steps of contacting or introducing into a cell
a
nucleic acid molecule (e.g. ribozyme or antisense) capable of down-regulating
(inhibition) expression of a repressor protein which represses the expression
of a
target protein (repressed protein), such that the level of repressor protein
will be
decreased, resulting in the stimulation of expression of target protein in the
cell. The
target protein can then be purified from the cells using standard techniques
known in
the art. Those of ordinary skill in the art will recognize that the method
could also
be utilized for the increase expression of other repressed proteins in
addition to the
proteins mentioned above.
The inhibition of expression of repressor transcription factors using nucleic
acids may also be utilized in non-human organisms. Particularly since negative
regulation of genes has been demonstrated in plants (Preston et al., 1998, J.
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Bacteriol. 180, 4532-4537). For example, plants and fungi may have repressor
transcription factors which, when inhibited, would allow for the increased
expression of beneficial proteins for increased crop yield, disease
resistance, and
increases in synthesis for desired amino acids, oils, and the like. Ladner &
Bird,
S International Publication No. W08806601 describe the suppression of genes to
inhibit the proliferation of viruses. Applicant describes the use of nucleic
acid
molecules to down-regulate gene expression of repressors in bacterial,
microbial,
fungal, viral, and eukaryotic systems including plant, or mammalian cells.
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. All
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 may 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 invention illustratively described herein suitably may be practiced in the
absence of any element or elements, limitation or limitations which is 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
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of the features shown and described or portions thereof, but it is recognized
that
various modifications are possible 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.
Thus, additional embodiments are within the scope of the invention and within
the following claims
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TABLE I
Characteristics of naturally occurring ribozymes
Group I Introns
~ Size: --150 to >1000 nucleotides.
~ Requires a U in the target sequence immediately 5' of the cleavage site.
~ Binds 4-6 nucleotides at the 5'-side of the cleavage site.
~ Reaction mechanism: attack by the 3'-0H of guanosine to generate cleavage
products with
3'-OH and 5'-guanosine.
~ Additional protein cofactors required in some cases to help folding and
maintainance of
the active structure.
~ Over 300 known members of this class. Found as an intervening sequence in
Tetrahymena
thermophiIa rRNA, fungal mitochondria, chloroplasts, phage T4, blue-green
algae, and
others.
~ Major structural features largely established through phylogenetic
comparisons,
mutagenesis, and biochemical studies ( ;u] .
~ Complete kinetic framework established for one ribozyme ["','",°,"'].
~ Studies of ribozyme folding and substrate docking underway ["","."','~].
~ Chemical modification investigation of important residues well established
[~,"'].
~ The small (4-6 nt) binding site may make this ribozyme too non-specific for
targeted RNA
cleavage, however, the Tetrahymena group I intron has been used to repair a
"defective"
(3-galactosidase message by the ligation of new ~-galactosidase sequences onto
the
defective message [""].
RNAse P RNA (M1 RNA)
~ Size: 290 to 400 nucleotides.
~ RNA portion of a ubiquitous ribonucleoprotein enzyme.
~ Cleaves tRNA precursors to form mature tRNA [x~'].
~ Reaction mechanism: possible attack by M2+-0H to generate cleavage products
with 3'-
OH and 5'-phosphate.
~ RNAse P is found throughout the prokaryotes and eukaryotes. The RNA subunit
has
been sequenced from bacteria, yeast, rodents, and primates.
~ Recruitment of endogenous RNAse P for therapeutic applications is possible
through
hybridization of ~an External Guide Sequence (EGS) to the target RNA ("'",x"]
~ Important phosphate and 2' OH contacts recently identified (~"',""'i]
Group 11 Introns
Size: >1000 nucleotides.
Trans cleavage of target RNAs recently demonstrated (""'~,"~']
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Table ! 51
~ Sequence requirements not fully determined.
~ Reaction mechanism: 2'-OH of an internal adenosine generates cleavage
products with 3'-
OH and a "lariat" RNA containing a 3'-5' and a 2'-5' branch point.
~ Only natural ribozyme with demonstrated participation in DNA cleavage
('°"°"] in
addition to RNA cleavage and ligation.
~ Major structural features largely established through phylogenetic
comparisons (xxu].
~ Important 2' OH contacts beginning to be identified ('°'~']
~ Kinetic framework under development (""'°]
Neurospora VS RNA
~ Size: -144 nucleotides.
~ Trans cleavage of hairpin target RNAs recently demonstrated ("""].
~ Sequence requirements not fully determined.
~ Reaction mechanism: attack by 2'-0H 5' to the scissile bond to generate
cleavage products
with 2',3'-cyclic phosphate and 5'-OH ends.
~ Binding sites and structural requirements not fully determined.
~ Only 1 known member of this class. Found in Neurospora VS RNA.
Hammerhead Riboryme
(see text for references)
~ Size: -13 to 40 nucleotides.
~ Requires the target sequence UH immediately 5' of the cleavage site.
~ Binds a variable number nucleotides on both sides of the cleavage site.
~ Reaction mechanism: attack by 2'-0H 5' to the scissile bond to generate
cleavage products
with 2',3'-cyclic phosphate and 5'-0H ends.
~ 14 known members of this class. Found in a number of plant pathogens
(virusoids) that
use RNA as the infectious agent.
~ Essential structural features largely defined, including 2 crystal
structures (""" ~""""]
~ Minimal ligation activity demonstrated (for engineering through in vitro
selection) [""""']
~ Complete kinetic framework established for two or more ribozymes [""'~].
~ Chemical modification investigation of important residues well established
[~'°'] .
Hairpin Ribozyme
~ Size: -50 nucleotides.
~ Requires the target sequence GUC immediately 3' of the cleavage site.
~ Binds 4-6 nucleotides at the 5'-side of the cleavage site and a variable
number to the 3'-
side of the cleavage site.
~ Reaction mechanism: attack by 2'-0H 5' to the scissile bond to generate
cleavage products
with 2',3'-cyclic phosphate and 5'-0H ends.
~ 3 known members of this class. Found in three plant pathogen (satellite RNAs
of the
tobacco ringspot virus, arabis mosaic virus and chicory yellow mottle virus)
which uses
RNA as the infectious agent.
~ Essential structural features largely defined (xxxi~xxxii xxxiii xxxiv]
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52
Ligation activity (in addition to cleavage activity) makes ribozyme amenable
to
engineering through in vitro selection ("'°'"]
Complete kinetic framework established for one ribozyme ('°"'"'].
Chemical modification investigation of important residues begun (xxxvu,xxxv~].
Hepatitis Delta Virus (HDV) Ribozyme
~ Size: -60 nucleotides.
~ Trans cleavage of target RNAs demonstrated (""""'].
~ Binding sites and structural requirements not fully determined, although no
sequences 5' of
cleavage site are required. Folded ribozyme contains a pseudoknot structure
("i].
~ Reaction mechanism: attack by 2'-OH 5' to the scissile bond to generate
cleavage products
with 2',3'-cyclic phosphate and 5'-OH ends.
~ Only 2 known members of this class. Found in human HDV.
~ Circular form of HDV is active and shows increased nuclease stability ["~']
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"' . Herschlag, Daniel; Cech, Thomas R.. Catalysis of RNA cleavage by,the
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thermophila ribozyme. 1. Kinetic description of the reaction of an RNA
substrate complementary to
the active site. Biochemistry (1990), 29(44), 10159-71.
'" . Herschlag, Daniel; Cech, Thomas R. Catalysis of RNA cleavage by the
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thermophila ribozyme. 2. Kinetic description of the reaction of an RNA
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mismatch at the active site. Biochemistry (1990), 29(44), 10172-80.
". Knitt, Deborah S.; Herschlag, Daniel. pH Dependencies of the Tetrahymena
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an Unconventional Origin of an Apparent pKa. Biochemistry (1_996), 35(5), 1560-
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" . Bevilacqua, Philip C.; Sugimoto, Naoki; Turner, Douglas H.. A mechanistic
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"' . Li, Yi; Bevilacqua, Philip C.; Mathews, David; Turner, Douglas H..
Thermodynamic and
activation parameters for binding of a pyrene-labeled substrate by the
Tetrahymena ribozyme: docking
is not diffusion-controlled and is driven by a favorable entropy change.
Biochemistry (1995), 34(44),
14394-9.
"~ . Banerjee, Aloke Raj; Turner, Douglas H.. The time dependence of chemical
modification reveals
slow steps in the folding of a group I ribozyme. Biochemistry (1995), 34(19),
6504-12.
'" . Zarrinkar, Patrick P.; Williamson, James R. The P9.1-P9.2 peripheral
extension helps guide
folding of the Tetrahymena ribozyme. Nucleic Acids Res. (1996), 24(5), 854-8.
Strobel, Scott A.; Cech, Thomas R. Minor groove recognition of the conserved
G.rntdot.U pair at
the Tetrahymena ribozyme reaction site. Science (Washington, D. C.) (1995),
267(5198), 675-9.
Strobel, Scott A.; Cech, Thomas R. Exocyclic Amine of the Conserved G.rntdot.U
Pair at the
Cleavage Site of the Tetrahymena Ribozyme Contributes to 5'-Splice Site
Selection and 'Transition
State Stabilization. Biochemistry (1996), 35(4), 1201-11.
Sullenger, Bruce A.; Cech, Thomas R. Ribozyme-mediated repair of defective
mRNA by
targeted trans-splicing. Nature (London) (1994), 371(6498), 619-22.
°". Robertson, H.D.; Altman, S.; Smith, J.D. J. Biol. Chem., ~ 5243-
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Forster, Anthony C.; Altman, Sidney. External guide sequences for an RNA
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(Washington, D. C., 1883-) (1990), 249(4970), 783-6.
'". Yuan, Y.; Hwang, E. S.; Altman, S. Targeted cleavage of mRNA by human
RNase P. Proc. Natl.
Acad. Sci. USA (1992) 89, 8006-10.
""' . Harris, Michael E.; Pace, Norman R.. Identification of phosphates
involved in catalysis by the
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
53
ribozyme RNase P RNA. R~~iA (1995), 1(2), 210-18.
"" ~ Pan, Tao; Loria, Andrew; Zhong, Kun. Probing of tertiary interactions in
RNA: 2'-hydroxyl-
base contacts between the R~lase P RNA and pre-tRNA. Proc. Natl. Acad. Sci. U.
S. A. (1995), 92(26),
1'510-14.
'""' . Pyle, Anna Marie; Green, Justin B.. Building a Kinetic Framework for
Group II Intron Ribozyme
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(1994), 33(9), 2716-25.
°' Michels, William J. Jr.; Pyle, Anna Marie. Conversion of a Group II
Intron into a New. Multiple-
Turnover Ribozyme that Selectively Cleaves Oligonucleotides: Elucidation of
Reaction Mechanism and
Structure/Function Relationships. Biochemistry (1995), 34(9), 2965-77.
" Zimmerly, Steven; Guo, Huatao; Eskes, Robert; Yang, Jian; Perlman, Philip
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Alan M.. A group II introit R:VA is a catalytic component of a DNA
endonuclease involved in introit
mobility. Cell (Cambridge, Llass.) (1995), 83(4), 529-38.
""' . Griffin, Edmund A., Jr.; Qin, Zhifeng; Michels, Williams J., Jr.; Pyle,
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introit ribozymes that cleav a DNA and RNA linkages with similar efficiency,
and lack contacts with
substrate 2'-hydroxyl groups. Chem. Biol. (1995), 2(11), 761-70.
""' . Michel, Francois; Ferat, Jean Luc. Structure and activities of group II
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""'" Daniels, Danette L.; Michels, William J., Jr.; Pyle, Anna Marie. Two
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°" . Guo, Hans C. T.; Collies, Richard A.. Efficient traits-cleavage of
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Scott, W.G., Finch, J.T., Aaron,K. The crystal structure of an all RNA
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'""" . McICay, Structure and function of the hammerhead ribozyme: an
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2, 395-403.
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""' . Hertel, K.J., Herschlag, D., Llhlenbeck, O. A kinetic and thermodynamic
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"'°' . Beigelman, L., et al., Chemical modifications of hammerhead
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Hampel, Arnold; Tritz, Richard; Hicks, Margaret; Cniz, Phillip. 'Hairpin'
catalytic RNA
model: evidence for helixes and sequence requirement for substrate RNA.
Nucleic Acids Res. (1990),
18(2), 299-304.
'°"''' . Chowrira, Bharat M.; Berzal-Herranz, Alfredo; Burke, John M..
Novel guanosine requirement
for catalysis by the hairpin ribozyme. Nature (London) (1991), 354(6351), 320-
2.
Berzal-Herranz, Alfredo; Joseph, Simpson; Chowrira, Bharat M.; Butcher, Samuel
E.; Burke,
John M.. Essential nucleotide sequences and secondary structure elements of
the hairpin ribozyme.
EMBO J. (1993),12(6), 2567-73.
"""" . Joseph, Simpson; Berzal-Herranz, Alfredo; Chowrira, Bharat M.; Butcher,
Samuel E..
Substrate selection rules for the hairpin ribozyme determined by in vitro
selection, mutation, and
analysis of mismatched substrates. Genes Dev. (1993), 7(1),130-8.
"""' . Berzal-Herranz, Alfredo; Joseph, Simpson; Burke, John M.. In vitro
selection of active hairpin
ribozymes by sequential RNA-catalyzed cleavage and ligation reactions. Genes
Dev. (1992), 6(1), 129-
34.
"~'"' . Hegg, Lisa A.; Fedor, Martha J.. Kinetics and Thermodynamics of
Intermolecular Catalysis by
Hairpin Ribozymes. Biochemistry (1995), 34(48), 15813-28.
"'°"'" . Grasby, Jane A.; Mersmann, Karin; Singh, Mohinder; Gait,
Michael J.. Purine Functional Groups
in Essential Residues of the Hairpin Ribozyme Required for Catalytic Cleavage
of RNA. Biochemistry
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
54
(1995), 34(12), 4068-76.
"~'""' . Schmidt, Sabine; Beigelman, Leonid; Karpeisky, Alexander; Usman,
Nassim; Sorensen, Ulrik
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internal loop B of the hairpin ribozyme: implications for secondary structure.
Nucleic Acids Res. (1996),
24(4), 573-81.
'i"" . Perrotta, Anne T.; Been, Michael D.. Cleavage of oligoribonucleotides
by a ribozyme derived
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21.
'' . Perrotta, Anne T.; Been, Michael D.. A pseudoknot-like structure required
for efficient self-
cleavage of hepatitis delta virus RNA. Nature (London) (1991), 350(6317), 434-
6.
''' . Puttaraju, M.; Perrotta, Anne T.; Been, Michael D.. A circular traps-
acting hepatitis delta virus
ribozyme. Nucleic Acids Res. (1993), 21(18), 4253-8.
CA 02364577 2001-10-03
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Table II: 0.2 ~mol RNA Synthesis Cycle
Reagents Equivalents Amounts (p.L) Wait time (sec)
Phosphoramidites 15~ 31 465
SET 38.7 31 465
Acetic anhydride 655 124 5
N-methyl-imidazole1245 124 5
TCA 700 732 10
Iodine 20.6 244 15
* Wait time does not include contact time during delivery.
CA 02364577 2001-10-03
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56
Table III. Hammerhead ribozymes tar~etino GATA Transcription factors ( l, 2,
3, 4, and
6) and the complementary Sequences
Pbs Tar get Seq. RZ Seq. sl~bstrate
LD. LD.
Pb Pb
37 F~ Fl 1 CL~J CL~AL7GAG X QUA AUr~CFL~1697 CCIl7GG?1T C
PCACiC~G
48 HSF RY~12 G~OC Ct~FG X ~ PGCtK~1 1698 ACTt~DCr T O~G~C
56 HSE I~F13 aC~G C~A~G X Cl'~ .AIJ~OOCA1699 2C~C~ACAT C
CCCAPL30C
76 fLS ~F1 4 LJOC~7UO;.G CUGAL7GFG 1700 OGAAGCCT C ~CAAC(~
X CL~A PL3O~JC~
96 FiSFI~tF',15 L1~3GALlU CL7GALJGFG X 1701 ~OGr T AATCCC.'C'A
Q~r1 ACCUC3:33C
97 HS ~'F16 CU03GGAtJ CZJGAiJGFG X 1702 ~C~IT A A'ICL~Cl~
CG~r1 APDCUOCIi
100 FiS~YFl 7 C~TK3Ch CL~LJ~ X Q~ r~LATAAL~CU1703 AC3GI'rAAT C
CL"'CAGFL3G
111 FL~ tFl.8 PGTJCCAL7G CtJtrAIJGFG 1704 CPI~OCr C CA2C3:3~GT
X QUA rY.3CCL~
120 HSF ~YF1.9 OGCC~3G CZJGAL7r~G X CIA 1705 CA2C3GAGT T
ACUCCAiJG CCCInGCC
121 F~ 'F7.10 PDOL1~ Ci~iJGFG X ~ AALTICCALJ1706 A'IC3GAGIT C
C~L~.T
135 F~ E1. 11 TJC0.'~CPDG CVGAIJGFG 1707 CCIC3GC~T C
X CL'~A ALCCC~OG TOGA
147 Fi~ CFl 12 (3000CLfiU CS~AL7C~1G 1708 O3~C.T C PGpGC'L~CC
X ~A PaCI~pC
157 HS ~F1 13 AAGU033G C(JGAIJGAG X 1709 GAGLCCCr C CCCI~GIT
CC~A P~OOGCtJC
165 HS ~7. 14 GaIJCCACn. CUGAL7GAG X 1710 CCC~Gr T 'IGIC~GATC
O~A ACLJOCI~
166 HSF RYF115 C~GAUCCAC CIJ~G X CC~A 1711 ~~GIT T GIC3.aA2~C
AAL~x33~
173 FLS ~CFl16 CAGF~CFG CZ~AIJGpG X ~ 1712 TIG'I~GtIT C
AIJCCACAA CIC3CI~.'IG
179. HS ~Fl 17 Q;,~~, X CC~A PD;AQ;ALT 1713 AT'L~CP C TDGIGhCC
186 F~ tFl 18 ~~~FG CUC~L7GFG X CC~A 1714 TC.'n3GIGT C
AC~LQ~F. CILCACPC
189 HSE ,F~Fl79 CtJG~7G CUGAI7GAG X 0.A 1715 dG'It;rCCT C
PL3G:4CHGC CFL~CPG
201 Ii ~Fl 20 AAAG~LttT C<JGAUGpG X 1716 ACCAGAAT C PaGOGITr
aC~A AL)UCTJOC~J
208 HS ~'1 21 O3GAAGAF. CUGA1C~FG X 1717 'ICAQOG;,T T
Q~AA A0.~CL~A TI~T~OC
209 H5 ~YF122 030C~PGA CL7GALX.~ X ~A 1718 CFI.~GChIT T
AACtCI~iJG TC.'hI~LZT
210 F 7. 23 AD33C,APG C<JC~FG X ~A 1719 AGCI3GriT T
AAFGCCCU Cr1C00LT
2ll HS ~Fl 24 GAOOOGAA Ct~AL7GFG X CGAF.1720 O3GGITIT C TICX:cCCIC
AAAA0.'~CC
213 HS ~F1 25 CAC~D03G CC7C~JGF~ X Cite.1721 OC~C.'r T 0.'~~.'IC.'IG
PCAAAFpC
214 I~SEl~tFl.26 CCF~OOG CLJC~G X CX'AP. 1722 GIZTrCIT C 0.'~CICI03
AFGAAAPG
219 HS ~f1 27 C~3CCC'A COGAL7GFG X CAA 1723 CTI10CCCT C
PD~G 'IG300.~IG
234 F~ tF1 28 CUOCAL~ CLOG X CG~A PDT. 1724 'IGFL~33CT T
~CPG
248 HSE ~tJ:129 Pi~JOGAGG Ci7GAIJGFG X 1725 CAOCP:GCT T
0.~AA AOCZJOCiJG Q'IdCAL'r
249 FiS ~Fl 30 CAC~IO~G CL7GAIJGFG X 1726 PDC~DCIT C CI~CIG
03~A AFD~T
252 F~ tF7.31 C~OO;~C~JG CL7t~IJCAG 1727 PL~C~X.'T C
X Ct~ POGAAOCtJ CPL'IC~OGC
297 H ~Fl 32 CLCtJ~G CL7~LJGAG X ~A 1728 ACIL~GCCT A
P~C~T C~D3G
300 HSE ~1 33 ~Ct7G C~IJG~G X QUA PL~CC1729 GGOL'~C~ A CF~G~
318 Ft ~E1 34 P~7G Ct~PG X aC~A PD3C~. 1730 ACCT A CA~GT
327 HSE I~(E135 PGFGTJOGG C<JGAIJGAG X 1?31 CAGACpL'~ C
CX~A P~JG C~GPLT
334 HS F~Fl36 POCTJC~AA QJGATJGAG X 1732 'It=COCPGT C
CAA AC~OO~r TI~1~~T
336 IiS ~Fl 37 AC~SOCUC~. CL1GAL~G X 1733 C~(2~'IC.T T
~A PGAC~OG TCAOGIGT
337 HS ~Fl 38 L~CAL~JG CLX~IJGAG X C1~A1734 0~'IT T CFD~'~H
AF:C~OG
338 F ~tFl39 ~1TJ CUGAIJG.~G X CGAA 1735 CAGI~'IT C PL3GIGTPG
AAFC~LTJG
345 F ~Fl 40 CL~AUr3GG CUGAI~G X CGAF.1736 'IC~DGI~T A
AC'r~CCtJGA CSC
351 HS ~F7.41 P~oC GUGAiJGAG X a~F. 1737 GTAC~CAT T c'~iCAACr
Ai7GG~C
355 H ~7. 42 AL~f1 CZ7~G X O~A PL3CAALJCIs1738 CCATIOCT C AFT
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57
Table III. Hammerhead ribozymes targetin? GATA transcription factors (1, 2, 3,
4, and
6) and the complementary sequences
362 HSFRYFl 43 CC2VCG~. CiJGALTGFG X OG~.1739 'ICA?~TC~T A
ACP~ TOGA03C~
373 F~t Fl. 44 CGC.~CUGG CUGAUGF~ X CAA 1740 GAL~3:~1T C CCFL3003G
ADCCC~TJC
384 HSF~tFl 45 CALL9L7C3GU CL~ALJGAG X 1741 POOC?30CT C ALCATA'IG
0.A PL~2L~CC.U
390 HSERYFl 46 ~L3C~ CtJGAIJGFG X CAA 1742 CIC~Lr~IT A 'IC3C~OC1'
AUGG.~G
405 HS~(Fl 47 LJC(JI~C~ CtJGAtJGaG X 1743 CIC~L~:I' A CO~IPf~.
Q~1P. PC33CLT~G
421 F~ F1 48 C3C'CiJGAtTGAG X CGAA rY3CCCL~J1744 ALl~OCT C 'IP~CIOC
423 HS~ Fl 49 .~L33CAC3C~ CUGAL7GaG X 1745 c~C'ICT A CCCInCCT
C~1A PG~GCL~.C
432 HS~ Fl 50 CV~G X CL~AF. PDOCFD3G 1746 CL~'IC3CCI' C
AACI~
443 HS~ Fl 51 00CLIGAtJGPG X O:~A AGPCPC?G1747 CI~ItzT C CT~CGb3C
459 FLSF~Fl 52 ~G~ CC~ALJGFG X 0.A PGUCCUC~1748 CMG ACr C ~OCC
461 HSF1~CF1 53 CZX~GpG CUGAUG~G X CuAA 1749 PL3GAL'ICT C
PGFC~~CLT CI~CC~G
464 f~C F1 54 03CZJC~1LJG~G X QG~F. PC3GPL~T1750 AL'1~ C CCCAOOCC
.
482 F~t Fl. 55 LK~~TJ0.~ CTfiALTGFG X 1751 'IL'3C~lAC~aT
OGAA AID C 'IC3GA~
507 HSF~F1 56 L~.LKJCAOG CTJGAL7GPG X 1752 CAL~CT T 0~IC3G~.
QUA PL~C~JC3QJG
508 F~ Fl 51 C~JC~PG CTJC~1L7GAG X AAA 1753 ACTT C CIC~AC~FG
.~P~CC~J
5J.8 ~i I'1 58 LJ~. Ct7C,FTJG?~ X ~ PC~~TJ~.1754 '1C3GAGACr T
~FL~.
519 FiSE~YFl 59 Ct)C~JUC C~lcJr~G X 0.A .1755C3GAC3ALTr T
AF~JCC C-~C~G
547 F~ Fl 60 ~a~ C<JC~G X AAA PL3G~G 1756 CCFGALCT C CTGPL'CGT
572 HSF~F7. 61 C~L~JGAiJG CLK~LJr;~G X 1757 CACIC~CLT T CA~ACIC
CL~ PDO~JG
573 Fi9~CE1 62 O:~AGJ~IU CtR;At7GpG X 1758 AL~!CIT C AT~CIrC
~P. AFD3CPCZJ
576 F~ tF1 63 CA03GF~(J CL7C~IJC~G X 1759 c~CI~T C ACICCCIG
O~F. AI7C~P~3C
580 HSE~tFl 64 O3GACPL~ ~G X C''~F. Pte. 1760 2~Cr C CCTGI'OOC
586 FiSE~CFl 65 CLIATJtX3~ CiJGAL~G X CuAA1761 CICCCIGT C C'L''CAATFG
PL~DO~G
593 HS~ tFl 66 AL1AAOCAC CT~L7r.~G X AAA 1762 'ICOCCAAT A GIOCITAT
AtJUO~
599 HSF~Fl 67 C3C'CCCCAiJ C~IJC~G X CGAA1763 A'1~CT T A'IC~OC~3GC
POC~CL~L1
600 H~ Fl 68 03C~OCp. CL7GALJC~G X Cu"'P.A1764 '1'AGIC~CIT A
APL~GL~. 'IC~GGC~
6L5 F~ Fl 69 L~3,~Ap. CL~ALJGAG X Q;AA 1765 CCCiG~GT T TI~CFGTA
P~D3G
616 FiSE~CFl 70 CGa. CZ~G X Q'~A AA~G 1766 O~A~IT T 'I~GrPG
617 F~ J. 71 aGL~G CUGA1;JGFG X ~ AAF~G1767 CIC~LT!'r T
618 HS~ Fl 72 P13~JG CtJ~L7GpG X CAA 1768 'I~GTI'IT C CAGI~OCT
AAAA~A
623 HS~ (F1.73 AAAGAPrOG CZJGAUGAG X ~A 1769 TI'I'UCpGT A
AC~C~AA CCTIC.'hIT
627 FiSFRYFl 74 C~AAAG Q~G X CAA PO~JG 1770 CAGTAOCT T CTI'I'I~"'IC
628 FtSF~l. 75 aGFGAAAA CtJGAUGAG X QUA 1771 PGT.~LCIT C TIrITCTCC
ACT
630 HSE'fiYF1 76 LJOOGAC~A CZ7~G X CuAA 1772 '1~CGTICT T TIC'ICJLCA
PC~fAC~
631 HS~ CF1 77 C~bOGAGp. C~L~AG X 0.A 1773 PLCrIC.'IT T
P~F~T 2CICCCAC
632 F~ tFl.78 aC~30GAG Ci7~IJC~G X C~1A 1774 CCIZC,'ITT T
AAFGAFDG CTCCCAOC
633 t~ cF1 79 ao3JOGC~. ~x~G X a~A AAAAC~AFG1775 c~rI~TrIT C T~LOG
635 F~ Fl 80 CCOOGi~ CTJGAiJGpG X QUA 1776 'IrTITICT C C~G003G
PL~AAFL~.
652 HSF ~Fl 81 C3Ci~AW CUG~ X 0.'A AO~OOC<J1777 PGCCCCCT C AATIC~C
656 F~ F1 82 ~TJGCUG ~G X 0.;Ap. AL7t~00G1778 CCL'I~AAT T C90CAOOC
.657 FLSF~1 83 AC30CUOCU Ci~G X CC~A AALRJ~31779 CC'~A'IT C PDCPGCCT
666 F~ fFl 84 GAGFDGAA QJGAt~ X D;zIA 1780 P~CCT A TIL'~CZCIC
PD~J
668 HSF ~Fl 85 C30CT~~L7C~G X CGAA PI~OOL~7G1781 CPL~CCTAT T C~C'tOOC
669 HSF~5tE7.86 UO~G CLOG X AAA A~GU 1782 POC~L'~TT C CI~OCA
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58
Table III. Hammerhead ribozymes targeting GATA transcription factors (1, 2, 3,
4, and
6) and the complementary sequences
5'72 HSERYF7.87 C3CUC7t3C~'~F. CU~.~., 1783 CTATI'CLT C 'I~CCP~P~C
X ~A AOGAAIpG
I H5FR~1 88 ~OCWt3G CLX'~AIJ~ X CGAA 1784 ATmC'ICr C CCAFDCZT
574 PGFL3GAAIJ
6a2 Hs~t~1 a9 cup ~ x o~A ~vcvu~oc 178s c~c~.r~cr T oG~c,~c
-
583 ~ ~~ ~ x ~ ~~ 1786 CCAPDCTT C GInGAACT
- _ .
-
692 ~ ~~ ~ X ~ ~~ 1787 CtInGAACr C T~CL''~
- -
694 ~ ~~ ~x ~ C 1788 aGAACICT C CC~CC
- -
--
704 ~ ~G CLIGALJGAG X Ci~IA PDOCF03G1789 CCCIC3CCT C CCI~IC-~G
~ x ~ ~~ - 1790CAC3CCNGT C CAG'I~G
- -
780 HSFR(F1 95 tx3CAUPL3G CUGAL1CFG X 1791 PL70'C'AL'r A
CG:9A PGIJOOCC.L1 ~~
784 HSE~tFI.96 0.'~C~CA CUGAi7C~G X CVAA 1792 CACrACCT A T3CAPLGC
POGC17~7G
802 HS~1F1 97 L~JGAI7A CLGAL~G X Q'~P. 1793 2G~0.~r C 'rATC~CAA
ACA
804 HS~tF1 98 LJC'tJGA CL~L~G X 0.7AA 1794 CnG~I' A 'r'~CAAGA
PGFL~OCOG
806 F~E~tE7.99 C~K~1 CL7GAIJGpG X Q;D.A 1795 OCCIC.TAT C A(2~
At~3C .
835 HSE~Fl 100 dOC<'7C~GAIJ CLX 0.A PL3300CCU1796 PC~X'CCr C AT'C~3CC
838 HS~tFl 101 UtX~CC~ CUC~TJGPG X CGAA 1797 CC~CCIC.~T C
ALJGA033G C~3CC~A
859 HSFRS,'Fl102 (~AGLJ~C CVGAUGpG X OG~A 1798 Q3C~T T GAF.
ALICAOOCG
862 HSF~tFl 103 CGVUUACTJ CL~IJC~G X O~A 1799 CrC~TTGf C PGrAAACG
ACAAUCP~
866 I-ZS~CE1104 UOC~tJ CUC~1UGAG X Q~1A 1800 TIGPG~GT A P~OOCA
PLTJGACAA
878 HSEIaCFI105 c~CC7C~G CLOG X CGAA ALC.L70CCC1801 C~G3CAC~T A CICpGIC3C
881 H~'~'G'!106 C~'~tJGCACLT CLJGAUGP~ 1802 CAOG'rACr C PGIGCACC
X ~A PL~IACCUG
941 F~~iF1 107 O~CACaG CL~AUC~ X Q1AP. 1803 GIC~3;~.T C C~7GIG~C
ALXCOCAC
964 HSE~CFl 108 L. CTJGAIJGpG X AAA FY.33000CP.1804 T303pCCr C TPI.'~A
966 HSE~fFl 109 OC~G C~LJC~G X 0~1A PGAC~3COG1805 0.~OCCICT A CSC
969 HSf~(F1 110 C~CU(JG CT7GAL7GpG X AAA 1806 CCI~'TPGT A CAAGCgG
P~DG
976 HS~'Fl 111 PCCUOCZJG C~JC~iJG~G X 1807- '~OCr A CACCALaGT
C~.A AOCUf~
1016 HSEla'Fl112 ?GtJCL~AA CiJGALJGpG X 1808 PGGATt3Gr A TrQ~LT
CAA ACCPL1CCU
1018 HS~Fl 113 CC~7Ci~G COC~1;JC~G X CGAA1809 GAZL~fiP.T T
AL~LCAIJC CpGAL'It7G
1019 HS~Fl ll4 L7C'C~T C~L~AG X Q'~.~.F. 1810 AZC3GTATT C PL~L.'ItC~
AAL~CAtJ
1025 HS~Fl 1L5 Q00~J(FJC C~AL~G X ~1A 1811 T~Cf C C~AAL~3C
PCZ7CZ7C~1A
1041 H.SE~F'1116 Q~CA CLOG X QUA AC~OQJI~ 1812 CAF03CAT C 'IDGAAAAG
1068 HS~tFl 117 a~JG CLOG X 0.7AA ~ PL~~T 1813 P100C~30CT C
CAGn'IOG
10?3 HS~(Fl 118 C~CC'A CU~LJC~G X Q~Fa 1814 OCICJCFGT C 'IC33GF~OC
PL~JOC~C
1 1.19 aCAC~L~. CTS X CC~A PL~OCF1CC~1815 ZC3GTC~OGT T
i TA~IL~GiLaG
i
~
1114 HSfCFl 120 ACCAOCALT GLX CG9A AAC~GCALC1816 CaGIOOCTr T AZL~'tL~GT
7.115F~Fl 121 C:~OCF~ CZJGALJGF~ X CGAA 1817 GIt;t3CITP A
AAFDCC~C GIG
1139 FLSF~Fl 122 AL)tJCL''03C CLX~I:JGPG 1818 C3C~3C~T A 0030GAAT
X CQ~F. PLX~CUOC
1148 F~Fl 123 Q.R~'L~CAC CT~G X O~A ALRJCOC3C1819 CaCCQIJAAT T
GIC~3C3C~G
ll63 FWFl 124 C:4Gr3CCUG CZJGAIJGaG X 1820 PoGnI3CT T CAC~CCIt;
CC~A ~~00~J
1164 Ii~Fl. 125 L~OC~.TJ CUGpTJGaG X AAA 1821 C~IC30CTT C PaOCC~.
AFDCCPL~
1190 HS~Fl 126 AL~33CAG CL~L7C~ x aC~F. 1822 CCCCADsr A C~'C4T
P~33G
ll99 HSSERIIF'1127 LJUC3~ CT~PG X CGAA AL7030CAG1823 Ct<3CCCAT C 2C.'~AG~1A
1201 H~1 128 CCLJUOC~i~. CT~G X CGAA 1824 G~CCCA'ICT C
PGALJC300C 'IPDCAFDG
1203 HSF3~F1.129 Q~TJUO;1 CL~FG X CC~A PL~ALL3J1825 CCAT~TC.'r A
CC~A00~
1230 HSE~Fl 130 CPL~OCCCU CUI~ILJGaG X 1826 C~3C'IL~'r C
CL~A PC~OCAC~ ~CCIG
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
59
Table III. Hammerhead ribozymes targeting GATA transcription factors (1, 2, 3,
4, and
6) and the complementary sequences
1240 HSE~Fl 131 ?DGU03CU CUGALTG=,G X CVAA1827 aGOC~IC~T T p~CCACCT
AO~C~C
1241 E'~Fl 132 C-~1GGLR~3C CMG X c~A AACalJOCC1828 OGCCIGIT A 0.L~.~'It:
-
~49 ~ ~3 AAFQ3CA1J CUC~1LIC~G X 1829 AGC~e CCI' C
AAA P~~JOOCU ATC3C~'~IT
1256 HSf~'Fl 139 UCC~flOGA CLJGAC7GpG X 1830 'IC'AZGC~.T T
CC-AA PC33C~1LX~. '~.L'IC3GA
1257 135 C~OGG C~ALGPG X QUA AF~DOCAIJG1831 CAS T C~GAC
1258 F~iS~(F'1136 OGtJ~OG CCIC~LIGFG X CL~ 1832 A~CTTT C CL~C~ACC
AAPDOCALT
1270 FiS~iFl 137 GAGCC~G C~JGAI~FG X 0.F. 1833 c~L~CC.T A CIC3GOC1'C
PC3O3C~JCC
1278 HSE~fFl 138 CCC~JOOC~J CTJC~7GpG X 1834 ACI17GOCT C AL~'GG
CGAp. PLaLL~CAC~T
1290 HS~tFl 139 UC33~APG CtIGATJGpG X CGAA1835 CACOGGCT C CrI~CL~.
PC~C<T7G
1293 HS~Fl 140 CUaJt3CC~ CUGAL7GpG X CGAA1836 030CICCT T CCCCACpG
Pf3C~IGOCx
1294 HSF~YF7. 141 CL~JC~.X~ CZJ~G X O~P. 1837 GGCICCIT C OCCA~G
A~FC3CC
L328 FiS~Fl 142 CALCACAG CL~JGAG X CGAA 1838 CCAC3CACT A C7GTC~GIG
PL~JGCtZ3G
1340 Fi>~!Fl 143 C~L7C~DCG CVC~Itl~G X OC~A1839 'IC~~3Cr C CC3CIr~.3C
PC3~
1345 HS~7:1 144 CAUGAOCU CLJC~IJGFG X CAA 1840 ~C~3CP C F10CIC~2G
PC303C~OC
1350 HSF~CFl 145 c~CCT~~TJ CUGAL7GFG X CGAA1841 C3CIrA0CT C A'~3C
POCiJr~OC
1373 I~(Fl. 146 CUCCC1CTJG CVGAL~G X Q~1A 1842 CA2~(~.T C C~1GAC3~G
P~C~CC~L7G
1391 ~F1 147 POGpGAFG CUGAtIGAG X CGAA 1843 aG'n3GIGT C CI~CT
~CAGC
L394 F~(Fl 148 ARGFL3GAG CT~UGAG X O:~AA 1844 OG'IG~'T T C'ICCI~'IT
PO~GC
1395 HS~CF1 149 CAAC~O~ CT7GALJt;~G X QGAA1845 GI~CIT C 'I'L~CIC.TIG
APL3~~C
1397 Fi~tFl~ 150 L~AGFG Ct7GAIJC~G X Ct;FIA1846 Gn'1CI'IC..T
PGAAOC~C C CI~.'~.
1400 HS~1 151 03C(~A CUGALJGAG X 0~1A 1847 GT~PCLT C TI~'L~3CC
POGPGAFG
1402 F~tF1 152 CtJt33C(7AC CLOG X Q~F. 1848 'IC'~,'r T GTAOOCAG
AGFl3GpGA
1405 Fi5~1 153 AL1ULZJt30C CTJC~G X Cx;AA1849 OCIC.'IZGT A
ACAAC~OG OCCAC~AT
1414 ~iF7. 154 UUC~JGCF~ CTJGAZJC~G X 1850 aCCAGAAT T C'IDGF~A
CGAA AL~3C
1415 HSEEy~tFlL55 COCA CL7C~UC~G X ~1A AALA7CUOG1851 OC~AATr C 'IC~GAC~AC
1430 HS~F1 156 ~CFC~. CZ~G X Ct;~. ACZRb3C~J1852 ACCCAPGT C 2C.'IL~GOCC
1432 ~Fl 157 0003CCrA CUt;~G X CGAA 1853 CC~F?GIC.'r C
PGpGVUOG Tt~CCC.C
1456 HS~Fl 158 C~FC3~7fJC C<7GAUGFG X 1854 C~GT T GAACCI'IC
AAA PC~Cv~O~
1463 FiS~Cf1 159 AHGCZ7tJt7G CUGALK~G X 1855 TIC~ACCr T CAAF~CIT
CC~.A PL3GUC7CAF.
1464 H~tFl. 160 AAAC3C.ZJtJU CUGAtI~G X 1856 ZGAFCCIT C AAFC~CIZT
CAA AF~OC~JrA
1471 HSF~fF1 161 IJUtA~A C~J~L7GAG X CGA" 1857 'IC~1AAOCr T
A PL3Ci~ 1'IGTAAAF.
1472 F~1 162 AIJ(~r CCX~It7GPG X 0.A 1858 CAAAGCIT T ~TAAAAT
A~L3CIx~
1473 Fi5~1 163 t~lL)tAJ~C .C~Ut~G X CGAA 1859 AF~3CTIT T GTAAAATA
AAFaLTJW
1476 HSE~F1 164 IRI~IIUU CLOG X CGAA ACAAAF~C1860 aCIZ'I~ItsT A
A~.~AAF.
1481 FLS~Fl 165 OGUO~IUtJ CLJ~1JGFG X C1~A1861 '~TAAAAT A AAAOCAOC
AUtRJC~Y'A
18 HI~TA2p. 166 L7030G~ CZJ~G X Q~ PC~TJO~OC1862 0300CpGT C ~~'A
20 FB~T,~ATA?A167 aCUC~OGC~ CtJGAIJGPG X 1863 CG~~L'ICT A OTCC~DC
Ct~A PL~JOOG
30 HI~~ATA2A168 CAf30C~T~1G CUGAI~G X O~A 1864 CCCC~!' C CTALCC~
PDC~
33 I~.~ATA?A169 C)C~C~100G CUGALJC~G X 1865 CPL3CICX.'r A
OG4A PDG~C~QJG OCCIr~AA
40 HtI~F.TA2A170 aC0030CU X CGAF. AC~D~ 1866 'hAOCCIGT A A00.~003C
55 xtn~2A In c~a~roG x o~A ~cu~ 1x67 acc~ccr c cGGAOCic
68 HCllK.~.TA2A172 030C~CFG C~ALK~G X ~F. 1868 CGIC~CIGT C C'IC~OCC~
ACA3CAOG
79 F~.~2A 173 C~GFO33C C(X~UGPG X Q~P. 1869 aG00.'~~T C C30CCTt'x.~
P~300.T
85 H~?A 174 ~C~ CZJGAIX~G X CVAA P0300~C1870 G'IC70CCCT C
(303GrCCC
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
Table III. Hammerhead ribozymes targeting ciATA transcription factors (I, 2,
3, :~, and
6) and the complementary sequences
I hT~t;ATA2A175 (~GC~ CUr;ATJG?G X C<~A_A1871 CIC'OGGGr C vC.T3C~
91 AL~CGPG
103 i~lJh~.Ta2A175 C~C~JGp~ CZJGAIIGFa X 1872 CC3C~1AC'r C
OGAP. PL~O3G CI~CP~'~C
106 HUNhATA2A177 L7GFGAC~JG CLJGAI7C~G 1873 c~IACI~CCZ' ~
X AAA POG~7UC CAG'I~IrA
107 HI.R~ATA2A178 C(JGF~T CUGALIGaG X a~A 1874 AACI~CTT C ~G
APDGF~JtJ
111 HU~,ATR2A179 C3CCU'TJGA CGTGALJ~G X 1875 Q'TI~C'T C MC~GF~OC
fir. PC~JGAPQ3
113 HC~.TA2A 180 C33L~T~.V CUCX CC~A PC~A 1876 TI~.T C ?C~L3GCCG
125 Ht.I~ATA2A181 ~3~G CL7GALJ~G X Q;AP. 1877 03CCGFGT C CcICCC.Cr
ACL1CC~GCC
129 HUhI;F.TA2A182 OQ3~~OC~ C~JC~JGFG X Q~1A1878 C~GICC~.T C CC~TC~CC
1~L33GAGW
134 HI~ATA2A 183 aCCGt~OG C~JGAt~ X a~A 1879 CCICCCCT C OTC
Pa0GG~3G
156 F-1~TA2A 184 aCPC~C CT~AI~~G X ~A AC~OCCAC1880 GI~3CC~'f T OCGTCIOC
161 Ht7~RTA2A185 U0~70CA CL~FG X O~A PdX3CAACG1881 ~TOCGT C '~C~CCCA
264 H~TA2P, 186 C~JO~T CLl~IJC,FG X QUA 1882 C~CCJGACT C ?~C
PI~JC~
291 HC~ATA2A 187 QJUCC'AI)G CUGACR~G X 1883 CCP~ACI' A CA'~C~1AC
O~A PL~JtX~JOC
317 HC~2P. 188 CtJC~ilCpG C17GALJGFG 1884 '1T~I~3CCr C
X ~1A PQOC~OCA CFGAC~G
334 HC~~ATA2P.189 LXJGAAGHA C<JC~1LR~G X 1885 G'IC3GACGr C
0.'A P~CAC TIC'I'IC21A
336 F~TA2A 190 CZJGAL7GpG X 0.~4A PC,P~C~C1886 O;~A~.'T T CTI~A~C
337 H~2P. 191 L7GALnJC~A C~L7GpG X Q~P.1887 G~TCt'I' C TIt'AATCp.
APC-ACC~7C
339 Fit.~ATA2A192 OGUGAUUG CtJ~L~FG X ~A 1888 C~I~I~C.T T C
PC~AG~3
340 F~tJ!i~'~F.TA2A193 ?L3~JC~W CL~RLfi~G X AAA 1889 GPCI'IC,.'IT
A~APG'9C C ?P.~
344 HIJh~~TA2A194 C~C,A0~1 CL~IJ~G X CAP. 1890 TCTZCAAT C ~CTt~C
AIJUGAF~1
349 F~:~2P. 195 UGC~ CUGAI~AG X CAF. A~JG~JfJ1891 AATCALLT C C~L'P03CA
354 HCA 196 UOOOCIX~ QJ~JGFG X c~A 1892 CCZt7GALT C Q'~300C:~
~!C~JOC~3G
369 HII~~TA2A197 LpOC~L~G X Q;~. PI3~C~nJG1893 CAPLCJCCr ? C~CCA
372 FAA 198 aC~JfJ00CA CTJC~G X OG9A 1894 ~CCTACr ? 'IGL~AAOC
AL~03C~
386 HI1~.TA2P.199 c3COC~GC~J Ct7GAt7C~G 1895 PL0.~CT C ?L3~OGOC
X aG4A PL30030CTJ
397 HC~ATA2A 200 GZ~GF. CT~IJC~G X C~1A 1896 CT3~r C 'It,CTPCAG
PLJGCa3CV
399 H~ATA2A 201 C3G<.1~G CZ~AI~ X Q~1A 1897 CZ3~.T C CI~CpC~CC
PGAL'~CC~
402 HC~2'~Ffl'A2A202 ~CiJG CC~.t~G X Q'~1F. 1898 ~ICCP z CF~OCOG
POGAC~
453 Fif.~2A 203 LCA~C CLJGAL~FG X 0.;A 1899 CLCAL:AGT T GTI~CF~CA
A~JG3G
456 FAA 204 QOCUQJOC Ctl~t7GAG X 0.A 1900 AC~1L'I'IGT T
P~?C~JC~T aC~DCC
470 HC~.~2A 205 ~0~ CL~AIJ~G X CG?A AON03C3C1901 aC'C173GGT T
'IL~7CIL3G
471 HL~.~2P. 206 0.T~OD3C CUGAUGpG X CAA 1902 0.'~OOGGIT T
AAOC003G QOCL'IC~OC
502 F~~~ATA2A207 C~CFC~. CiJ~TJC~ X AAA 1903 OCAOCCCT C 2~~3C
1~00C~CCX~C
504 HUNL~2P. 208 (3300COCA CL~IJGAG X CC~A1904 PGCGt'ICT C 'I~OC~3CCC
~ AC~Cd00.'U
540 F~~2A 209 L7C.TJIJOC~G CtJ~L7GpG 1905 C~3CCCCT T CICC~FGp.
X CGAA PDOOOCtJC
541 HC~~ATA2A210 ~. C~ALJ~G X UC-AA A1~OGOOCU1906 PGCCOCIT C 'IC7CAFC~C
543 HIl~'I'A2A211 C~OQ7CTJUG Ct~ALX.~ X 1907 C~!CL'TIC.'r
OGAP. AGAAOG3G C CAAGF~3C
564 F~F.TA2P.212 CAOCPC~CU CZJr~L7G~G X 1908 aCPL~CGT C ?I3CIC~CI~
CLEF. PL303GtX3C
591 f~2A 213 L~ C~FG X Cu"AA PC~J03LZZJ1909 P~OOCACT C '~'IG~GTP.
593 Ht~.TA2A 214 a~C~CP. CLX~IJC~G X CC~F.1910 0.'~CACIC.'r
PC,FC~03C C 'IGIGTACC
599 HL~ATA2A 215 CCCCT~ Ct)GF~ X Ct;zlA 19ll CrCIGI~T A CCCP~f30C~
PEG
639 F~2~2A 216 ?L30CCACL1 CiJGAIK~G X 1912 ~OCT C ACCT
O~A POC(7CL~G
648 H~~ATA2A 217 03C~JC,PL~3 CL~ X Q'~A 1913 PGZL30~.'T C
P03CCPLTJ C~.'I~CCC
652 Fif.~2A 218 C~J CMG X CuAA PL30~~DOC 1914 C3~.'m~.T C ?L~CTAC
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61
Table III. Hammerhead ribozymes targeting GATA transcription factors (1, 2, 3,
~, and
6) and the complementary sequences
i ~wr~ATA2A219 o~czc ~_ x o~A Pm3~ 191s T~cr a c~ac.~acc
659
672 HC1~ATA2A220 CCCA CLJGAL7~G X CVAF. 1916 PL3CCCACr C '1T.3GCIL"'L~
r~GCU
678 HCI~ATA2A221 PAPaQJOG CUt~IIfJC~G X 1917 C~cr C CCACCITT
~A PL~!CAGFG
685 Ht~AT?~,2A222 AAOCCG'4A CLJGAZJ~G x a~A 1918 T"CO'ACCr T TICGCIvIT
Pc3~Gp.
686 HfJL~ATA2A223 C~AAGCCZ;A CtJGALGAG X 1919 CLCACCIT T T~33CrIC
CVAA .AFL3GUOOG
687 HC~ 2A 224 c7C,APGC~ X SAP. AAF~70G 1920 CC~ICi'TIT T
~3cI'I~C
688 HI~ATA2A225 03GAAC3C.L CTJGPI~G X CCAA1921 CALcIfiiT C (?~.'rrCCC
AAAAOGtJG
693 HL~.TA2A226 QJOC~OGG C~JGAUC~G X CVAA 1922 TrIC~OCT T CL~CCAC
POGCGAAA
694 Ht~ 2P.227 ~GUGG CVGAZ~AG X C~'~F. 1923 TI~GcIT C CCACCACG
AAOCCGAF.
720 F~AT A2A228 ~GGA CUGAUGFG X CGAA ACC 1924 aGAACIGT C 'l~clG~
722 HC~ 2A 229 PL30GLJCAG CiIC'~G X D~P. 1925 P~ACI'GIC.T C
PCT CIGACCCr
731 HL~ 2A 230 CC~JO~JOC CUGA<fi~ X CC~A 1926 CI~~.T A GCAL~
P03~G
750 I~AT A2P.231 PC30C~A CLGAZfi~IG X Ct~AF.1927 03C~OGr C T"r~OCCT
A~CL~3C7C
752 H~ ~12A232 L7GFD3CUG C<JGAL~FG X CGAA1928 CAGC~'ICr C CFL~:C'IC~
AC~:.L7G
759 HCll~A'I~,2A233 COGAAC,AI1 CUGAUGAG X CGAA1929 T'~GOCT C A2CrI~C~
PaOL~X~A
762 FiC~~2A 234 CLl~GAP. C.L1GALJGF~ X 1930 P~CG2C~T~ C TI~OGG
QUA AL)GAC~3CLJ
764 - 'A2A235 CCC~G CZG X CuT~A PC~L7GAOG~31 C~.'IC.T T C0;3
- HI~T~~ -
765 F~d~TA2P.236 CC~C~O~ CZJGAIJGpG X CGAA 1932 CTCA'IC.Tr C
AFC~L~1G C~703bOG
776. F~. TA2A237 Q3CTJGAAC CI7GAUG~G X 0;~1A1933 ~~A~x
ACCCCCCG
779 HI~ 2P.238 tJ003GCiJG CLIGi9L7GaG 1934 030GTPGT T CFGC'~GA
X CG~A ACL~O~C
780 HIE~ATA2A239 CtJCD00CU CMG X G~1A AFGT~OOC1935 aC~TAGrr C PL3LL'~Q~FG
808 FH~F.T~.2A240 U~.W CTJC~L~G X CGAA ACDOOGL7C1936 C~30Gr C AFGTACC~.
813 2A 241 P~LU~G CLJGAL7C~ X CGAA 1937 CZ;rCAFGr A CCA030GT
PLL7C7GAOG
822 Ht~ 2P.242 COJ CZJ~G X 0.A Pl>3CCU03 1938 ~OCGT C ACIt;F03G
857 HC~F.TA2A243 OOGG~3G GAG X 0.;AA AOOC3CC~C1939 GIC~OGr C OOCIL100C
874 HI.~'IA2P.244 AL~OC CLOG X CGAA PLlOCCtJCIs1940 OCpDOGC.T A OCrACTAT
878 HLIN>JATA2A245 OC~G CZJC~G X CGAA AO~L~OGC1941 C3CC~L'T A C'~3C
881 HC~ 2A 246 Q~C0.~A CZJC~TJGPG X CAA 1942 'rAOcrP1'I' A
~CLg1 'IC30GCAGC
899 F 2A 247 QJ03JC~JG CZ7C~LJGAG X 1943 PL3~3CI' A ~C
Qa<1A PL~900CU
9L3 HIIN~2P.248 tT~~ CL7GAi~ X CGAA At>D~ 1944 CACaCAT C COCA
921 fBl~ ?A 249 POGF~OOG CZJC~ X Q;AA AOCAX133G1945 0.'~~OCT A CD~CT
927 FO P. 250 aCH~IIpG C1~G X Ct;AA PL30GC~TIF1G1946 Cr~C~.iCT C CSC
930 F~. ~2P.251 CJD~C~ CLOG X ~9A POG~OIGG1947 OCCCrCCP A ~~L300C1u
954 I~ 2A 252 COLTJOQJG C1~G X CuAA AC~31948 CC~OGAC'I' A
CFDC~C~
967 F~ .2A253 O3~A CtJC~I7GFG X aGAA 1949 PL~3GF1GT C TICCANC
PL~7COC1CU
969 HC7~ATA2A254 C~G(173 CLfi~G X CVAA PG~JOOG1950 OOGAC1CT T 0.A000.G
970 HI~ 2A 255 CCOOOGt7G CLOG X Q~1A A~JCC1951 a GACrCIT C C~L0.~70G
984 HIIr~ATA2A256 CCC~G CUr;zIIJC2~G X ~1A 1952 030C'~GT T C~.'IC33~3G
PL3CL)~OG
985 HC1~ .~2A257 CC'OCCCAG ~ X QUA APL3G~C 1953 dOGAOCIT C CIC30003G
1002 FiUM~TA2A258 LJGAFDCUG Ci7GAt)~ X O~A 1954 AL~X,T C CPC~CTtt~r
A~!IOOC~T
1008 Htl~ 2A 259 ~C4JG C<JC~,L7GAG X CC~A 1955 Cl'~OCT T CACCCt'1'A
PL1C1~G
1009 HtIM;paTA2A260 L7C~30~T CMG X ~ AFL3CZJOGDr1956 T~DCI'r C PL~LZ'rPp.
1016 F~ 2A 261 O~C~J C<JGAZ~G X CC~A PL1303JG~.1957 2CPL~IrCr A
PDCAOC0.~C
1034 HI1~ 2A 262 PC~Y3GAAC C1~AL7GFG X C1~A1958 Q~1FC,FGT C GI'i~C~GT
P~L~3C
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
62
Table III. Hammerhead ribozymes targeting GATA transcription factors ( 1, 2,
3, 4, and
6) and the complementary sequences
1037 h~~~2A 263 L~AACppC ~ X ~F, AC7GAC~~J1959 ?~GACI~GT T
CCI~IT~
1038 hLM~TA2A 264 CUGAACAG CUGAIJr;FG X AAA 1960 GACICJ~IT C
ppp; C
1043 HG2~TA2P,265 C~CCCt~CLJG CC7CAIJGFG 1961 GITn'CIGT T
X Cl'~A ACPL3GAFG C~fGAPDOC
1044 HCd~L~ATA2A266 C3GC~C1CU CUGAUGFG X CAA 1962 TICCIGTr C ~AAOOx
AAC~3GAA
1063 HI1~I~2A 267 CCAC'AC~f1 CUGAI7GpG X 1963 GHGIGIC~T C
OQ~A ACAC~L.TJC AFC
1088 HUhL~.TA2A268 0."OCC~ C~AI~G X Q;~p, 1964 CAAL~C~ C 'IC.'IC300C~
pappC~~JG
1090 f2P, 269 ~C~ CtJGALJGFG X pC~p, 1965 ACCCCTC'i' C
pC~ppQ7 'IC~~
1116 Ht~TA2A 270 UC~CACFDG CLOG X CK~F. 1966 C<30CCACr A
PL~JOOCL'G CCIG'I~CA
1137 F~L~2P, 271 UGC~3C~G (T~L~G X ~A pO~pCFG1967 C1~CT T CI~CCFG~
1138 Ht~.TA2A 272 UtJGtJOC4~. CUGAUGAG X 1968 ~CIT C TAL~'1~L.~A
CC~F. AF~C3C~C~.
1140 Ht~TA2A 273 L~CUC~ C(~FG X Ct~, PGAAOQ3;7969 ~I'IC.T A CC~CPP~
1171 HC~F.TA2A274 C~CCn7C-AIJ CI~AL7~G X 1970 Ci~CAGT C A~~
~A A(~3C~Jl~
1174 HI~2A 275 ULC~OCW C~A~FG X CAA AUGAGUC3G1971 O:~ICA.T C AAOCC~AA
1194 HU2'~'IA2A276 UC3G~3CC Q7C~GFG X C~A 1972 AF~C~CtGr C
ACPGfJCW c33CC1~00A
1220 HOh~2A 277 AUC~C CL~AL~G X O~F. AC~GZJOC1973 C3CACCTGT T
GIT~AAAT
1229 HC~.2P. 278 ~7r:~C QTGALJGFG X ~F, 1974 GIC~CAAAT T
AUUUOCAC GI~DG
1232 HC1~~2A 279 UC~O~iT CZ7GHC7C~ X CGAA 1975 CAAATIGT C PC~L~.
ACAAIJUt7G
1251 HC~1TAZA 280 l3GCC3C'C~LT CUGAIJC~G 1976 CACCAC1.T T
X CC~F. PL3GUOC~JG r~C3~
1252 HG22~TA2A281 Cl'~OOC3CC'A CI7GALJGFG 1977 P~IGLTt' A 'I'0f.3000Cts
X CG?A AF~C~JO~L1
1282 HtJL~ATA2A282 a~CA CUGAIJGAG X CAA PI~OOC~JC1978 GACL~T C 'IC~CAAOC3C
1300 HC3~.TA2A283 UfXCUGAL7~,G X C73AA PL30C'C~1C111979 'IGIC3C3CCT
C 'IAC~F.
1302 F~L~,2A 284 aC<AJ~AG CUG9LJ~G X QUA 1980 2C~OCCI~r A
AC~OOOCA C~OC
1305 HtR~ITA2A285 C~OCt7tJG CL7r~i)GAG X 1981 CC'ICTAL'r A
CQ~A P~ CAAC~ClI'~
1321 Ht~ATA2P.286 Q3~JCT CT7GAL7G~G X CIA 1982 CACAA7.~T T
ACAUt~'~JG AACF030C
1322 FI~M~2Pv 287 Up3CCtJ~T CUGAL7GpG X CZ7AFr1983 PCAA'~IT A PL~OOOC'A
AAC3~J
1354 HC~.TA2P.288 CGFQJCUG CUr~IJC~G X OC~A 1984 GAP~3~~,T C
AL7CX~COC7C CPC~L'i~
1361 HClr~2A 289 CSC CIJG~TJC,AG X CC~A 1985 'ICCPGFL'r C
AC~7L~3~ a~1AC00G
1377 HC~ATA2A 290 AGUt~AJG CUGAUGAG X OC~A 1986 GAFGA2GT C CAACAFGr
P1~L~Tx7C
1386 HI.~2p, 291 LJC~AJCT7(7G CUC,ALK~FG 1987 C~PCA~T C CAFC~AC~.
X CVAF. PLUJC4JtJG
1416 Fop. 292 C~CUCCUCG CZ7G~G X CGAA 1988 C~AGIC~.T T
PDC~ ~AOQ~DC
1417 HIM~2A 293 1~OC~LTJC C.T7C~G X OQ~Fi 1989 C~CIT C C~OGF~CT
AAOCAGUC
1428 HId~~.2p,294 t~Jt7U CtX~IJC~G X CC~A 1990 OGFDCTGT C AAAG~~a
PG9C~CTJCC
1449 2A 295 PL3000GALT CLOG X CGAA 1991 aC~AGr C All."~ONLT
PGZAJ~OC
1452 HC~P~2A 296 UGAA033G ~IJGFG X O~A AI~~L,TxJC1992 C~FGI~.T C CC~
1458 H<~2P, 297 CUOCAGTJG C<JGAIJ~G X C;.~A1993 AT0.'~CCCT T
AOOC~O~IJ C~3CPG
1459 F2P, 298 C~.ZJOCACU CiJGAL~G X C0~1A1994 T.xCCCIT C PGI17C~OC
AA~300G~.
1493 WP, 299 C~JC~CCC'A CtK~L7GAG X 1995 2~30CACCT A
CAF. PO~JOOCA 'IUf300CF~
1504 HI~,2A 300 AAOOC30C~ CUr~GPG X OGAA 1996 ~LCT C C03CC~'IT
AC3QJC300C
1512 fB~2A 301 P~CUG CL~JGFG X ~ PL~3000G1997 OCOOCCCT T CFOCC~C:T
1513 HCa2~.TA2A302 C~1~'33zJ Ci~G X OC~A AAOC3003G1998 CCOCCCIT C POCCACIC
1521 HI;~,2A 303 UC~JC~C03 COGALJGFG X CL~A1999 CAOCCPLT C Cue.
P~O~JG
1531 F~d~2P, 304 C~C~G C<JC~AG X C~1A AIJ~Jf~JOC2000 (3G~1C~AT C
CIL3COCFC
1541 F2A 305 0300C~JC~ CL~~TJGFG X CC~1A2001 ZG~ C CGA000.'L~
~OOCA
1552 F~2A 306 C~30GUG CLOG X CC~A AI~3CdOCGtJ2002 ALX~'CC~.T C
CPL~CeIC
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63
Table III. Hammerhead ribozymes targeting GATA transcription factors ( l, 2,
3, :~, and
6) and the complementary sequences
1550 HtmrATA2A307 ~ c~cur~c ctx~c x ccaA 2ao3 cr~c~cr c ~cc
~~oc
1563 HUN~ATA2A308 ~flOCL~ CLJGFi~ X CGAA 2004 CCCLICK.T C C~CIC:'
PL3G~G
1570 HUI~ATA2A309 CCGAAC~'~1 CLOG X CuAA 2005 T'~PGC~.T C ~3G
PL30CL~A
1572 HtJI~ATA2P.310 C~GCC~AFG CVGAL1GAG X ~A 2006 CAOCCICr C CTIC.C~GCC
PGpI~CUG
1575 HCll~T3~TA2Aall ~C~G CUGALX~G X CGAA PL3:~G2007 ~','I' T Ct~3CCACC
1576 Fit~~TP,2A312 QOC~CC CtJGALJ~G X CuAA 2008 C'I'C1~CTT C
AAO;~FC~1G ~CAC~CC
1593 HCn~A~2A313 CCAUOCUG CUGAITC,FG X ~A 2009 CCACCCGT C CAOCA'1~3G
AG~3G(JC~
1617 HUh~AT.A2A314 COQJC7CL~ CLX~LJGaG X ~A 2010 CAT33C3Gr A 03;~AACpG
ACCLCAIJG
1634 HCaT~.TA2A315 ~CUC CUGALx~FG X CG~F. 2011 ACC~GACtsT C
AO~JCIOC~J G~1C~ACC~
1649 Ht~ATA2A316 CAWCO~ CUGAL'GFG X CGAA 2012 C~~OCPLT C C~3G~G
PQJ00.~
1673 HI~T~F.TA2A317 ~JO~J CWALJGFG X CGAA AOD~JfJG2013 CAAACCCr T ALSO
1674 Ht~ATA2P.318 tJ030.'LK3G CC~AUG?G X 2014 AAAGCC'IT A COCA
WAA AF~G~JfJC1
1687 HC~ATA2A319 C~~X703~1 X C1~A AIX~CUC~3G2015 CCCP~T T 1~CC~1AC
1688 F~2A 320 OC;ZJWO~ CWAL7GpG X Q~F. 2016 CCpDCATT T 0.'~CGAPLC
AAUOCUC~
1689 HUN~2P, 321 03~G CLJGAL7C~AG X AAA 2017 C~.TTT C CCC~ACC~
AAAWCUG
1708 HL~2A 322 clCt7C~CAG C~AUGpG X OGAF.2018 P~CCAGT C CIL3C~
PL~X3QJC~J
1724 HGtTATA2A323 C~.T7GOOCC eLGAIJGF~ X 2019 CLQ300Cr C 03WCFC3C
CAA PC~OD3G
1740 HC~ATA2A324 CUCCAC3GA C~~IJGAG X O~A 2020 CRLCCCCr C 'ICCTdC~G
PL3f33aC~7G
1742 HC~A2~,2A325 Ci~.TJCCFG ~ X CGAA P~~3G 2021 CC~ C CIC~
1775 HC~ATA2A326 LW1C~(T Ct~PG X QUA PLL7GCUOG2022 CCAOCP~T T Ai.'i~I~A
1776 HI~.TP,2A327 AIJUCACPG C~,G X CGAA AACU3CUG2023 CAOCAGlT A CI~'iGAAT
1787 HI.ll~T,ATA2p,328 ~G3G CtJC~AL7C~G X QUA 2024 G'~A7I~T T CO~OOG
PCAIJ~C
1788 Fi~l~.2A329 0~3G CL~L1GAG X ~'~F. AAC9I3UC~12025 ZC~A2GIT C CCCACCW
1810 Hf.~2A 330 CAOC~JO~ cZJC~FG X a.~A 2026 ~CLT C COCG1CCIG
PflOCPDCx ~
1838 I-~A~2P,331 ACJC3CAG~ C~AUGpG X CGAA 2027 GG~pOGT T TCCI~AT
ACGLCPGC
1839 Ht~ATA2A332 CALJC~CPDG CZ~IJGF~ X QUA 2028 GPO~GIT T CCInCP.TG
A~CK'.~C
1840 FB.fi~F,TA2A333 CCAIJOCAG C(JGALJCFG X 2029 'Ir3C~TIT C C'IT3CA'~
CI~Fa AAAO~A
1854 Htd~~TA2p,334 CWCAAAC CL~IJGpG X CGAA 2030 'IC3C'~ACl~Gr
PLEA T GtTIC~GAG
1857 Htd~ATA2A335 C~7t7CT~CA CLIGp.UGaG X 2031 P~G~IGT T '~C~AAC
QUA PC.'9AC~1
1858 FAA 336 L~C~JCTJCC CT~G X ~Fa AFCP~PLZ7G2032 CAG1~C~'!T T
aC~GAACA
1879 Ht~TA2A 337 UL~L~1 CMG X CAA AC~JtJC~~C2033 OGFL~ALT T 'I~G'~
1880 HI~2A 338 Q~C1 CL7C~G X AAA AFGC7pCJGt7C2034 G:9CAACIT T A1G'~G
1881 HCE~.TA2A339 LJWCT~r CMG X OG~1F. AAFGWC~J2035 P~C~ACrIT A 'IG~
1885 HI~2P, 340 QC~ X Q~F, pCAL~G 2036 CI~TATGT A GFGAAAAG
1923 HI~2A 341 QX~AA Ci~G X Q~IA .AtJ0~3C2037 OC~ACCAT T 'I'I'~AG
1924 F~T,~2P,342 ~J(JCL~A CLOG X ~F. AAUGGZRJG2038 C~AL~'ATr T TI~GAFC3G
1925 HC~~ATA2A343 L7CGWCig1 CUGAt)GF~ X Q,;F1A2039 AACCATiT T 'IPGAFaC~A
AAAtJO~tT
1926 HC~2p, 344 UUCCinXZJ C~J~PG X OC~A 2040 PLCATIZT T PGAAO
AAAAZJOCU CAA
1927 F~.P, 345 WtJCCUJC CMG X 0~1A AAAAAVOG2041 QATTTIT A GApO~AF.
1942 HC8~:~2A346 WWf3CC.ZJ CTJGAUGpG X CAF.2042 AAAM3GAT T P~3CAAAA
AWCWUIJ
1943 Ht~ATA2A347 WUWt3CC Ct~IG X QG~F. AAWCt7W2043 AAPDGATr A a3CAAAAA
1953 Ht~2P, 348 AAAI7AAAL1 CMG X CAA AWUIJWC2044 O:~AAAAT A ATITATTT
1956 Ht~T~TA2P,349 OCAAAAL~ CL7G~L1GPG X CAA 2045 AAAATAAT T 'TATIT~C
AIJt~,LJ~J
1957 Ht~.TA2A350 PL3CAAAAL1 CtX~IJC'~G X 2046 AAATAATr T ATITIL~T
CVAA AAt7t~IJUtJ
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64
Table III. Hammerhead ribozymes tarjetino GATA transcription factors (1, 2, 3,
4, and
6) and the complementary sequences
1958 hT~TA2A 351 GAC3CAAHA CL7GATJC~G X 2047 AATAATIT A TITIC3CIC
O~ PAA1;JUAW
1960 HC1~ATA2A352 rlaGF~CAA CZ7GAI~FG X CVAA2048 'P4ATITAT T TIt3CIC.Tr
ACTA.~ALJUA
1961 Hc~TA2P. 353 CApc~OCA CUGALJGpG x o~A 2049 AATTTATTI' T
AAI~AAW 'lr3CIC.'IZG
1962 H(R~.TA2A354 ACAF~AOC CLGAIJGPG X ~A 2050 AZTIP~TIT T pCI~T7~;GT
AAAUAAAI7
1966 Ht.IN~ATA2P.355 nGAAACAt. CUC~IUt~G X CZ;AA2051 ATTITC3Cr C TIGTI'~'I'
FflCAAAAL1
1968 Htll~.TA2A356 (~PC~AAC CTJG~G X QUA AG~3CAAA2052 TI'Ir3CIC.T T
GITTCTAA
1971 HUM~ATA2P.357 UUC~C'~GA CiJGALJC'~AG 2053 OC'ICl'I~f T
X C~1A P~AGF~ 1~.'~ACP~.
1972 HUhhATA2P.358 CT~G CL~GAZTGFG X CCAA 2054 CrCrPGIT T CT~CAAG
AACAAC~G
1973 Ht~'IA2A 359 CG~ CZ~At~ X OGAA AAACAPC~.2055 ~GITP C 'fAACAFL3G
1975 HId~ATA2P.360 PDC~T CLGALJGF~ X Cz;AA 2056 'I'I~TI'IC.T
PC~A~A A AC~FaOCP
1984 H(7~F,TA2A'361 C C(X~I7GFG X ~A PDG~J 2057 AC~OCT T OGAAACIT
1992 Ht~2P, 362 ~~C CUGALJC~G X OGAA PL~~~2058 'I~GAAACT T C~IDGPCT
1999 c~E~TA2A 363 AL~OCtK~. CL~AIJGFG X CL',T.A2059 TIC~IC3GT C 'I~FGC~AT
AGC~L~CAA
2006 HCll~F.TA2A364 PL~JC33GA CLJGALTGnG X 2060 T"It''~OCr A
QUA .~13C(~GA T~CAAGI'
2008 Fop, 365 PGAC<JLX~ CLJG~LI~G X (AAA2061 ZGFL3CTAT C Q~IC.T
AL~GCUC~
2015 HUI~ATA2A366 GAACCC~ CL~AIJC~G X AAA 2062 'I~0.~,PGr C
PGWOOGA 'ICOOGI'It:
2017 F~ATA2A 367 AAGAACLG CL~IJ~G X (AAA 2063 CCAFGICT C ~GFICTr
PCFGZ7UC3G
2022 Ht~TA2A 368 C~~L~AFG X CC~A AL~AGA 2064 ~3GP T CT'It!C'It3s
2023 HUM~TA2A 369 C~GF~A CL7GAIJGAG X CG~P. 2065 CI~GIT C TIt~3G
AAOCC~G
2025 HI~ATA2P.370 UCC~AC~ CT~F~ X OC~1A PGAAOOOG2066 CL3GITCI' T CC.'m~P.
2026 HL7~A'LA2A371 AIJCC~FG CUGAIJC~G X ~A 2067 OOGI~C..'IT C
A~P~C~v C'ICC~3GAT
2029 HUB' 2A 372 CCAALTCCC C<JGALJGAG X 2068 TIC.TI~Cr C QOC~1TIL~G
~1A PD,~AFL~Fa
2035 F2P. 373 CALZCOGC CT7GAUGAG X Ct'~F.2069 CZt~G~~1T T C3GQ3C~'iC
AUCC~G
2043 HI~TA2A 374 OGCAACZJG CiI~UGFG X CGAA 2070' 'IC3C~3GGT C
PL0.~CC~ CAChI~30C
2048 H(7~TA2A 375 C~CCCUGGC CUGAZJ~G X CGAA 2071 C3GPCCAL'r T
PL~JGGaLC C3CC~C
2058 H(~TA2A 376 UGCL~CCA GiG X CGAA PC~C~ 2072 OCAO3GCr C 'iC.30000C~
2070 HtB~T~.TA2A377 UCH CUr,~AIJGFG X QG~A 2073 C~OGCAGAT T Tu~In03GF.
AL~CCC
2071 HC~F.TA2P.378 C~CAC CLI~t)C,FG X 0.~AF. 2074 c~C~GA2T T GT33GGAC
APl7Ci~OC
2082 HId~.2P~ ~ UGCFt30GtJ CIJCAUC~G X 2075 dOGGACCT C PDOC'It~
379 AAA PDC~~~C
2095 fB~.~2A 380 C~OG~AA CZJC~TIGAG X Q~1A 2076 'IC3CAG'CX.T
F100GUOCA C TIt'ICCTC
2097 F~P~'A2A 381 CFL~3,7AG CT~G X d~A .'oGGA00aJG2077 CAfJCT~C.T T
CTr7CIC.'I'G
2098 HI7L~:hA2A382 aC~ QJGAIJGAG X 0.~. P~FGAOOQJ2078 pLC~IC'IT C TCCIC~G
2100 F~T~2P, 383 P~OCAC~1G CUGAIJGAG X CGAA2079 C~~C.TItT C C~CT
PGAAC~G
2103 F~d~2P. 384 ~CC'A CMG X QUA AOG~AFG 2080 CTIr'ICC.T C
'ID3L'PIC~
2109 F2P. 385 AGAC~OOG CZJGAt7GFG X ~ 2081 CrCTnGCT T CCCTCIC.T
P(30CFGAG
2110 HI.~.2A 386 CA~GAOG CUC~T~AG X CGAA 2082 'I~OGCIT C CCICZCZG
AAOCCAGA
2114 HI~ATA2A 387 AI~C,A CtJC~C7GFG X OC'~A 2083 C3L'I~OLT C 'Itr'1~
Pl3GGAAOC
2116 HC~ATA2A 388 CL~JUUL'~. C~PG X CX'~P. 2084 TIC.''CCIC.T
PGAGOGAA C ZC~AATPG
2123 HCE~.TA2A389 PGtlIJC03C CLOG X O~A AUUUC~.2085 ~AAT A C3C'CCF~1~GT
2132 H' 390 CL~OCCUG CUC~L7GAG X AAA 2086 aC~ C CPLa3CIC~
PC~LJU~
2193 HIH~~TA2A391 O3CCttJrA C:L7GAIJGAG X 2087 'IC~CC1C3CT T
OGZ1A PC3CP~C1C1~1 'It;aGnOCC
2194 HI~.TA2A 392 UGGCCQIC C~L7GFG X AAA 2088 C3CCCI~3CIT T
AFC~~30C GAOOGOCA
2225 FiC8~2A 393 OCG0~1 CL1GAL7GFG X CC~A 2089 SAT C PDT
AWC~TJC
2235 HiU~2P. 394 UCCUC~PG C<JGA~AG X CC~. 2090 0."l~3COGr C
AG'CL~003s CIC~O~.
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WO 00/61729 PCT/US00/09721
Table III. Hammerhead ribozymes targeting GATA transcription factors (l, 2, 3,
:~, and
6) and the complementary sequences
2246 HUr~2A 395 CGAOCZJCG C(JGALJGFG X 2091 C~CFI3GAAT T Ci,~I3GTC~,
Q~AA AIJCK~3C
2247 ~ 396 CL~~3CZJC CUGAL1GAG X CGAA2092 CAOGAA2T C C~GTVL3G
AADUCCUG
2253 HC1~ATA2P.397 PL30~C Ct~AG X CGAA PDCUCVAA2093 TIC~AOCT C O.GIACGCI'
2257 HCR~ATA2A398 WOCA03G CUGAIJGAG X CGAR 2094 AGCI~T A CCG'I~A
ACCGFC3CU
2271 HC~~ATA2A399 03CCiJGOG CL~AL~G X CG?~A 2095 CAACAGAT T C~x
AIJCUGtJUG
2272 Ht~~FiTA2P.400 IJO3CGUOG CUGAZJGAG X Q~F.2096 AACF~C,ATr C C'Cpa0CC~1
AALJCf~JtJ
2290 HC~2'~.T.~.2A401 CppCCUGtI CUGAIJGFG X C'~A2097 03C117GGT C ACFDGAFG
PLL~OCC
2309 HUN~F.TA2P.402 WCAAGpA CTJGAUGFG X CuAA 2098 AACAACAT T TI~TIC~F.
AiJGUtJ~fJ
2310 F~ATA2A 403 LCL~IJGAG X dC~IA AAL~T 2099 ACAACATr T TCTIC~AA
23ll Ht)f~F.TA2A404 CUtnJCAPG CCJGALJr=FG X 2100 CAACATTT T CrIr;AAF~G
~A AP~FT~J(JG
2312 HI~F.TA2A405 CCUUUCAA Cv~t7C~G X CX~A 2101 AACATI~T C T1~P.1~
AAAAI~Jt1
2314 F~A~2A 406 C~TJfJUC CS~AZaGFG X CuAA 2102 CATIfiTC.T T GAAPL~03G
PG~AAAIJG
2329 F~~ATAlA407 GAL7Ci~ C~JGF~G X ~ P~JCC 2103 OGAAAOGr T
2330 HL~'A2P.408 OGAT.)C<JC3G C~ADGFG X 2104 GAAALGTr T CCFGAZCJC
Ct~A AF~JtJC
2331 H(~TA2A 409 PG~ALJCUG CTJGAI)C~G X 2105 AAAL~'ITT C CPC~.ZCCT
CuAA AAFLC~tJ
2337 HI~F.W2P.410 PL~OC~PG CUI~UGAG X CGAA 2106 TI~CCAGAT C CIG'TC~CT
Al:
2342 HUI~ATA2A411 c~CAAPL~ CTJG~LJGAG X CLAP.2107 C,A'ICCIGT C CCIfiIC30C
ACPOGAUC
2346 HC~ATA2A412 CAAAGCC~1 CIJGAUC~G X CC~1A2108 C~L~.T T T33CITIG
P~3GFL~G
2347 HC~P~TA2A413 L1CF1AFDCC CZJGAUGpG X 2109 T~LCCCTr T 03GTT~.
CGAA AP~3GPL~
2352 F~.~A~2P.414 WOLF. CUGAL7C~G X O~A PL~CCAAFG2ll0 CfiI~3GCT T
'It;~3CC7G
2353 HIP. 415 LJ~3C!Ci7C CTJC~G X CGAA 2111 TTIL'3GCTT T GAGGCQ~1
AFflL~Q3AA
2379 HIQ~ATA2A416 C~AAGOG GL~G X QUA AC~7C 2112 C~AG'I~IZ;T C
C~CTITPC
2384 HI~TA2A 417 O~ GAG X Q~Fr PL~GAC~.. 2113 'tt;'rCCCLT T
'~ACrGpDC
2385 F~T.~ATA2P.418 03CtJC~J CTJGAt~PG X ~, 2114 GI~CCCIT T ACIGFOOG
A~p33~C
2386 HC~,ATA2A419 C3~~JCFG CL7GAUGFG X CQ~A 2115 'ICOCCI'IT A CTGM3CaC
AAA.
2408 HC~r.~TA2P.420 CLZJGPGAF. CtG X o~lA PC~DC~C.ZJG2116 CAGCC'I~T C T
2410 FiA 421 CAOCiJC;pG CUGAIJ~G X GSA 2117 aCCIG2~T T C'I~GIG
P~3C
2411 HIaT~ATA2A422 CC~LCUGA CLOG X CAA AF~G 2118 CC'It;ICIT C TCFGGIC~
2413 F~.E~2A 423 ~OLV CUGpiIG~IG X QUA PC~AGACA2119 ZGIC.'I~T C PC~GIt~FC
2428 HUN~2P. 424 GAL1L~IJfJ CL7GAt~G X CG~F.2120 PLOCA1GT A AA~C
PC~LIOD~J
2432 HI.~2A 425 AAAOQ~UC CtJGAL7GFG X CAF.2121 ATGTAAAT A C~CITl'
AI7t~~~CAIJ
2436 F.2P. 426 PC~AAAAG QJGAL~.~G X CGAA 2122 AAA'I~.T C CTTTIZCT
AL~T~I7W
2439 Fi~;~2A ' 427 AOCAGAAA C1~G X CC~~A Pte.21?3 TAC~?.2C~!' T
TIT<.'IC3L'T
2440 FAA 428 L~L3~. C~ X 0.,F~A AAOGAUCLT2124 P~ATLCIT T Ti~'LC~CTA
2441 F~2A 429 UI1~OCAC~. CL7GAI~G X ~A. 2125 GATLCTIT T ~CTAA
AA~3C~TJC
2442 HtJL~ATA2A430 C~C~3CpG CLJGALJGAG X CGAA2126 ATtJCTITr T C'IC3CTAF~C
AAAAf~I1
2443 Hta~ATA2A431 OGiJC~OCA CVGAIJGAG X Q~F.2127 'ICCTITiT C 'It3CIAA0C
AAAAFL~A
2448 Ht~TA2A 432 t7G~A0GC~J CUGAU~G X OGAA 2128 T~C.'IC~CT A PLLC'hl~.
POCAGAAA
2454 HI~ATA2A433 UOOOC~Jt7G Ct~ X QUA PD3GtJ(~G2129 CTAACXXT T CAACC17C'A
2455 HI1~2A 434 Ct~3C~JtJ CZJGAL7G~G X 2130 TA~~LCG'IT C AALJLCCpG
CZ;AF. APO
2474 HC~2A 435 CCAG~G CT~G X CG~F. P~DOC 2131 03CIG~T C CTGACIt3G
2485 F2P. 436 C~ACCUC~1 C~1L~G X CGBA 2132 C,ACIC3C~T C TC~L3GIC.C
PDOC~JC
2487 HI~2A 437 CUOGACCTT CtJC~~IIGAG X 2133 C'It33GTCT C PEG
CGAA 1~0~G
2492 FiC~2P. 438 AAF~JG CL1GAL7GFG X ~. 2134 'IC.'I~GGr C C~C~'IT
P~GA
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66
Table III. Hammerhead ribozymes targeting GATA transcription factors (l, 2, 3,
4, and
6) and the complementary sequences
2499-~~~ 439 CCAC~1 CUGAIJGaG X CG~A 2135 'I~CFGACP T 'L~IGIn;,
PL~.JCUO;,p.
2500 hL'L~ATA2P.440 C~pG~IG(1 CGGPZ1C~G X ~1 2136 CCI~GAf~'IT T
APC~KLT3G AGTGTa3C
2501 HULK~.TA2A441 PL~~ CUGALJGAG X CG?~A 2137 CFC~~GTZT A CTGIr~Cr
AAPL~.ZJG
2516 F~ATA2A 442 L7CX3G;,AAG CUGAIR;~G X 2138 CIG~3GAT C CrICCCAA
AAA AIJCCACFG
2519 ~TA2A 443 AC!Ct7(JC~ CtTGALJGF~ X 2139 TC3C,ATC<.'f
OGAP. PL~ALJCCA T C~CQ~3Gr
2520 HC~F,TA2A444 (IACCtJCJC~ CZJGAC~G X 2140 C3GA'I~CTP C
O:~F. AFC3:~AC7CC CCAAC3sTA
2528 HC1~TA2p,445 LTACpOCZJG CZ~AZ~AG X AAA 2141 CCCAAC~T A CAOCTGTA
AL~LJ~
2536 HL~TF,TA2A446 CC~L~ CL7GAL7GAG X OGaA 2142 ACpflCIGT A '~ATAAAOG
AC~OCOCZJ
2538 FTA2A 447 CA~UUC1A QJGAL~ X CunA 2143 AC3CIGTAT A TAAAOGIG
ALZ~CU
2540 Ht~ATA2P,448 C~CACGUU CZJGAIJGFG X O.~AP.2144 CIGIATAT A AACtsIt;IC
At7AL~C~G
2548 HC~T~F.TA2A449 A~TJCX~ CL~G~G X ~Ap, p,CA~J2145 AAA~T C C~OCIT
2556 HC~T~TA2p,450 CpGAACTCiT Ct~TJGnG X ~F. 2146 CCCGAOCr T PC~~TICIG
Al3CCI~C~G
2557 F~ATA2p, 451 ACPC~AZJC ~F~GF~ X QUA 2147 COGp~CIT A GA2~
APDCIJ03G
2561 FiC~ATA2A452 OCAL~G CL~C''~FG X CJ~A 2148 OCITpC~:T T C'IGI'A2GC
ALICi~AOC
2562 Fi~.'IA2A453 ~CF~LE~cA CZJGAL7GFG X 2149 CT~AC,A2T C ~TAZT330G
O~A AAUCT~PG
2566 HC~T~ATA2A454 L7CACC'~. CL7C~At7GFG X 2150 GATIC.'IGT A
AAA ACAGAAUC TC303GIGA
H9GATA3R 455 O3GAL703G QJGAUGFG X CAA. 2151 CCCF~CCT T CCCATCCC
P~3CLJGC~
11 H9GATA3R 456 030GAIJOG CV~FG X C1~A 2152 CCF~L3CC'IT C
AP03COOG CCATCCCC
16 H~P3R 457 ~33G CUGAIJGAG X CVAA ALx.~3:~AFG2153 CIZC7CCAT C CCCLCAC~
35 HS~ATA3R 458 CGO~AALJ C~JC~IJGAG X Cx;AF.2154 AAOCAAAT C ATIt~A~
AvUUC3CUU
38 H9C,A~S3R459 aGtJ~fJUG CU~G X CL~ AL~JI7UG2155 GAAA~.T T CAAO~C
39 H9GATA3R 460 C~O~JO~IJ CUGALJGaG X 0.3AA2L56 AAA2C'ATr C APDG~GCC
AAL7GAIAxJ
56 Fi9GATA3R461 t7C~~ CTJGALJGPG X QUA 2157 CC~C.1.T C CGi~
PD0~3
80 H9GATA3R 462 CC<3CCt70G CZ~G X CuAA 2158 ACT C ~003G
PL3~
97 F~F,TA3R 463 030G:~G C(JGAI~~G X Q~P. 2L59 AC~CCLT T CSC
PL~33Q~1
98 H9GATA3R 464 Q~30GAOG CTJGAUGaG X Q~1A 2160 CCO~CIT C ~~
. AA03000G
102 HSGA?'A3R465 03~OG (:tJGALJ~G X CG~F. 2161 CCITOCCr C ~Cl~
PL33GA~3G
114 FL9C~ATA3R466 C~000.'~03G CZ~JGaG X 0,7AA2162 OCZ30.33GT T
ALO~C C~300NC
115 HS~ATA3R 467 Q~CCCG CZ7GAi~ X 0.A AACX~2163 COOmGIT C ~~
208 H9GATA3R 468 Lx~~C1 C1JGAU~G X CL~Fa 2164 C~Cr C ACA
POCA~C
244 HER 469 C~C~OQJ ~G X QG~A PDOCCOC~2165 ~CLT C AOOCAL'1~
252 H9G:ATA3R470 OC~G C~ALJGpG X CuAA PL~JOOQ7G2166 CF~OC~GT C CMG
255 H9GATp3R 471 aC~JOCAtJG CL7GALJGFG X 2167 Q~C.'rOCr A CA'I~OG
CC~A AOG~
273 I~TA3R 472 aC~G CZ~T~G X O~A PLLX~CGCC2168 03mC.~I' A C~3CIC3C
301 H~3R 473 ALX~AA CLJG~tJC~G X CVAA 2169 c~.TGTOCT T 'TT'~.ACAT
PDCACF1L7C
302 FAR 474 GALA Ct~AUGFG X O~F. AAOCACAIJ2170 A'IGPOCTP T T~AC~C
303 H9GA~3R 475 aGZJGAUGAG X QUA AAAOQ~CA 2171 TGn3CTIT T '~AP~CA2~G
304 H9C~TA3R 476 L7CGAZ~JU CiJGAZ~G X CG~Pa2172 G'IC~CITIT T
AAAAOCAC AFCA~.
305 fLS~ATA3R477 C~JO~~I~1 CL7GAL~G X G;AA 2173 'IC~CTITIT A
AAAAFL3CA ACAT~AC
310 FiS~ATA3R478 LIGpLCC~ CTJGAIX~G X ~1A 2174 TITAAC~T C GAOOGn~.
AI~AFv
317 H~TA3R 479 C~)UO~J CL7~LJC~G X O~A 2175 TCG~LC3GT C APL~OCAAC
ALA.
331 H9GATA3R 480 L~3GC~ CLJ~~T,JGpG X 0.A 2176 AAL~CAGGT C Q~CTA
PDC~331U
339 H9Gn.TA3R481 UUC~G Ct~ X Ct~P. FOC300D3G2177 CCOOC~GT A CTA00.'~
342 H~.TP3R 482 PI~CCG CZJC~IJGAG X Cu"AA 2178 C~C.OCI~CT A
PC~~033C CO;~IAACr
CA 02364577 2001-10-03
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67
Table III. Hammerhead ribozymes targeting GATA transcription factors ( I, 2,
3, =1, and
6) and the complementary sequences
351 HSCATA3R483 C~JGACC C~T~G X CGAP. 2179 CT~C~AP~GT C
PL~JCnJCCG C~I~PL30G
355 H9GATA3R484 t~.~CU CZTGAI)GFG X CFA 2180 AACILC~I' C
AO:JU P~33~C
375 H9GA'TA3R485 LKX3 ~AOC~.S CUGAIJC~G 2181 O:pC~' A CCCI~CrA
X D~Pa ALLUCtx.~C
380 H9C~ATA3R486 C~7C30~JC~ CLOG X O~A 2182 C3C~'fACCCT
P~t.3r C CCAGC~2C
416 HSt;P.TA3R487 aLJGAFL3CA C(7GAIJGFG 2183 c3C'~CC.'T C
X 0.;AR PaOC~C ZC3~T
421 H9C~.TA3R488 GAUC!CALJG CUGAL7GFG 2184 CCIC.'InCT T
X CVAA AOC~C'~DG CAZt3GATC
422 H9~ATA3R489 C~ALfiCAtJ CUC~LJGpG 2185 CIC.'InCTT C
X QUA APaCpGAG A'Ir33:~C
429 H9C~~.TA3R490 PDO~DG CL~7~G X Q~P. 2186 TC~T3Gp.T C
AL1CCAZJGA CCI'ACC~T
433 H9GATA3R491 ~L3C~G CUGFTJGPG X Q'~A 2187 O~~ A CCL'IC~OCT
PC33CAI~
480 HSGATA3R492 UOCFL300G C(7GALJ~G X 2188 CAC03CC.T C
CZ;~A PL~~ 0.'~CCIC~A
491 H9GATA3R493 QOC13CUGA CVGAUGpG X 2189 CCIC3GAAT C
Cl'~A AUUC~ 'Ir.~L3CCCC
493 HSGATA3R494 AAOa3(~.U GLG X (X~A 2190 'IC33GAA2C.T
PC~UOCA C PL~~LIT
501 Fi9G~.TA3R495 CCiIUOGAG CUGAL7GFG X 2191 CAC3CCCCL'1'
QUA PL300C3CL7G T CICCAAGF.
502 H9GF.TA3R496 C~K.TnJOC~. CL7CALJC~G 2192 POCCCCIT C 'I~1~FGAC
X Q~A AAOOC~TJ
504 H9;~ATA3R497 ACQJC<7~JG CUGAL7~G X 2193 COQTIrT C C~GAC~T
CAA P~GAFL3C~
5L3 H9GATA3R498 D~ ~AUG CiX;AIJr;FG X 2194 CAAC~CJ~T C
QUA AO~ ~C
517 HSrATA3R499 C'L''C~J~JG CUGALJGFG 2195 AOGICCAT C CACCA03G
X Q~A AIJOGAQ~J
528 HS~TA3R 500 OCOCGC~OG CiJC~IL7~G 2196 CC~LC30CT C
X CVAA PL3WC~70G CC'C3003C
541 H9G~A3R 501 L~C,ACOC~. CL7GAtJGpG 2197 aC~.~CCCT C
X C~1A PDOOC3CCC 'IL~'IC.'I~.
543 H9GATPL3R502 003 CUGAUGpG X 0.A AGpI330C3C2198 (3CLCCICT C
~C
547 Fi9C~3R 503 C30033C~ Ct~L7GpG X CT~A2199 C'rCI~~ C 'IrPCCGCCC
A00~~FC~
549 H9G~3R 504 CC133003G CMG X Q~F. 2200 CI~~ A CCC~
PGAOOC~
561 H9GATA3R505 P~10C~AC CTJC~G X CAA 2201 0.~~30CLT C
AOOC~ GICL'PCCT
564 H9GATA3R506 P~GAG CLOG X QUA A~OCC 2202 DOT C CILZ'ICCT
567 H9GATP3R507 Pf~D~G CL7~iLX.~G X ~A 2203 CI~TCCr C CIL~T
PL3;~G
570 R 508 CCGACAAG CZJC~LJGFG X 2204 GDCC~C.T C CTIG'~03
Q'~1F. PC3GAOG~C
573 H9C~ATP3R509 ~(~C CL7~IJC~G X CL~A 2205 CI~.'mGT T ~'It~03G
PaC~G
576 H9C~.3R 510 C30C00.2C CTJGF~1G X 2206 CTCCI~,'r C
0.'A AC~A03AG a30333CC
601 H~.TP3R 511 AAO~A CU~L7t~G X AAA 2207 C~OC~LT C TI~OCTI'
P~CI'~
603 H9CATA3R512 dC~AC3C~ZJG C~L7C~ X 2208 OCFIJCItrT T
Q~A PG~~C~~3C CFCCTICC
604 H~.TA3R 513 03GAAOQJ CLX~G X 0.'~1F~2209 CA~.'IT C POCTI~C
AF~OQJG
609 H9G~.3R 514 nC~000G CL7G9Ur~ X ~1A 2210 GT1~OCT T CL~CC~.
PD~G
610 H9GA'~3R515 CTJ0000~ CT7~L7~1G X 2211 TIC~OCTT C C~~C
f3s4A AFOQJC~A
634 H9GF.TA3R516 i7C~ CTJ~G X 0.A PC)OfR~12212 P~PL3~T C 'Ir7~.
636 H9~3R 517 aC~JCOC~ CT~ALJG~G X 2213 aGA~IC.T C 0.'~3G~
CC~A PG~OC~L~C
648 H9C~.TA3R518 UOG~PDC CC7r~IJC~G X 2214 C3C~AL~.T C
QUA ALJ03C~C aCIGmCA
654 H~3R 519 Ct100C3C~JG CT~G X O~A 22L5 ATOC~~T C CpL:CLI~G
PL~D03pT1
666 H9GA'I~3R520 AO~00~ C'LX~L~G X Cite 2216 0.'~C:~OOCT
P13C~TJ03G C 03CCa0CT
675 Fi9GF.~3R521 C~LCMG X QUA PDNCx30C 2217 OG0.730Cr C
OOCCOO3C
703 HSC~3R 522 UOC~CW CL~LIGAG X 0.F. 2218 GAGIT3CCP C
PL?3CACxJC AFG~OC'A
708 H9~TA3R 523 Q~CC~OG CZ7C~L1GFG X 2219 C~It~AGT A CC~'3GIC3C
C'-AF. P~OG
744 H~ATA3R 524 P~~C CC7r;~TJGPG X O~A 2220 ~GAGr C GI~'CI~CT
ALT~C~flC
747 H9GF.TA3R525 Q3GFL~I7C~ CtIGAT7G~ 2221 O:~T C C~CIO~
X 0.A AOC~70C
753 H9C~R 526 UOC~G CU~I7C~G X a~A 2222 GI~C~:T C C~~
PCTJOOC~C
CA 02364577 2001-10-03
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68
Table III. Hammerhead ribozymes tar~etin' GATA transcription factors ( 1, ?,
3, 4, and
6) and the complementary sequences
786 H9GA'IA3R527 . ~~ ~ X CAA PL30CUCC~. 2223 'IL~L3CCT C CICGIC~F.
789 H9C~,TA3R528 O~GAC Ct~LJGF~ X OGAA PI~OOCTT2224 r~C~CC'ICCT C
GIC~,AG~C
792 HS~A~3R 529 ~GLTC ~ X 0.A A~C~G 2225 CI~CICX,T C GA~CALC
808 H9GAZP3R 530 CP~Gi1 Ci~L7GAG X QUA ALJG03GUG2226. CF~'C~T C ACCACCTA
816 HSGF.TA3R531 A~C~OG CUGAtJGFG X OQ~A 2227 CALCAL>rr A CC~0.'~.'r
PCdG~
825 H9G~,~.3R532 OOOOCFLiG Cite X CK~F, 2228 C~CuCCCr A ~C~
P030~pG
837 H9C,F:I'A3R533 C~GFGCZJG CUGALJC~G X QUA 2229 aL~GAGr A CFGCTL~
ACUCOOOC
843 H9GATA3R 534 PC,FC~1CLG CLIGAL7GFG X 2230 GTA(C WGACrCr
CLEF. PC3CUC~~C
850 F-L9GATA3R535 QOO30GAA C~IJC~G X ~ AC~JCOC~,F.2231 TO~ALT C TI~C~CC
852 FL9C~.2~13R536 UOOOOOGG CLlGAI7GFG X CK~A2232 COGAC'IC.T T
PC~G CCCCC~
853 H9C~TA3R 537 CL7O3GC3~ GUGAI~AG X O~A 2233 OGACICIT C 0.~CCCpG
AFGAGUCC
879 H9GATP3R 538 COC~OG ~ X O~A PG~ 2234. p3C~.T C C~CACCG
891 H9C,ATA3R539 UO~LJCL'~ CT.IGALJC~G X 2235 CALL~OCr T a3GA'I~'A
Q~1A PDCI:'OC~~.
892 H9GA2~.3R540 UCJC3CALJC~ CUGAI~FG X 2236 AC~CIT C C~A2C~CAp,
Q~1A AAOLLC3~J
903 H9GATA3R 541 UOOOCCiJG CTfi~GPG X 0.A 2237 ATCCAPGT C CFL3GCCCA
ACWOCATJ
921 H9C,ATA3R542 C(~CiJG CUGALT~G X CGAA 2238 OGC~T C CAGCACAG
AC!OOGOCG
960 H9GA'I~3R543 C~JC30pc~JC CL~L~G X O~A 2239 C3GCAALL'r C
PL~C7C3CC CAC
996 H9C~~13R 544 UOC~G GLIGAL7~G X 0.F. 2240 ~CPLT A CC1GIDCA
P~CC
1018 F~9GATA3R545 t~7GAL7A CLJGALJGPG X ~A 2241 'It'~~ C '~F.
PDC~~A
1020 Fi9GATA3R546 WtI~JGA CiJ~JC'~PG X CAA 2242 CC3C~C.'IC'r
.~A00."C~ A TC~CAAAA
1022 HS~F.TA3R547 CATJUUUQ1 C<JG~G X Cc~A 2243 C30CIt~lT C AC~AAAZG
AICC
1051 H9GAT.43R548 03CIJt~ALT C<JGAL7GFG X 2244 CGGCC'C~.T C
CGAA PL~3G~G ATrAPaCC
1054 H9GATA3R 549 Ut7C30GCiJU CUGAUGAG X 2245 CCCCI'UAT T AHOC0.'~A
CZ~A AUC~OC~
1055 H9C~1TA3R550 Cpp000CU GT~G X AAA AAL~A0332246 CLCICATr A P~FG
1074 H9GATA3R 551 UC~iX3CA CMG X CGAA AC~G~CT7U2247 AFL~O'~'It;T
C 'I~OCCA
1098 ~TA3R 552 iJCOCA('pG CLOG X CC~A 2248 Pl33GAL.~T C
POC~J00.~J CI~3~
111.2H9Gp.~i3R553 OGUC~C~TT CLJGALJGAG X 2249 CGAACiGT C PGALCACC
OGAA AC~G
1132 Ii~.~P.3R554 CUCCVCCA CMG X O~A PfT7GV03T2250 ALCACAGT C 'IC~OQ~G
1162 F~?.TA3R 555 aCAL~OCA C<JGAZ)GAG X CVAA2251 GA~'~'iGr C 'n3CAAZL~C
AC~OOGUC
1180 H9C~3R 556 ('~. C<JGAI~FG X O~A PL~CCCArA2252 'IGID30Cr C '~L.'~9A
1182 H9C~~TA3R557 OQxX~!G CUGAL)GFG X AAA 2253 TCOC1CICT A C'~OC
PGFL3Ct~'A
L185 H9GF~3R 558 C~A~ Cf~AL~IG X 0.;A A~OC 2254 aCDCI~GT A CAFI3CrIC
. H9C~3R 559 AI~7G CTJGAL~G X OGAA PDCI~r2255 TAC~AC~Cr T CACAA'2'
1192
1193 H9G~R 560 AALmIJt7QT C~L~G X CL~A 2256 ACAAOCTT C AC2F.TATr
AFD~J
1199 F~3R 561 UC~F. CLOG X CAA ALnJ~A 2257 'Z~CAAT A T~AAC~A
1201 Fi9GATA3R562 a7IJ CU~IJGAG X ~A AI~7C~7G2258 ~ T AACAGACC
1202 I-I9GATA3R563 (30~JC~T G~AL7~G X CGAF. 2259 PL~ATA'IT A PC?GPL'CC
PJ
1217 H9C~Tl~3R564 CUUCTJLJC'A Ct~~L~FG X 2260 CCC'IGAGT A TVAAGAPG
a~lF. PL~JCpDGG
1234 Fi9C~.T.~3R565' CL~TJCtJG C~U~ X QUA AL~C.TJUC2261 GAF03CAT C CAGACCFG
1257 :i~TA3R 566 ALnJUC3C0A CUGAIJGFG X 2262 AAAAA'IC~T C
OC~A ~UUCRJ 'TAOCAAAT
1259 Fi9GATA3R567 0~~AiJUUt3C QJGAI~~G X 2263 AAATt;''ICT A
CGAA A~i~IJ C,~AAAT1C
1266 F1~ATA3R 568 ACI7IJIJt7UG CCJGALJC~G 2264 '3CAAAT C CAAAAFGT
X ~ ALnAJC3CC1~
1293 FAR 569 CC.UCCFGU C~F~ X Q~F. P~I33C2265 aCA'~ACr C AL'InGPL~G
1305 H9GF.TA3R570 LJCSJUC303G CCJG~GAG X 2266 C3GFL3GAGT T
CAA PGUC~TJCC CCCCAF~
CA 02364577 2001-10-03
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69
Table III. Hammerhead ribozymes targeting GATA transcription factors (l, 3, 3,
4, and
6) and the complementary sequences
1306 _ H~.TA3R571 WCWGOG CLGAZ~ X Q;_z1A 2257 GAO~CIT C C~C~,pC~lp,
A~L~JCCi7C
1320 H9C~TA3R 572 C~C7L~1AAC CUGAL7C~G X 2268 GAACAOCI' C GTTTAACC
CC'~A FGCiX;IJ(.C
1323 H9Gr~TA3R573 CCOGC~JC1 C:L~LJGFG X OC~~A2269 CAGCIC~T T TA1~~G
ACGAGCUG
1324 fL~T~3R 574 C~Gt7U CLJGAL~G X (A AAOGAC~.U2270 PGCI~GIT T AACC~3C
1325 EL9G~.TA3R575 O3L~G(~T CC~LI~G X ~A Ar~ACC~GC2271 GCPCGTIT A p~Cpp(~
1339 H9Gp.TA3R576 UC~X.TJOGA CVG~LJGpG X 2272 OCCnCLLT C 'ICCAGAC4
~P. PL~~
1341 H~3R 577 UC~7G ~ X AAA PGF~30CG 2273 CGCCCICT C (~GAL~.
1353 H9G:4TA3R578 tJCAGOGFG C(7GALTGAG X 2274 ACACA~T C CICCCIGA
CAF. PL71L~T
1356 H9GATA3R 579 C~CUCpOG CUGAt7GPG X AAA 2275 CA'IC~'i~C.T
PL3~CALJG C CCIGFL3CC
1369 H9GATA3R 580 AA03G~. CUGAIJC~G X CAA 2276 PGCCACAT C 'I~3C~CTT
AtJ~OCU
L371 H~.3R 581 UGAA003C C~AIJGAG X o~A 2277 cC3~~ir.T C c~'CCi~PCA
PGALGUOG
L377 H9Ga.TA3R582 PC~~OCtJG Ct~AIJGAG X CAA 2278 CICX3CCGT T CP~CCAGT
PL~33~
1378 Fi9GA2~13R583 GAC~JOOCU CMG X QUA AF~L30~2279 '1~CCCTT C PC~L~CIr=
1386 Fi9GATA3R584 tJGIJOGCiJG X 0.;P. PL~OGGLJG2280 CAGCC~LT C CAGL~
1428 H9C~.TA3R585 PC~GCUG CUGAL1C~G X ~ AIJOGQ30G. 2281CCC17CC'AT C
CFL3CCIGT
1437 H9GATA3R 586 QJCC~APG CU~G X QUA AC~C3C..ZJG2282 CAGCCIt;T C CTTTOGFC
1440 ~i9G~R 587 G(~CA CC~SJGpG X ~''~P. 2283 CCIGTCCT T 'IT3;~C
P~03
1441 H~A'L~3R 588 U~GUCC CUGAL7GAG X Q~iA 2284 CIIGPQCTf T GG21CCFSCpa
API33GACFG
1458 I~1TA3R 589 CCAL7C3CUG CiJGAIJGAG X 2285 CCA0.2Cr C CAGCAZC~
QUA PO33Q~
1468 H9G~TA3R 590 AIJOO~C7 CLIt~IJGpG X AAA 2286 AGCATGC~T C AL'Q3~T
AOC'ALJOCU
1481 F~1TA3R 591 AGOOCOr.TJ CUC~LJC~G X 2287 ~3;~T T PGPC30CX.'r
QUA PGn~
1482 Fi9GATA3R592 CAOGGCUC CtJGALJr~G X ~"~F.2288 CA'R3GGIT A G~L3CC1~.IG
AACCCAUG
1493 H9GATA3R 593 L7GAOCAL1C CLOG X ~'AF. 2289 C3CbCIC~CP C
AGCAOOOC GAS
1500 H~3R 594 03CC~J C~FTJGHG X 0.A AGE 2290 TZ~Cr C ACpODOL~
1521 H9GATA3R 595 ACI~3CAGG CLOG X ~A AL~OC 2291 a~FGP C CCIC3C~T
1530 H~3R 596 (JCaJAAPaG CUC~IJGAG X 2292 CL'I~3CF~GT C
O.~AA ACTJC3CFI3G CG'rl~~.
1534 FZ~3R 597 CAFaI~ C'~L~FG X ~ PL30G~ 2293 CAGIC.CCT T 'I'UC'~L'I'iG
1535 H9GF.TA3R598 aCAAC~J3 CL7GAL7GFG X O~A 2294 PGrG'~1'1'ZT
AP~GGALTJ T CGACITIC3C
1536 H9C~TA3R 599 LJGCAAQJC Ci~I~FG X QUA 2295 GI'hLLTIT C C~IDC~
AAF~3C~C
1541 HS~R 600 P~AAAAiJGC CTJC~G X 0.A 2296 TTInGPCr T OCP.TTTIT
A~AAA
1546 H8G~3R 601 dCL70CAAA Q~ X QUA AIJOCAAQJ2297 ACI~3CAT T TI'IL3CFL3G
1547 FAR 602 t7LZU3CAA CUC~LJC~G X CG~A2298 CTIt3CATT T TIL3CPl~.
AAUGCAAG
L548 F~.3R 603 CL7~.L~3CA CTX~IJC~G X 2299 T1C3C11TIT T
Q;AA AAAUC~C,9A 'IC3CAO~G
1549 Fi~.TP.3R604 OCZJCCTJGC CL~L~AG X CGAA 2300 TGCA2'iTT T OCF~C~OC
AAAAtiOCA
1561 H9GATP3R 605 Q)U~IJ~. CUGAtJGAG X 0.;A 2301 C~C~Gr A
PL~CL7C~
1563 F~F.TA3R 606 QOCi7~iJ CL7~IJC~G X CG~.F.2302 AGCAGI'AT C A'I~APDT
AL~CTJ
1573 H9G~3R 607 AU0.~O~JCT CLJGAUGAG X 2303 2GAAG30.T A AAmQG:IT
O~A PD3CU~A
L586 H~3R 608 AAAACAL~. CLJ~G X 0.A ATJOCAL7C>s2304 C~ATnGAT A TAZGITIT
1588 F~3R 609 CAAHAACp. CUGAIJC~G X QUA 2305 A'IC~GA~T A 2GTITrIG
AL~1L10~LJ
1592 H9GATA3R 610 0.'~JUC~P~A Ci7~IJC~G X 2306 ATATA'ItsT T
O~F. PL~LZAImtJ TI~AOG
L593 F~3R 611 C~CCWCAP. CLOG X OGAA AAC~GAL~r2307 TATAZC~IT T TIGAAG3C
1594 F~3R 612 UGCCOC1CA Ci7GAIJGAG X 2308 ATA~'I~T T 'I~~AO3CA
CGAA AAFL~I~LJ
1595 ~3R 613 CLx3ocvt~ cu~c~cr~ X a~ 2309 TP.~crrrr T c~poor~
A~tm
1614 F~3R 614 GCAAACAU CUGAL7C,FG X ~ 2310 POCAAAAT T A'IGIZ'It3C
AIAA7t13CU
CA 02364577 2001-10-03
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Table III. Hammerhead ribozymes targeting (BATA transcription factors ( 1,
'_'. 3, 4, and
6j and the complementary sequences
1615 HSrATA3R 6L5 GGCAAAC~, CLX Q~1A AAUUCTtJOC2311 GG~AA2T A 'IGITIr3CC
1619 HSC~.TA.3R616 APC~~CA CGGALK'~FG X ~ 2312 AATFA2C~T T
ACAL~~LJU 'IC~CCpLZT
'i HSGA2~.3R617 ArlAC~3C CVGALTGAG X ~ 2313 A~'hA2GZT T
1620 AACAL~ALT G~GTTT
I HSGATA3R 618 Crin7CTOC'A CUGAI~ X pC~A2314 2'IC~ALT T 'It3~AFDG
1627 p~,~7pC~
I H9Gp,TA3R619 UC~C CLGALR~G X CGAF. 2315 'It3CCACIT T
1628 PPL~3CA GCAAPC3~1
1640 HSGA2~3R 620 ACCACAGU CLIGALJC~G X 2316 APDGAOCT C ACI~T
CGAA PL3CtJCCL)CT
1651 H9Q~~13R 621 GGAACACP. CT~J~G X CGAA 2317 2~IC3GnT C 'It;IGTICC
ACALCACA
1657 H9GATP3R 622 GU0~3 CUGAZ~AG X CAA ACC 2318 GICItJItiT T
CAC
1658 H9GATP3R 623 AGUOGWG CZJG~FG X dJAA 2319 T~TGIT C G~CACT
AACAC~.
1671 HSGATA3R 624 00('~~CCA CZ~FG X QUA 2320 C'~CIGAAT C
AI~QJG '1C~L'L~CC
1682 HSGAT?3R 625 tIAUtJCACA CtJGA~ X CG?~A2321 GrLCCG~T C 'I~It;AATA
AUGGOC~JC
1690 H9GATA3R 626 GAAIJpGCU CvGAUC~G X Q~1A2322 CIG'IGAAT A
AUU~C~ PL3CCATIC
1697 HSGp.TA3R627 CCUGALJGFG X ~A AIJ03CUfg12323 TPrY~CCAT T
CIGACIrA
1698 F~F.TP3R 628 AL7Gr~JC~. LUGALJGpG X 2324 Pr~C3C~ATT C
CT~A AAIJOC~W ZGACIT~T
1704 H~.TA3R 629 GGGG~LTAU CL~FG X CC~A 2325 TI~IGACr C A~~C
P~C,AF.
1707 H9GATP.3R630 At~GC,~. CUGAUGpG X QUA 2326 2~C.'ICAT A
AZ~JCP, TCCCCCI'AT
1709 H9~R 631 AAAL~OC~ CUGAZ7GFG X CAA 2327 PL'IC'ATAT C
AC~TJC~J C~'ATIT
1714 H9GF~.3R 632 CUI~JC~AA Ct7GAUGpG X 2328 TAn~LCP A Tl'1'AAC~G
CG4F. PC~3GAL~.
1716 HS~,Tl~l3R633 CC~ CUGALJGFG X AAA AI~300C~.2329 2CCC~'I~T T
'I~ACPAOG
1717 HS1~.TA3R634 AC'UCi~7IJ CUGALJGFG X 2330 ~C~.'rAZT T
AAA AAI7AOOOG AACAL30Gr
1718 H9C~ATA3R635 GACCCi7QJ CZ~G X O~A AAAL~OOG2331 CL'CTATIT A
AC~~03G1C
1726 H9GATK3R 636 GCPLL~GA CT7C~G X 0.F. 2332 AACPO3GP C 2C.'L~GZC3C
AL2~~JCT
1728 H9GATA3R 637 CAOCALLTP. CL1GAL7GAG 2333 CPL~GICI' C
X AAA PL~LOCtJG '~CIG
1730 H~JGATA3R638 C~3CAC ~ X ~A PL~GACOC 2334 03~ A GIl'3C'IG'IG
1751 Et~R 639 AL~AJ~G C<7GAL7GFG X OGAA2335 AAAAAAAT C CIGAPLP.T
AUUUC7f1t7tT
1760 H9GF.TA3R640 UC~L~J:JOC C:L~LJGAG X 2336 Cit;AAC~.T T
CAA ALIC~iICIC~G GCATATP~.
1765 H9GATA3R 641 Ai~t~. Ct~G X CGAA AIx3CAAUG2337 CATInCAT A TAPCITAT
1767 HSGA'I~R 642 ALI~AGU ~G X QUA ALI~CAA 2338 TIC3Cp.TAT A
ACI'rATAT
1771 H9C~1TA3R643 tI~AtIP,iT CL~L~AG X 0.A 2339 A'~TAACr T ATATI~
PGUC1AL~1J
1772 H9GATA3R 644 L~ALB~ C~7~G X AAA AF~LA 2340 TATAACIT A TAT1~A
1774 H9GD.TA3R645 UCi~F1 C~7GAU~G X QUA 2341 'PAPCITAT A
AL~AGC7~ 'I~GI~r
1776 Fi9~R 646 LC~AUC~G X ~Fa AI~i~FQJ 2342 ACITATAT T G~AAGAAA
1779 FL~3R ' 647 C~I~WUCU C<JGAI~FG X AAA 2343 TATATIGT A PL~AA~C
ACAAI;~
1786 H9Gp.TA3R648 LAG CT~ADC~G X QUA P 2344 TAPL~AF~T A
CTGW
1791 H~.TA3R 649 A~7t7G ~G X CAA AC~txJ 2345 AATACIt;T A
C~ATC~L.T
1800 H9GATA3R 650 ACJC~CAAi~r CLJGAIJC~G 2346 CAAZGAGT T 'I'ATl'GCAT
X QUA P~
1801 H9GATA3R 651 GAC1C~CAALT CUGALJGpG 2347 AA'It~CIT T
X AAA AF~J ATIt3CATC
1802 H9Gn.TA3R.652 AGAUGCAA CUGAIJGpG X QUA 2348 A'I~L.'I~T A
AAAGUCALI '~IL~CA2CT
1804 H9G~'A3R 653 CC~AL70C CtJGAL7GaG X 2349 C~LTI'ITAT T
a.~AF. AL~;AFQJC GCATCtDG
1809 H~3R 654 C~~1CCCA CLX~G X Q~AA 2350 '1'P.T1C~CAT
AUGCAAIm C 2C33GI~L3C
1815 Fi9GATA3R655 CTJ~CpL3C CUGAUGpG X CGAF.2351 AT~IGr~ A C~.T"T~~G
PLxCpGALI
1821 H9~R 656 UCPJJOCX,U CUGAZ7GAG X 2352 GPAC3C'I~T A
~A PL:~OCi~C PDGCA'IGA
1845 H9C~ATA3R657 AUUOCtnIA C<JGAL~ X ~ 2353 CAPGAAGr T '1'AAC~GAAT
PLVUCUUG
1846 H9~~TA3R 658 UAtJUCCW CL~IJGFG X O~A 2354 AFGAAGIT T AF~GAATA
AFLT7~W
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71
Table III. Hammerhead ribozymes targeting GATA transcription factors (I, 2, 3,
4, and
6) and the complementary sequences
1847 H9GATA3R 659 AL1AL7(JC'CZJ CLJGALJC~G 2355 PC,AAGhIT A PL1GAF.TAT
X AAA AAACUUCU
1854 HSGATA3R 660 ' UUCUCCCA COGAG'C,FG X 2356 'PA?C~AAT A ~3~FGAA
AAA AUC~CUCL4
1865 H9C~TA3R 661 UUCCACAC CLIGAUGAG X O~A 2357 CGFC~AAT A ~
AUt7G~L7CC
1876 H~GATA3R 662 WCUUGW CVGAtJGFG X CGAA 2358 GTt3GAAAT T APGAAGAP.
AUtiUCCAC
1877 H9C,A'IP3R663 CUGAIJGFG X ~1A aAUUUCCA 2359 'Ir3G:9AA2T A
PL~AGF~lA
1888 HSGATA3R 664 ALJCAGACC CUGAIJC~G X AAA 2360 AAGAAACT A aGI~IGAT
PQUUC7CW
1892 H9GATA3R 665 GAAL~L1CA CUGAtTGFG X Q2~A2361 AACTAOGr C 1CATA?'IC
ALCt~JU
1897 H9GATP~R 666 C~LIUUGAA LL~AIJGFG X ~ 2362 aGPCIGAT A TICAAATG
AL7CpGAOC
1899 H9GF.TA3R667 UCCAUUUG CUC~,LJGFG X O~A 2363 TCI~TAT T CAAA'I~.
At.
1900 Fi9Gp.TA3R668 C~TCL'At7UU CL~A~G X O~F. 2364 CIGF.TATr C AAATO~~C
AAL1ALJCpG
1920 H9GA~3R 669 C3GAAAC1~1A CC7~IJGPG X 2365 CIC3C~T T TIGITICC
~A AGZJOC3CF~G
1921 H9GATA3R 670 PL~CAAACA CTJG~UC~G X QUA 2366 'IC3CCAG1'T T
AAL'L~G~ ZGITTCLT
1922 H~.TP3R 671 AF~AAC CLJGAIJC~G X OG~A 2367 O'JC~TIT T GTI'IC!CIT
A~3C
1925 H9C~.TA3R672 L7GAAAOGA CZJC~1UGAG X 2368 PGTT'I'IGT T
CGqA P~AAPL~J 2~CI'IZC'A
1926 H9GATA3R 673 ~AAOG CT~AIJr:~G X C<.~1A 2369 GIITIGIT T CC~C
AACAAAAC
1927 H9GATA3R 674 PGUGAP~PG CUGAIJGAG X CIA 2370 TrI~'I'r C CITTCPLT
AApCAAAP.
1930 HSGa.TA3R675 OCCFGtJGp. CI:~AfJC~G X 2371 2GZTmCT T 'I~L'Il'~GC
~1A PL3GAAACA
1931 H9GF.TA3R676 OGCCAC~JG CUGAUGF~ X ~A 2372 GI2~CIT T CAC~CC
AAOGAAAC
1932 H~.3R 677 UOOCJ C~ALJGPG X CC~F. 2373 TTTCCTTT C ACIT30CCA
AAFDGAAA
1945 I~.2~R 678 CAUCAAAC C1~1L7GFG X CC~F.2374 C~CCACAGr T GIT~G
AGiX~~30C
1948 H9GF.TA3R679 AUGCAUC~. CZJ~G X 0.A ACAAG~J2375 ACAGThGT T Tr;p.TOCAT
1949 Fi~F.TP3R680 AAL70CAL7C Ci~G X AAA AACAAGL~2376 C~4GTIGTr T C~L~CATr
1957 I~.TA3R 681 U(~TJUUU CUGAiJGPG X ~A 2377 SCAT T AAAFG~AA
AUC3CAUCA
1958 F~.3R 682 UUtiUCT7tAJ CUGAIJGpG X 2378 GAZC~C'4TT A
OGAF. A~,I70CAIJC AAPGAAAA
1968 H9GF.TA3R683 CTJUUU(IUtT C<JC~ X CC'~AA2379 A~AAAT A AAA~1AAFG
ALJt7IlfJCW
2009 H~F.TA3R 684 UCGCCtB~C CL~1IJ~?G X ~1A 2380 AAAAAPbT T GI~GCGP.
PGLI(7t~JU
2012 I~PP3R 685 GAL7~JOLC CL7GAUGAG X QUA 2381 AA~T~T A (30CGi'aF.'I~
AC~IACtJUIJ
2020 H9GATA3R 686 ' GAAC~AAtT CZ7GAIJGFG 2382 PL300GAAT C Al'rIGTIC
X C~1A AUt70GOC(J
2023 H9GATA3R 687 CRJ~ACA GUC~1I~G X CAA 2383 CGAAT'~.T T 2GTI~AAA
AL~AL1UOG
2024 HSGA2~R 688 CUtiVGAAC CLJ~L7C~G X CVAA2384 C~AA~ATf T GI~AFG
AAt7C~IAJC
2027 H~3R 689 CAOCWUG CLOG X OG~A PL~AF~L7C~.2385 TCAThIC~T T CAAAC3CIG
2028 F~3R 690 11C~OCUi7U Ct~G X OC~A 2386 C AAFL3CIGT
P~C~A~IJG
2037 Fi9C~R 691 AGAL1300C CLOG X 03AA PG~10CUUI12387 AAFDClGT T
C~OCIr,CIC.T
2044 Fi9C~ATA3R692 CCUtJUGC~. CvC~LJGFG X 2388 TI~.T C 'n3CAAFDG
CC~A I~30GOCAA
2057 FL9C~.TP3R693 AGAAG~JOG GT~G X aC~A AUWOCW2389 AAO~AAT A CCpGTIC..T
2063 FAR 694 UUC~0.~G CCX~I7G~G X OC~3A2390 ATPOCAGr T CTOGOCAA
pLUOC~J
2064 R 695 AUU00.CA CLJGAiJGpG X Q~F.2391 TALCPGZT C 'I~.AT
AAL1J0~.
2073 H9C~.'I~3R696 CL1AAL~LZJ Cu~~JGpG X OG~A2392 'InC30CAAT C
AtnX30CCA PGiGITAC
2079 F~F.TA3R 697 LJGF.F~C~J C~li7C~G X AAA 2393 AT'PGIC~'r T
P~IJ PLC.
2080 H9C~R 698 Q7r~Ap~ C1~L7GpG X O~F. 2394 'IC~GIGIT A CSC
AAC~A
2085 H9GA7~3R 699 A~,LTX3C~JG CTJGAT~G X ?395 GIZ~L'OGT T C9G~IT
0.A AOO~C
2086 H9GATA3R 700 ~~J CL7r~LJGpG X Q~F. AA03f~F.2396 TI'PCCGIT C AOCAGTIG
2093 F~.TA3R 701 L7C.~AtIOGC CZJGAUGFG X 2397 'IZ~GC~GT T aCCA2'I~
Q'~AF. PLZJC~C~JGA
2099 H~F.TA3R 702 P.AACCL~7C CTJGAUGpG X 2398 GI~CAT T C~3GGITT
CAA AUOOCAFC
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72
Table III. Hammerhead ribozymes tar~etin' GATA transcription factors ( l, 2,
3, 4, and
6) and the complementary sequences
2106 H9GATA3R 703 CLJC<JC'UGF1 C~A~G X CVAA 2399 TIG~OGT T 2rPGFC~G
AO~.L~A
2107 HSGATA3R 704 C~TJGLJCUG CLJGALGFG X 2400 'I~3GGTT T C
0.~AA AAL~CixA
2108 H9GAT~3R 705 c~C~.U CUC~1LJGAG X~ 0.A 2401 G~3Gt'IT C AC~LIr
AAACGLTJC
2118 R 706 OC<.1PGAAP. CL~TJGFG X 2402 ~GF~C'C,'P T
CVAA .~L~CL~.L7C 2'~DG
2119 H~FTA3R 707 OO'~C~P, CT.J~L~G X CJ~A 2403 PGFL3C~IT T T~~PL30C
APaOCUC<T
2120 H9GA'~3R 708 OGCCZ~C~. CUC~FG X QGtIA 2404 C~OCCt'IT T ~C30C~
AAA03GZJC
2121 H9GATA3R 709 PDOCCUPG CCJGALJC~G X OC~P.2405 PGC~ITIT T C'rPL~GCLI'
AAAAC33CU
2122 HS~F.TA3R710 UPD3CCI~. CZ7C,ALIGFG X 2406 aCCI'ITIT C 'IPDGC~rA
0.AA AAAAPDOC
2124 H9GATA3R Ill L1GC~C~CC CVG~JGAG X OG~P.2407 CT~TI~T A 03L~.
AC,AAAA~G
2130 H9GAT.43R712 AAFC3CAUG CFG X AAA PQ'3CCC~G2408 CTS A CA2GCTIT
2137 H9GATA3R 713 I~JCACA C~JGAL~pG X 0.;AP.2409 'LAG'A'R'3Cr
PL3CP~LK~ T TG'I~AACP.
2138 HSGATA3R 714 UU~JC1CAC CCJGATJGpG X 2410 ACATuCTr T GI~AACAA
O:~A A~L3CAUCMJ
2149 H9GA~3R 715 AUC~C~L3G CTJC,AUGFG X 2411 GAFL4PGr C CCI~TAAT
O~A PL~lI7C
2155 H9GATA3R 716 ACAP,CAPSJ CUGALJGFL3 X 2412 GI'C~P A ATRTIC~T
O~P. ACAL30C~C
2158 H~.TA3R 717 CAAACAAC CTJGALR;AG X CAA 2413 C~'IGTA~1T T
AI~G GI~GTI~LG
2161 H9GATA3R 718 AL~AAC CUC,AL7GAG X CK~F. 2414 GTAATZGT T GrIT"TAT
AC~AIA~C
2164 H9GATA3R 779 t'A CUGAIJG~G X CC~F. ACAACAAL1. 2415ATIGI'1~ T ZGTA2~IP~
2165 H9GP.TA3R720 AL~C CLR~LK~G X Q~F. AACAAC~A2416 TTGTIGZT T G~2G'~T
2168 H9GATA3R 721 AUtl9t~. CLJGAIJC~G X aGAF.2417 TIGT~G~ a 1~TATAAT
PC~AP~A
2172 H9G~TA3R 722 ULG9AUCTA CUGaTJGAG X CGAA2418 TIGTAT~T A '~AAT~A
AC~9A
2174 H~.TA3R 723 CUVUGAALJ CZJGAU~G X O~A 2419 GPA~T A ATICAAF~
AI~L~C
2177 H9~TA3R 724 C,'~CUUUG C<JGAUGpG X CAA 2420 ZG'~AT T CAAAL3CAC
AL7C~L~
2178 FL9GA~R 725 0~70GUI~J GAG X OQ~A AAUtiAL~IC2421 GI'ATAF~LT C
AAAGCAC~
2192 H9GATA3R 726 UCUWt7CU CUGAI~ X Cu"AA 2422 ACCAAAAT A P~AAAF~.
AUUUU3GU
2204 H~.TA3R 727 AALIAAAUC GZ~1G X c?~.F. 2423 A~PGA'IGT A GATITAZT
P~CAL1CSJUU
2208 H~TP3R 728 AL~AAL~1 CTJGALJGpG X OC'~A2424 A2G~AC~AT T '~ATI~'
A~JCUACATJ
2209 HSGATA3R 729 G~IJC~1AAIJ CL7GF~IJG~G 2425 ~'PC,ATT T ATITCAZC
X CGAA Pte.
2210 H9GATA3R 730 LJGAUGAAp. CL~FG X CAA 2426 GrAGATIT A
C
2212 I-R 731 L~AUGp. CL7C,~TfiAG X 0.~AA2427 pC~'I'L~T T ~~
AI~AAL7CTJ
2213 H9GATA3R 732 A~1UC-AUG CLJGAC7~G X dC~A2428 T CA~ATAT
AAL~1F~AL7C
2214 H9GATA3R 733 AAI~1IJGAI1 CMG X CGAF. 2429 ATITAZTr C
AF~AI~AU
2217 H9G~3R 734 LmLmAL~TT CUGAUGpG X CC~A 2430 '~T~AT C A~'IA~.
FJJC~AAL~1
2220 . H9G~R 735 CL~L~A CMG X Of~A AI7~L7C~1A2431 TI~ATCAT A TIP.~G
2222 HSGATA3R 736 CiT CLOG X OC~A AI~li7C~JG2432 CATCA~T T ABC
2223 H9GA~3R 737 O~JGt~ CT~AL~G X CIA AAI~LT2433 A~Tr A TACK
2225 H9GATP3R 738 UOOQJC~7G CZ~JGFG X CC~A 2434 CATATI~T A CPI~OOI~
AL~Ai~IJG
2239 FL9GA'L~3R739 AvU~I~G CU~LJGAG X CGzIA 2435 CGAACIGT T G~~'AAAT
AC~JIJOG
2242 F~FrTA3R 740 L~lApT7UVA CTJGAL~.~G X 2436 PL'~I'IGT A TAAATITA
QUA AC~AC~J
2244 H~ATA3R 741 AAUAAAW ~G X CAA AI~ACp. 2437 'i~lAT A AATITATr
2248 H9GAZA3R 742 PG~AAL~. CL7GAUGAG X CC~A 2438 G~AAT T TATITACr
AIJUUAL~C
2249 H9GATA3R 743 CAC~~AALJ CUGAL7GAG X Cl'~A2439 'L~TAAATr T A2'~I~L.'IG
AA~JC~.i~
2250 H~A3R 744 C3~AA CLJGAUGAG X O~A AAFT7fJUPTJ2440 ATAAAZTr A
TIfiACIOC
2252 HS~ATA3R 745 UAOC~ CC~AI~G X CGAA PST 2441 AAATITAT T '~~'IC3;.'TA
2253 ~3R 746 CC~G3CAC~J CtJGAt7~G X 2442 AATTTATP T PCIDCT?G
Q~P. A~1AAW
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73
Table III. Hammerhead ribozymes tar~etin~ GATA transcription factors (t, 2, 3,
4, and
6) and the complemenc~ry sequences
2254 i~rl'L"~13R747 :~GCFG CVGAUG'r~ X ~A 2943 ATITATTT A CIGCTpGT
~ PAAL~AAtJ
2260 i~lTA3R748 _ 2444 TrACIC3L'i' A
CtJUAAGAC G~JCFI~ X OC~A G
AOCAGt7AA
2263 H9CATP3R749 CAA G X C~1A AC~CAG 2445 C2GCI'AGT C TIPAC~G
2265 fi~TA3R750 C~GUUCZJU CTJGAIJG~G X 2446 aC'IPGIC.T T
Q~A PGACU~C APGAA6.'IG
2266 H9CATA3R751 OG~~JCICTJ CVGF.UGAG X 2447 CrAGi~IT A PGAACIC3C
CGAA AAGALT~G
2276 Hit 752 PLC~APGF. CUGAL1GFG X 2448 GAACn3Cr T 2'G'LTIC~~T
TA3R CAA POCAC~7tJC
2277 F.SCATA3R753 rlA~AAAG CVGAL~GAG X 0~1A2449 AACIC3CTT T CITrCGTT
APL~CPLW
2278 H9CATA3R754 PaAOGAAA CVGAUGFG X O~A 2450 AL'IC3CTIT C
AAPDC.~TJ 'IfiI~GITIT
2280 HS~.TA3R755 P~AF~ Ci~PG X AAA P~APDCP.2451 'IGCrI~C.T T
ZC~T
2281 H~.TP3R756 G CV~FG X CAA APC~APaC 2452 OCZTICTT T C~GrIZGZT
2282 Fi9GATA3R757 A2C CUGALJG~G X Q~ AAPGAAnG2453 CTI~'iTr C GITIGI'IT
2285 H9Ga.TA3R758 AACAAPCA C~ X OGAA AOGAA~GA2454 TCT~T T 2GIT~IT
2286 H9G'~'IA3R759 AAACAAAC CL~JG~G X ~1A 2455 CITmGIT T GITIG12T
APL~AAAG
2289 Is.S~.TA3R760 UCJ~AACa. C'LJGAUGFG X 2456 'I~GITIC~T T
CX'3~F. ACAAAC~A A
2290 H~ATA3R761 AUUC-AAAC CUGAUC~G X CAF.2457 OGTi'IGrr T GIZTCAAT
AACAAAGG
2293 H9GATP3R762 A~JGP. cZJGAI~G X OG7~A 2458 TIGITIGT T 2CP~ATATT
Ate.
2294 H9C~1TA3R763 A~,AI7~1LRJG CUGAL7GpL= 2459 'IG'ITIUiIT T
X CC~A APCAAACA CAATATIT
2295 H9C~.TP3R764 ~F~AL~U C.LJ~G X QUA AAACAAaC2460 GT~ITr C AAT.4~TIT
2299 H9C~.TA3R765 aAGG~uAAAA CUG~IJGAG X 2461 GITI~AT A TITmCIT
CuPA AUUGAAAC
2301 F~F.TA3R766 ?GAF~L3GAA CTJGAUGAG X 2462 TICAATAT T TI~CI'I~T
CGAA AI~L7lJC~A
2302 F~3R 767 GACAAGGA CL~AL7GF~ X AAA 2463 TvAATATT T 'ICCITC'IC
AAtI~.
2303 3R 768 AC~GAFL~G C:UGAIJGpG X 2464 CAATATTT T CGTR.'IC.'r
~F. AAAI7AUJG
2304 Fi9~~.TA3R769 G~GAPG GTJGAUGAG X QJAA 2465 AATATl'IT C
C'rIC.'IC.'IC
AAAA1JLALHJ
2307 H9G~TA3R770 LJGAGAC,FG C~.7C~AG X 2466 ATi'IT2T T G'~'~A
O~A PL3C~1AAAIJ
2308 H9C~R 771 W~GA CMG X CvAA APC33GAAAA2467 TI~CIT C 2C~C~
2310 Fi9GATA3R772 AAUUGPGA G~I7GFG X CQ~A 2468 TI'CCTIC..T C
PC~AG~1A T'CTCAA2T
2312 H9C~.TA3R773 r~AAAtJU~ CMG X AAA PGAC~AAC~2469 CL'I'ICZC'r C
TCAATIZT
2314 F~.TA3R774 CGAAAAW CZ7GAUC~G X CVAA 2470 T~'IC.T C AATt'IT~
PGFG~AA
2318 HS~TA3R775 CAAOGL~. CIJC~LJGPG X 2471 CIC.'fiAAT T
0.A ALR~G TI~TIG
2319 R 776 L7~FCOl'~ C<JGALJGPG X 2472 T~n~lATr T 'IC70GTI~.
CAF. AAtA~.
2320 Fi~.TA3R777 UUCAPCOG CLOG X ~ AAAUUGAG2473 C'~ATIT T CO~.
2321 R 778 Ai~FDC CT~AUGAG X aC~IA 2474 TCAATITr C OGIT~1AT
AAF~ALIt7GA
2325 Fi9C~3R779 QJUVAIJUC CMG X CGeIA 2475 TITI~C~GT T GAATAAAC
PLOGAAAA
2330 H9~~TA3R?80 AL~C~IU CT~G X AAA AUUG~AOC2476 aGrIGAAT A AFC~.T
2335 F3R 781 AI7~AilC Ct7C~TJGF~ X 2477 AATAAACr A GATl~.T
QUA PL~JUUAW
2339 Ei9C~3R782 CL~P~IJQJ CtJGAUGAG X 2478 AAL'~AGAT T ACATPCFG
0.A AUCL~RJ
2340 F~.3R 783 PLZJGAAZJG ~G X CAA AALJC~J2479 PGTpGATr A CATI'~GT
2344 H~3R 784 c3CCAAC<7G Ctx~L7GFG X 2480 GATT T C~3C
CAF. AI~AI7C
2345 H~3R 785 UO~AC<J CT7GHIJGpG X CAF.2481 ATTACATT C PGZ'IC~GCA
AAL7C~l~AIJ
2349 H9GA~3R786 UUWt7f32 GtK~G X 0.;~1A 2482 C~TTC~Gr T O~'AAAAA
AGi~At7G
13 I~~TAF.787 ~UUG C<JC,AUC~G X ~A AL~JC~G2483 CC~AAAAT T CAAATIC~G
14 F~d~ATAF.788 CCQ~AUUCT CLOG X Cl'~A 2484 CAAAAA'IT C AP~ATIL~~
AALnJCRA~
19 ~ 789 AAAAU(xC CTJGAI7GpG X 2485 ~ T 03GATrIT
CuAP. AUWGAALt
25 HIM'~TAP.790 CI~3C~A CTJGF~IJC~ X Cue.2486 ATIC30GAT T TIL~G
AIJC2CAATJ
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74
Table III. Hammerhead ribozymes tar?etinj GATA transcription factors ( L, 2,
3, 4, and
6) and the complementary sequences
26 h P. 791 aLZJCCC3Ct1 CL7GAIJ~G X 2487 TT3C3GATT T 'It:~C~GT
CC,AA AAC7CCCr?P.
27 HI~A'L~A792 LIACLKCCC~ CZJGAL1GFG X 2488 2GOGATTT T CC~3G~.
CC~1A AAtIIJCCC~.
28 HL~~TAP.793 WAC(JCGG CUGALTGFG X CC~A 2489 QOGATTTT C C~3C~GrAA
AAAALJCCC
35 ~ 794 CCJCTJC7QJfJ CLTGACTGFG 2490 TCCI'3GAGr A
X O~A ALTJCL~. AACAP~FG
47 HC~T~ATAA ?95 AFa~GCUC CUGAIJG~ X CG?1A 2491 AAGAGCrT A G~GCC~IT
PD3CtxLICJ
55 ~ 796 AUUC,AGCA CUGAL~G X CGAA 2492 PGAOCCCT T 2~AT
PDajCC7C.U
56 ~ 797 C~LItJGApC CUGALJGFG X 2493 GAOCCCI'r T 0
CL'~A AAOOGCZJC
60 HC~T~.TAF.798 CCAGCAW CL~LJ~G X O~A PDC~AFOG2494 CCIZ2~3CT C
AA'IC3CIL~G
71 F AA 799 ALGC1AWA CL~ILIGpG X CC~1A2495 TGCIC3GAT T TAATAOGT
AIJCCPDC~.
72 HCEK',A2~p.800 LTAfJ~UU CLJGAC1GFG X CGAA2496 OC'IC3GATT T
AAIJCCAGC AATACGTA
73 HI~ATAF.801 AL~IkIIJ CUGAIIGaG X 0.~F1A2497 C'IC~'~F.TTT
AAAIJCCAG A ATACGTAT
76 HUt~~TAF,802 L~r OG CUGAfJGAG X Cl'~A 2498 C~TITAAT A ~~
AUCTAAAIJC
80 HIaT~ATAA 803 AAAAL7AI1A Ct7GALTG3G X 2499 TAATALGP A TATiATITI'
O~A AOC~TAIJCTA
8~ I~t7N~.'I~F.804 tTAAAAALIA CUGAL~FG X Q~F.2500 ATAOGTAT A TATITITA
AITACGtIATJ
84 HC~ A 805 CtnIAAAAA CUGAIJGFG X CC~A2501 ACGhATP.T A TriZTAAG
ALIT
86 HI7N~ATAA806 Ci3CL~TAAA CUGAIJC~AG X 2502 GTATATAT T TTTAFaCG
CVAA AL~1IJALTAC
87 HI&~F,TAp.807 tJCG~CUtIAA CUGAL~FG X 2503 'I'P.TATA~T T
CC~A AAt7ALlALTFa TrAAOCX'~.
88 H<.~TF,TAA808 CUOC~1 CLJGi~G X ChAA AAAL1AL~LJ2504 ATATATIT T
'ITAFCd~G
89 HC~ A 809 AC(JCGCUU CLT~IJGPG X 0.;F.2505 TATAZ'IZT T AFL3CG~GT
AAAAL~L~.
90 HCSHGA'I;AA810 AACUCOCV CUGAtJGAG X 0.7AA2506 ATATrTTT A PL30GAGIT
AAHAP~I~J
98 F~~ ATAF.811 AAAAAACC C<JG~JGpG X 0.A 2507 AAG~T T aGTITTTT
PL~GCW
102 HLaT~.TAA812 030G~AAA CtJGAt)GAG X QUA 2508 G~3GT T TITI~CCC
ALCAACT)C
103 ~ 813 PC303GAAA CMG X 0.;;9P. 2509 AGI~3GTT T TI'ICOOCT
AACCAAGU
104 HI.E~ATAF,814 AAC~30GAA CtJGAIJGHG X 2510 GTIC3GTIT T TIL~OCCIT
Ct;FIA AAFLrAAC
105 ~ 815 AAFaGGuA CUCAI~G X CGAA 2511 T'P03ITIT T 'I~CCCI3T
AAAP~F.
106 ~ 816 CAAP~C~ CL~L1GAG X CC~A 2512 2C'~GZ'ITIT T
AAAAA~. CCOCITIG
107 HI~ A 817 LX~AAGOG CLOG X CuAA AAAAAACC2513 a~TIfiITr C CCCITlGA
112 F ' 818 AAAAAIX~ CTJGAUGPG X D~Pa 2514 TI I~CCT T 'IGATITIT
A A003C;AAA
1L3 A 819 CAAAAAUC CZJGAIJC;pG X 2515 T~OC~CIT T C~1T~'ITIG
Q~F. APfl30~Fa
117 F~d ~F. 820 PCAi7C9AA CUCAtJr~G X CG~A2516 CCITIGAT T TIT~Cr
AL7C.~AAOG
118 HI~~~'TAA821 AAGAUr~IF. C<JGAI~.~G X 2517 CTI~T T TIGATCIT
Ct;AA AAI~A~1G
119 Fi(~ATAA822 C~AG~J~ Ct~AiJG~G X OC~1A 2518 TZ'I~'IT T 2GA'ICTIC
AAALIr'AAA
120 HI~ Fr 823 CGA~CAIJC CL~L~ X O~A AAAAL7C~A2519 TIC~TI~T T C~CI'IC~
124 HIE~A'i~,A824 CTJOOOC~A CT~G X 0.~4A 2520 Z'ITTIGAT C TICGOGpC
AL7C9AAAA
126 HIdT~ATAA825 Ct~OG CUC~1IJC~G X CGAA 2521 TTIGATZ:T T W~
P~ALIr~AA
127 HId~ATAP,826 PL~3C Ct~~IIJC~G X CAA 2522 TIC~CTr C a~T
P~F.
136 HCH~r~TAA827 ~GAGG CZJGAZJGAG X CJ~A 2523 OOGACAGr T C~C.'mL~AC
AC(~GC
137 HIQT~ATAP,828 ~GFG C~TJGAG X QUA AACi~G 2524 CGACAGrP C CT'~''CCF~C7G
140 Htd~T~ATAF.829 AL1C~~G Ci~G X QUA P~FLL~ 2525 CAGIZCCP C CCAOOCAT
149 Fi b 830 AAOGi~A CTJ~JGFG X Ct;AA 2526 CCACGCAT A T~~CJGIT
ALR'3CCTJOG
151 HI.E~A 831 AC.~ACGAIT CLJ~G X 0.F. 2527 A~ATAT T A~7GI~T
At~IX3Cl~J
152 I~T ~1P,832 AACAACGA CZJGAIX~G X CAF. 2528 CG~.TATT A TCGITGIT
AAI~OCG
154 H(H~T~A 833 C3CAFCAAC CC~AiJGAG X CAA 2529 CATA'I'~AT C
AL~Ii~lL7G GI~C
157 HI~ ATAF.834 A003CAAC CTJGAI~ X CC~A 2530 ATTAm~T T GT~3C.'C1;T
AOGAI~ALT
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
Table III. Hammerhead ribozymes tar~etin~ GATA transcription factors ( 1, ?.
3, 4, and
6) and the complementary sequences
160 HGfi~A'IAP.835 ~,~ ~ X ~ ~,;,~ 2531 ATCGTIGT T GC~T
166 I-P;~TATAP,836 ~ ~,~~ x gyp, p~~ 2532 GIT<3CCGT C GITTI~P~'
.169 E1C~ATAP,837 pGAC~GAA CtJGAIJGFG X CGT1A2533 aC~I' T TICK
ACGA033C
170 fifATAP. 838 C~OGFG'rC,A CLJGAUGr~G 2534 CCC~'L~GIT T
X OC~A AAOGAL~3G ACC
171 HIZh?;ATAA839 03GC~G CL7G~I7GAG X OCR. 2535 ~~TIT T C'I~I~CLC
AAFLGAOG
172 FiC~ATAP.840 Cr~33;PGA CTG X CuAP, AAkIF.CGAC2536 GICGTITr C 2LI~CCC.G
174 HtF.TAA 841 GGC~A CT~AtJ~G X QG~A PGAAAACG2537 C~'ITIGT C 'ICCCCC3CG
176 HI.~ATAP,842 CALI3Cnc~ C<JC~IJC~1G X 2538 TITI~IrT C C~3CGIG
CVAA PC~GAAAp,
188 H<1N~,ATAp.843 e'~C~)C~1FG CUGAZ~G X CAA 2539 OCG'IL3GGT C
PDC~C CTI~LT
191 F~~TAF. 844 CGCFC~JC CUr~IUGFG X CI~P.2540 T3GCrCLT T C~L'CZnC~
PaG~(3CCA
231. Ht~A'IAA 845 C~CC(JOC CUGAIJC~G X CGAA 2541 ~AOCr C OC~L30
AOCtK~~C~ CAC
245 HC1~ATAA 846 PGCL~ CUGAZJC~G X Ct;~A 2542 GACCAT:~T A TC~Cr
ACALX3CtJC
247 HI~A~,A 847 CAAOCUCU CUGALIGpG X CAA 2543 CrATGI~.T C AC~O~'IG
AL~CpTJC~
254 HI.R~ATAF,848 CCALJC~3~ CLJGAL7~G X OGAF.2544 2~C~C3CT T C3~CAW
.~OC(~
293 HIIL~ATAA849 CCGCCiJOG C~JC~I7GFG x 2545 C~'IOCCr A QCFC3COGG
CVAA PL30:~
317 HCI~A 850 O~JOCAUG CZJGAUGFG X CJ~A 2546 ACCT T CA2nCACG
P~300CCG
318 HC1~ATAA 851 CL'~tJOC~IiJ CLJ~Ur~ X 2547 03CCCCIT C A~CAOOG
CGAA AAQ~3CC
341 HUh~ATAA 852 CUGC~L~upG CUCAL7GAG X 2548 Q30CX30GT C CICOCi~G
CGAA A03CbOCV
344 fP~ 853 AGALTX3GC CiG X CAP. P~OG 2549 CGOGT'GT C OCCAGIC.'r
351 Fi~A 854 ~C~>P. CZJGACR'~AG X Cu~AP.2550 '1L'~3CCFGT C
PLU000~ '1~.'IDQC
353 Fitl~,F. 855 UC303CAGG CUGAIX~G X Cl';~A2551 C3CCFGrCr A CL'IL30~.
PGAGUOOC
377 ,A 856 C~1AC~CpG CC7C~UGAG X C>;AA2552 ~C~.T C CTl7CGTIC
P~GC
380 HIE~AT.4F,857 CCAGAAOG C~9LJr~G X CAA 2553 C3CC~rCC'r C
PI~030C CuTrCIDG
384 fitd~ATAA858 ~OCLCFG LTJGAUGAG X ~A 2554 TC~.'iCC>;T T
ACX3~~A CIC~30CCr
385 Fi~ATAP, 859 CAC~CCCA C<JGAUGFG X ~A 2555 CL'PCLGIT C 'In30CCIti
A~OOGFL~
395 HId~ATAF.860 C~C,F~O~ CZJC~JGAG X C1~A 2556 OGO~T C CI'ALC'rOC
AL~OOC>~
398 FAA 861 CCT~AOG CUGAL7GAG x o~lF. 2557 CL'IG'IC~r A
PDGAChL3G CCICCPL3G
402 FiCE~ATAF.862 C~CTJG CTJGAUr;pG X CC~1A 2558 TCC'IAQ'I' C
PL3C CF~C300CtCG
422 F~TAF. 863 C~3~OCA CUGAUC,~G X CGAA 2559 CG0330GT C 'I~C~
PL3CC~
428 HCB~ATAA 864 030CL7C~ CLK~G X ~ ACOCPGAG2560 CICInOGT C ACC
440 HII~P. 865 UOOG;3COC CL7GAI7GFG X 2561 AGOG~CCT C ACA
CGAA PDQ300LT1
467 Htl~A 866 NO~. CtIGAIJC~G X CGAA 2562 ~OGr C T3G1r300G
PL7C~0~
535 F~TAA 867 CG~1 CTJGALJGFG X CQ~A 2563 C~00.'~GC'r T
A0~3CZJC AC~L~
536 FAA 868 C~3GUG C~~LJC~G X ~A APL3003QJ2564 PD~C'IT A CACt!CCC~
554 HI3~ATAA 869 AGOC~C CUGAIJGAG X Ct;~A 2565 C'3COC~'~T C
AC~'OOOC ~CK~.'r
563 Fit7N~ATAA870 C~AP~C~ GLfi~G X CQ~A PGC>DOOGC2566 C~C~OOGC1C.T
T CI'CCT'ICC
564 HC 871 03~. CUGFTJ~G X CZ7AP. 2567 CC~~03CIT C 'IC'LTmCC
APOOQ~
566 HCE~ATAA 872 COOC~AF~ CUC~1;JGAG X CuAA2568 O~GTIrT C CIZCC~
AGAAOOC~
569 H<.~F.TAP.873 UCCCQ~ CT~G X CGAA FOB 2569 CTICTCCr T CCCfl03GA
570 F~ATAF. 874 C~CC!0~ CtX~UC~G X 0;3~A 2570 TIC.'I~CIT C
AAC~AGAA CCGGGGFC
587 HC~A 875 C~CC~DG Ct~G X QUA AC'COOCZJG2571 CAOC~C~T C O~C100.~
635 I~PCd4JF~TAA876 CACL~3CUG CUGAL~AG X CG4A 2572 'Il'30~.'r A
P~GCLt~CA CFO
686 HC~A 877 Ct'~GCCC>i CLOG X CGAA 2573 OGFL3~~GT A CcG30000G
PLT~GLJC~G
701 HUN~ATPA 878 PDT Ct~G X Q~1A PC12~30G 2574 CGCnOC~T T ~OOCT
CA 02364577 2001-10-03
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76
'Table III. Hammerhead ribozymes targeting GATA transcription factors ( l, 2,
3, 4, and
6) and the complementary sequences
702 HCb~r~.TAA879 GAC~C.'CLl~ C~AUGAG X ~A 2575 OC~CIT C G~C30CIC
P~C3C~GC
710 c?C7N~ATAA880 UOGFL~ CtIGALJC,~G X CVAA 2576 C~~ C C~',:.'A
PL~CCCOCG
713 F'1~ATAP.881 GGCL~FG CUC~G X O~A PL,~AOCCC2577 GGI~C'IL2'r A
CI~CP~CC
716 fiCB~ATAA882 PL~CL7G CUGAIJC'~ X CGAA 2578 C1~CIP~'1' C
PL~;~G CFC3CCC~T
725 HI7N~ATAA883 AAC3C~ C~IJGpG X Oc~A PD30C~TJG2579 CAL3CCCLT A CL~GCIT
733 HC~A 884 GOGrAIJC.1T CVC~G X CGAF. 2580 ACCCC~T T ACA'I~3~
: C3~J
734 A 885 GT33~UG Ct~GFG X CG~A APL3~2581 CC~3CIT A CA'IC30CCG
755 HCE~~ATAA886 Q~3C~ CfJGAL7CFG X CHAP. 2582 GOOQGCGT C Clt7GGCCG
A~CnCCC
779 HLd~ATAF.887 Gl'~.'G'C~3~ CL1G~TJGFG 2583 Cl'3C~.T C ~C33CC
X Q.~1A PL~3CGOL~
791 HC~F~A 888 C~CL~ QJC~I~FG X Ct;AA 2584 ~30CC~C.T T CGAC~3CC
P0300CCG
792 HC~~ATAA 889 030CU~ CUGAUC,AG X Q~F. 2585 GO~CIT C GAC~OCCC
APL~OOOCC
804 HLB~ATAA 890 CCTC~OCF~ CUGAL7GFG X Q'~A2586 PL~CCCL~'~T C
ASCU CIC3CAC3~
853 HI~A~F~ 891 CAL~LJ~ CZJGA~CFG X CVAA 2587 ACCLCAAT C 2t7GATA1G
AL7U000~J
855 FiC~ATAA 892 P~ACAL~IJC Ci7GAL7GAG X 2588 CCC'AP.TCT C
C1~A PC~T7UOOG GATAT~IT
859 ~ 893 GUCAAPCA C(JGAIJGAG X CAA 2589 ATCfiGAT A 'IG'iTIC~C
AUOGF~IJ
863 A 894 P~'CD CZJC~L~FG X O~A ACALTALIOG2590 C~ATP.2C~T T
'IGACGFLT
864 HC~2'~P,A895 A~C~,C CUGAUGAG X Cl.'~F. 2591 GATAT~IT T C~10GFG'IT
pp~7C
872 HI.d~ATAA896 CZJC~ CC~ALJGAG X QUA PLL~70~2592 'IC'~GAGT T C1C~GAAG
873 ~ 897 CCTJUC~JC~. CL~AIJGpG X 2593 GACGACTT C TCPC,AAOG
Q~F. A~C~JOQ7C
875 HI7~ATAA 898 LJG~LJ CUGALJC~G X CC~1A 2594 CGACI'IrT C PGAAGGCA
PGAFL~JOG
894 H~,A 899 CCAC~I1 CtJGAIJGFG X D~A 2595 GAG~IGT C ~
PL~C~7C
907 HC~ATAA 900 G~ACA CL~JGAG X O;.~A PL~'~C2596 GIC3C~3CT A 2C~'!'L~CAOC
911 Ht~A 901 GOOOOGi~ CL~LJG~G X O~A 2597 GOGTAnT C CACCOOOC
P~GOC
921 F-rfd~ATAF.902 OOCGL1CC'A CUGAIJC.~G X 2598 ACCO~LT C 'IC~GAGO~
QUA PDOOGOC,LJ
943 HC~TATAF.903 CAGFT~1 CLOG X O~F. AC~JCC2599 GGA~GGT C AC~A~C..'IG
947 F~ATAF, 904 UGCACP~. CT~ALJGFG X ~1A 2600 GGGTCACZ' A 'IC.'I~CA
PL~FL~CC
949 HL~F.TAF.905 C~3C~. C<JGAL~G X CT~F. 2601 GIC~L'~P.T C
AL~C 'I~~3CAAC
969 Fii:~ATAA906 LnJC~JOC~. Ci7GALJGAG X 2602 WPOGLl.T C '1'AOCACHA
CGzIA PDGCC7~r
971 HL~ATAA 907 L7CUIJC~70G CUGAIJGAG X 2603 'IC30~.'T A CC~AGA
O~A AC~00~'A
990 FAA 908 (330Ct~(T CL~ALfiFG X CGAF.2604 AAtX~CP.T C AA0.~OCC
ALx3CC~fJ
1002 HI.~ATAA 909 ~L7UGALJ C<J~G X Q~F. PL~3C~LOG2605 OOQ~GT C ATCAPL30C
1005 F~T~AA 910 UC~3~)U COC~UC'~FG X CAA 2606 C0.'~CIC'AT C
AI7~GOOG AFDCC~.
1012 HI~A~F~ 911 CC3C3CaCU GLJ~SJC~G X CC~A2607 TCAHOCXT C AC~OOLmG
Pf~CU~r
1025 FAA 912 GOGpDOCG CZJGAIJGAG X Q~1F.2608 C'L1~O~T C ACC
PL~3~70G
1031 HC~ATAA 913 Ct~3001'~ CUGAUGPG X Q~F. 2609 G~0.'T C C~3COGPG
PGG00('~C
1047 HI~ATAA 914 0~0~. CLOG X ~A P03COCAC 2610 GI~3CZT C 'I'UCIt;~C
1049 fi~ATAA 915 Lp3CAC~~ CZJG~J~G X CGAA 26ll GOOCCTCT C C~CCA
PGpOOCCC
1131 HLB~ATAF.916 UUC~LJC~ CL7~TJ~G X O~A 2612 'IC30C~.'r C
PL3GCOOC2~ TACA~A
LL33 F'AA 917 OCL~TJG CLOG X a.~A PC~OCCG2613 CGOCC'IC.T A
C~.'~AAOC
1143 ~ 918 ALL'~C~JG CLGATJGpG X Q;a.A2614 A~AOCT C CA0300GI'
PDCtJ~IJ
1162 I~~ATAA 919 CPSJIJGCAA CZJGALJGFG X 2615 CCAOGCCr C TIt3CAA'iG
CAF. PmCCLJGG
ll64 HCHr~ATAA920 ~CAUUC3C CT~G X 0.;A PGAOGCCU2616 PaOCCTCT T O~A1C~G
ll85 FiC~ATAF.921 CLJC~C~JI7UG CZJGAIJGFG 2617 GAGDOGAT C CAAAOCAG
X ~A AL1C1CC'JCZJC
1219 HLE~ATAPr922 Ct7C~G~AW CL~AL7GFG X 0.A 2618 PLCTGAAT A PA'IC..'TAFG
ALA~OCTT
CA 02364577 2001-10-03
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77
Table III. Hammerhead ribozymes tar~etin~ GATA transcription factors ( 1, ?,
3, =1, and
6) and the complementary sequences
1223 HCd~2'~F.TAa 923 cLGF.IJC~G x. CGAA P 2619 GaATAAPT C ',CAC
_
1225 HtdTATAA 924 tX3~JG~CJC.V CUC~FG X CGAA2620 ATAAA'ICT A PICA
PGAUUCR~L1
1240 FiCI~ATAA 925 c~JGAFG G X CC~A PL3CiJC3CTJG2621 CAOCAOC.T C CI'I~L33C
1243 HC~ATAA 926 ?LTJOCCUG CZ7GaIJGFG X 2622 CAGCTCC.'P T
Ch~A P~AOCUG CF~GCF~I'
1244 HCd~2"~PA 927 C?LT~3C'CV CLJGAUGpG X 2623 PL3CIC'CIT C
~A AFL~FDCU r~C33CFGI~
1260 HCll~TATAA 928 G~30GAGG CtIGALJC~G X CGAA2624 GpC,FL3LrT T
AO3CI7CTJC C~C003C
1261 HtJ~ATAP.929 03030GAG CZJGAIJGaG X CGAA2625 AGFL3CCIT C C~CC
AFD3CUCU
1264 H~ PA 930 (~.~3GOGG COGAUC~G X CGAA 2626 GCCITCCT C CC13
AOGAP~C~OC
1279 ~ 931 GUUC33Ci7GG CL7G<~J.1GDG 2627 C3CCGGIt3r.T
X CGAA P~~C T C~.PGCAAC
1280 ~ 932 COG CLOG X CAF. AAOCACCG 2628 ~OCIT C CFL~AGT
1289 F~~A TAP.933 Ct~JUOCUG CiJC~IJGFG X 2629 CAOCAACT C CPL3CAACG
AAA AC~7IJOCLJG
1327 Fi~TATAA934 CinJGAlJC3G CIJ~TJGF~ X 2630 PGAT~T C C~C~1FG
OG~A AC3CAZJC3J
1332 A 935 UCi~JCT CTJC~1I7C~G X ~ 2631 SCAT C AP~Gp.
AIX33GF10G
1352 ~ 936 ?~C~U Ci~G X QUA AC~OOCCA 2632 ~3CCICaT C ATGTCACI'
1355 Htd~T~ATHA937 ~G'OGp. C(7GAZJGFG X CX~A 2633 O~.T C 'I~C~A03
PT~D3
1357 HI~A TAA938 CC~T CtxAI7GAG X OGaA PGAUt;~2634 T C ACrA033G
1361 HC1L~T~ATAA939 L~OC'CCG CL~JC~G X SAP. . 2635AT'~GT A a300CACA
P~LJ
1376 HCE~ATAP.940 O3GAC~L~ CTJGAZJGAG X CGAA2636 CAGCAOCr C CSC
PL3Ci70CUG
1382 ~ 941 r~OGUCUOG CUGAUGAG X CJ~F.2637 CmOGIC;T C CCF~RCGT
AC~100.~~G
1391 HCH~TATAF.942 UCG CWG X CGF1A AC7C~7CLJC'~2638 CCPC~GT T C~GI~A
L392 Ht.~,TAF,943 C~ACjJGA CUGAI7C~G X Q~F. 2639 CAGACGTT C TC'AGIC2~
APGJGtxTJG
1394 HL~F.TAA944 C~CUGFC.V CLOG X 0.~~AA 2640 GAOGTTCT C PGI~
PGAACr~7C
1398. ,p,945 AI303CACU CZX~G X CGaA 2641 TIC~Gr C PGInOGAT
PLZJC~C~A
1409 HI~A 1~F.946 C~LJG3CC'~. CTJGAUGAG X 2642 'InCGA'IGT C
0.;AA AL~Lx~"A 'It3C-~'~Q~G
1424 FA A 947 GaJGGAUG CL7~UGHG X CGAA 2643 'IC~OOCCCT C
1~33COC~. CATCCACC
1428 ~ 948 ~~JG CiJC~G X O:~F. ALJOGAOC~2644 CCC~CAT C CACCCIt,'r
1437 Hf~ Fa 949 GCOGAC~G CLOG X CGAA AC~ODC~;2645 CALL'~CIGT C
CT~3C
1440 HC~A TAF.950 ?~OC~ CLX~G X CGAA PEG 2646 ACT C 'I~CT
1442 HCP~ATAA951 LJC~OOOC ~G X CGAA PL~DGPCA2647 TC~'IC~~C.T C
03C~C'IL~.
1455 H~ A 952 L7C~.~300GA CT~G X CGAA 2648 CTGAAOCT C 'ICCC~
.~L~Ct~
1457 F~T~ TAF.953 CUUt~~33 QJGAUGpG X QUA 2649 GAPDCICT C COQ~G
AG~LDCWC
1469 Hta2'~F.TAA954 GAG~CA CZJC~G X CAA PLaOC~J2650 PCAAOOCr A
'il'~CG'It_.'rC
1475 FA A 955 LJG900GGA CLOG X AAA AOOCAL~2651 C~~T C 'IL''LL~C'A
1477 HI~ F. 956 OCUGAOGG CLX'~LJC~G X 0.~AA2652 A2C30GIC.T C
PGAOO~IJ O~IC~DC
1482 Fit~ATAA957 GAGL700CU CiJ~LJC~G X OG~A2653 TL'~CGT C PL~C~IC
AC~OC~.
1490 HC~F .~9F.958 L~13 CT.X~LJ~G X O~A PG~JOO~JG2654 CPC~CFGP C
'I'L~CAC~C~
1492 HC~ P. 959 O~JG ~ X CC~1A AG~3C 2655 C~CCF~L~'IC.T
C CP~C~GC
L505 Ht~~ ATAA960 CCU3CWG CL~FG X QUA PDCOOQJC2656 GAC~OCT C CAAGCPL~
1517 HC~ ATAF.961 UC~Jt~CAA CL~FG X CGAA 2657 OCpDGA~.T C TI~3~ACF.
PL~CCUOC
1519 F~ A'L~A962 PL~'C CIJC~'ALJGPG X CGAA 2658 PL3C~~C.'I~T
PC~J T O,~A~GT
1528 ~ 963 CAPGACCA Ci~IIJGAG X CAP. 2659 C '1L3GTC.TIG
AL'~JIJOC
1533 F~T ~i 964 L~CCAA CLK~G X QUA AOCAGPLU2660 PGI~P C TIC300~A
L535 HII~T~ATAA965 L7C~OCC CZJGAUGPG X ~A 2661 'IC'IC~ICP T
~ PI~CPGA GOCCt;~Cp.
1546 HUhG ATAA966 QTOCL~iJ GTJGAI~G X O:~F. 2662 CCGACPGT C PmGd~IC
ALT~tJ~G
CA 02364577 2001-10-03
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78
Table III. Hammerhead ribozymes targetinJ GATA transcription factors ( l, 2.
3, 4, and
6) and the complementary sequences
1557 iit~T~A'L'oA967 (3C~.I1 CUGAL'G?G X ~1A 2663 OOOGtIC'AT A
ACGUCCCC A'~C1C~C
1560 HC~T~ATFA968 LlALT3CPL~J CiIGFJ: F~ 2664 GAI~.TAAT C PLIC~
X OGzli1 P~UUALJGiJC
1568 H<i~'AA 969 OOGAAC~IJ CUGALL~G X OG~A 2665 CACIGC~I' A A'I~T
P,L~30PL~~
1571 HUL~ATPA970 ~~DC3GaA CLOG X AAA AL~CA 2666 'IC3CGTAAT C
TICCC1L'I'
1573 ~A 971 GAr~CAO~ C~JCAUG~G X CGAF.2667 CtTAP.2C.'I'
PGAfJUPLG T 0~..'IC.'PIC
1574 FiI~ATAF.972 C~GAr~GAOG C<JGAI~G X C~'~F.2668 GTAATCZT C CCIC.'t'IC.C
APGAI~
1578 E~.~ATAA973 c3G~a CtJGAL~G X O~A A03JAFC~12669 ~ICCCP C Z'1~CC~
1580 HUNIr,F.TAP.974 C'~G:r'~3G CiJGFl~G X d:~F.2670 TI'~CIC.T T C~C'ICCIL
AGpOOGAA
1581 Hf~ATAF.975 UC,AGGFGG Ct~LJC~G X AAA 2671 'IOCCI~IT C C~CIC4
P.FGAGOGA
1585 F~~ATAA 976 AF~UUUGFG CT7GAUG?G X ~A 2672 TCTTLCL"I' C
PC~C~AAGA CIC~AATr
1588 HC~ATPA 977 nDGAAUUU CL7GAUQG X 0.A 2673 'I~CCrCrT C AA~:TI~':.'T
' PD~.O~.
1593 Fitd~ATAP.978 Cl';<JOCFGG CLOG X AAA 2674 C~AAT T CCIC~CALG
AUUUC~33 -
-
1594 HUL~ATPA979 C~JO(~G CZJC~AtJGaG X O~P.2675 CICAAATT C CIDCAOOG
AAIJtR~FG .
16L3 HU~T~F.'LAA980 LC CtK~IJGFG X QUA PC~JOCCAG2676 C'IC33GAL'r T
CGAO GATA
1621 HC~A 981 UUCUUUGC CLTG~7GpG X CT~A 2677 TGGFGGAT A ~1AAC~,A
AL1CLZJOC~.
1644 HUNrATPA982 C3CCC~L10G CZ~G X O~A PGGLCAGG2678 C~GOCr C CC~GOC30C
1659 HUNIJATAA983 PD3CAGpG Cite X QJAP. PG~~130C2679 aC~OCLfi C CICIC32T
1662 HUN~ATAF.984 ACCPGOCA CT)~G X QUA PGGAO~'C2680 O3CCIC1'.T C
~~
1671 HIJ~ATAA985 OGA~IJ CZJGAUG~ X ~ ALCA03C'A2681 'ICaCCI~T A A'IC~.GTCC
1678 HI.~TAA 986 C7U~lI7CTJG CL7C,ALK~G 2682 TAF~GFCr C C~PC~
X ~A AGt~t~
1703 HI1 987 UCGALTJC7C GZJGAIJ~G X 2683 AAGAAAGT T CAAGInGA
0.-AA PL~7UtJC<J~T
1709 FBATAF. 988 r~GAUI)C~..~ CLOG X CGAA 2684 CTIGAFyT C GFC~ATt.'r
PGTJCIC~.F~
1716 HII~~ATAA989 CCL~AGC'A CMG X 0.3F1A 2685 TCGACAAT C 2C3GT1~3
AID.
1721 HII~ATAP.990 CUU ~:CCU ~ X CGAA PL~C~1W2686 AA2~3~T T A030GAPG
1722 HUN~ATAA991 C3C~'CCC CUC~TJC~G X Q~1A 2687 AT<'IbGIT A OGOGAAFC3C
P~PGAIT
1737 A 992 GAAAAI7C~ CLJGAIJGFG X 2688 G0~ T (3GATITIC
CGAA ACACCCt3C
1742 A 993 LJCtJGAGAA CZJG~G X OGAA 2689 T~C~.T T TIC'I~.
ALJCCAACP.
1743 Ht~F~TAP.994 PJJGUGFGA C~i7GAG X CAF. 2690 GITPOGAZT T 'IC.'I~T
A.~L70CAFG
1744 HIR~F~AF.995 CALJC<JC~G CT~J~G X Q~F. 2691 TIC~GAZ'IT T
AAAIX~F. C'IG9C~:IG
1745 I~TAA 996 aQ~ Gi)GAL~G X QUA AAF~C~..2692 'IC~GATI~T C
~GA1D0
1747 HII~AF. 997 .a130CAIJC.U Ci7C~~TJGF~ 2693 GAT!'I~CT C PGATaCCl'
X 0.'A PGAAAAUC
1756 F~ATAA 998 PDC~ CUC~I~G X Q~1A ~LJCTJ2694 PC,A1CIOGT T
'I~OGCP
1757 I~ATAA 999 CAO~1 CL7G9i7GPG X Q~AA 2695 C~1~ T PC~C'IG
AA03CAL1C
1758 HC7I~ATPA1000 L7~GOCT>G CU~G X CJ~A AAFGOCAiJ2696 ATQ~TIT A CPL~CIL~
1790 ~ 1001 L~CLJG CUGAUC~G X O~A P~3G2697 CCC.~CCX.T T
CAOCAOGA
1791 HII~ATAA1002 GLR7GUOLZT CLOG X AAA AkY30Gt2698 CCPCCCIT C PGC~L7GpG
1810 H~A~A 1003 AC~L~GpGA CL7GALJQG X OG~A2699 CACIOCAT C 'IC.'mCIC~T
AiJt3CpL~
1812 Fifd~~ATAA1004 UC~L~F. CLOG X OC~A ~GAUC~C~G2700 CIC~.'ICT C
TCCI~G11;P~
1814 F~L'~ATAA1005 AGOG CMG X ~1A PGAGAVOC 2701 a~2C.'PGT C G'IGTGPGT
1823 F~ATAF. 1006 AFL~JCT>CC C~L~ X ~A PCUC~G2702 CIGIC~Gr T OGFGFL'IT
1831 HCB~F.TAA1007 UG~ CLJGALJGpG X Q~1A P~C~12703 'IC~C~CT T CIT?'CCCA
1832 HUN~A 1008 UUC3C~,~AAA C~U~G X Q'~F. 2704 OGAGtaCIT C TI'IC~A
P,P~T~C
1834 HId~ATAA1009 L1C~UC3C~~. CZJGAIJC~G 2705 AGAL'rfCr T 'I~CQ~AC,F.
X CGAF. PGAAC~JC~U
1835 I~A~Fr 1010 AL1C<JIJGOG CTX~IJGFG X 2706 C~CITL'IT T C~~CA~.~T
CC~A APC~PQ7C
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
79
Table III. Hammerhead ribozymes targeting GATA transcription factors (1, 2. 3,
4, and
6) and the complementary sequences
1x36 L loll c~ocuz~ cuGacrc~~ x a~A 2707 Acr~rrr c cry
a~
1x46 ~ 1012 c~cac~ cvc~,uc~G x o~A 27oa c~Tur c rricmoc
Ac~txvt~
1849 FF. 1013 CAC303GAC CL~AI1~ X Q~. 2709 GA~G~T T GI~LC~IG
PL33ACALJC
1852 I-~;~AA 1014 e~COC~30G C~F~L~AG X 0.A 2710 GI'UC~ C CLCIC~T
ACAAOGAC
1861 H(~~TAA 1015 C~03G CFG X CC~ ACx3CPDOG2711 C~'IGCGT T CLCCACIG
1862 xC~~TAA 1016 ~3G CUGALJGnG X QUA ~C~G 2712 CL'InCGTT C ~~T
1876 HUJN1;ATAA1017 CC~ Ci~LJC~G X Ct;AA P~OCCACP.27L3 'IG~GCCT A GAOOGIL3G
1887 HI~P,TP,A1018 CAAUOCAA CUGALK'~FG X 2714 CCGIC~OGI' T
~A ACL~AOC3G TIC~CATIG
1888 HI.d~ATAA1019 ACAAtX3CA CLOG X ~ AACCCAGG2715 ~GIT T ~TIGT
1889 HC~ATAA 1020 CACAAL7C~ C(JGALJGAG X 2716 G'~3G~IT T OC~.TIGZG
OGAA AAAOCC~G
1894 F~ATAP. 1021 AGAAACAC CUGAUG?G X CAF. 2717 T~'IC~CAT T GIGTIZCr
AtJGCAAAA
1899 Htll~ATAA1022 c~70CCT~A CLC~FG X AAA 2718 CATIt;IGT T 2C.'~C
AC~CAAiJG
1900 HC~ATAA 1023 OCC~JO~ CTJGAUGAG X OG~A 2719 ATI~IT T CIPDCAUC
AACACAATJ
1901 HI'~2'~.TAF.1024 C~~. CUGAtJGAG X ~1A AAAC'~A2720 TIG~GITIT C ~CG
1903 HUNIaATAA1025 C~~70C X ~ AGAAAC~C 2721 GIGTITCT A ~1GC~AA
1916 Hue. 1026 LCLT~LJGPG X QUA ALJt7CtlUC~2722 CGAFaGAT C 'IGF~ACA
1955 F~ATAP. 1027 LJ~CTJG CCJGAL~PG X OGAP.2723 0.'~CX.'iC~CT
F~GCF~OOOG C CFaC~.
1974 I-~~ATAF,1028 03CAAACA ~LG X QUA AUOCa.~JC2724 GACi3GCAT C T'T!'InOC
1978 HII~ATAF.1029 ACAUCaOCA CL~TX;FG X AAA 2725 GCA2C'IC,T T
ACPC,ALJC~C ~~GT
1979 F~F~F, 1030 L~AIJC3GC CUGAtJGF~G X 2726 CAZCPGIT T OOCA~
O~A AAC~C,AtJG
1987 FiC~A'I~A1031 CAUCCFL3G CLJGAIJGAG X 2727 'IC3CC~' A CC'IC~GAZG
CGAA ACA~3f~
2021 HIE~TF:fAA1032 C~SJ0003C CL~1IJGF~ X 2728 CA030CL'r T G0.CCAZC
QUA PC~GO~TJG
2029 HI3~T~'~'AA1033 .~L30GCAIJG CZ7GAL7GAG 2729 'IC3CCCCAT C
X CAF. ATJGOOOC~a CATCCDCP
2033 fBI~ATA~,1034 CLX~AOOG CUGALJGFG X ~F. 2730 CGATCCAT C ~CIZt;~
ALX3 GAL~3G
2038 HI~~'AA 1035 CAI~~C?CJC CT~T7GAG X 2731 CATC~CT T GA03CF.ZG
CGAF. P~C~OGGAUG
2061 HI~TATAP.1036 ~G CiJGAL7GFG X OC'~P. 2732 SCAT C ~ATAC
AI7t3CA00G
2065 HI~ATAF, 1037 Wt);3Gt~iJ (ZJG~IJGpG 2733 ~CL'f A ATAECAAA
X AAA PD3GAL70C
2068 HIATAF. 1038 PGAI)~3 C<JC~L7C,AG X 2734 'I'U2~I~1AT A
Q;AA At~3GA CCAAP~'C.'r
2075 HIaT~ATA~.1039 UGGAG~. CZJGAL7GpG X ~A 2735 ~AAT C TG~~
ALn7Ut3~.
2081 F~A'I~A 1040 C~AIUIJG Ct~At7~G X ~ 2736 A2~C~GT C CAAAACIG
PGUC~GAIT
2120 HIB~ATAF,1041 LJCO~ CL1GALJC~G X OG~F. 2737 TGAGCF1C.T T
PC~OCiJC'A CCImOGA
2121 HI7N~ATAA1042 CL~700CQG Gt~G X CC~A 2738 GF~DCAGTP C CIt333GFG
AFI~LZ7C
2132 HI7N~F.TAA1043 L7Ca0~7G CTJGAIJC~G X 2739 mOGAOCT A CAOGOOCA
OGI~A AOCTJ~
2143 Fif.~T~F,TP~,1044 Q'~30utJfJ CMG X Of~A 2740 t3G0~C.T T AALi~CAOC
PLZJ00."L~
2144 HICE~'~F.1045 UGQ~C~J C~L~G X Q;A~. 2741 030~CIT A ALA.
AF~70~
2164 ~ATAF~ 1046 AL1C7(7UGAIJ CUGAIJGFG 2742 WCAOCCT C ATC?AAAT
X OQ~A Pa0CU00G
2167 T~ATAF, 1047 UGCAUtAAJ CMG X CC'~4A 2743 AGCCn~T C AAAA'IL3C~.
AI~OOQJ
2186 FOP, 1048 UOG30C~ CLJGAZ)C~G X CC~AA2744 ZL30~ACr T C'I0.'~0~.
PL~JtX3~'A
2187 HI.84;ATAA1049 C00003GA CtJ~i~ X OGAA 2745 ~AGZT C T'"'~
ApI~JtJOCC
2189 HC~ATAA 1050 PGCiJC~ CZJ~G X O~P. PC~PL~OG2746 CAPGTZCT C COCC~T
2202 Htl~~ATAA1051 GCF0300G C~AL1GPG X ~A 2747 AOGIC3CCT T CL1CC.'IC3C
PGOCACCU
2203 HI$4;ATAA1052 .~L~C~O~ CZJ~G X 0.A AAOOCACC2748 (3GZnCC'iT C
CC.iCIC3Cr
21 H~6PR 1053 C~C~GC~ CUGAUGFG X Ct~A 2749 ~CCLT T CGOOC~DC
PDOG(IOCC
22 H9CATA6PR1054 03CUCG~ CZ~G X O~A AAOOC~i70C2750 C~CP~'IT C O3~
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
Table III. Hammerhead ribozymes targeting GATA transcription factors ( l, 2,
3, 4, and
6) and the complementary sequences
35 fL9C~1TA6PR1055 CC.2~1AACA CUGAIJC~G X 2751 ~L',C'OCIGI'
~ ACAGL~3C2T T 2~TI'IPDu
36 HS~.TA6PR 1056 C~.T~P.~C CtJGALTC~G X 2752 OCC3CIGIT T GTT'~O3G
(>;AP. AACAOC23C
39 H9GATA6PR 1057 C~1(3C~Ct~1 CVGAZJ~G X 2753 CIGIZ'IGT T '~3C3C3CIG
O~A ACAAACHG
40 HSC~.TA6PR1058 ~CCQJ Ci7C~U~ X 0.A APLARACA2754 ~ T A~OC3CICx;
41 HS~'A6PR 1059 CC~AGC1.2 C(X~.LK35G X 2755 GITIGTIT A 030
~1A AAPCAAAC
47 H9GATA6PR 1060 GAC<JCAOC CZJC~L1GFG X 2756 TI'PL30C3CT C
CGAA PL3LLCtlAA C3GI~GIC
55 FiS~.TA6PR1061 CCJGAUUG CT"~FG X QUA AGUC'.'9~2757 CC3GI~ C CAA2~G
60 HS~.TA6PR 1062 QOC~CZJCCIJ C<JGAZJGFG 2758 P~CAAT C PDC~3CCC
X CC~A ALIUt3C~J
79 H9GATP.6PR1063 Ut3CCOGAP. CLJGAL~AG X 2759 O~CFG'f T T~CA
CGAA ACZJOCAC3C
80 H9GATA6PR 1064 CtJt7CCt3GA CLI~LJGF~ X 2760 CIC3CAGZT T n~OC30CFG
CAP. AACUC~CPG
81 HSGATA6PR 1065 CJCi~3'~'COG CZJGAL7GPG 2761 20CAG'TIT T C'~C~C~GA
X QUA AAACUOCA
82 fL9GATA6PR1066 CtKLX3C<7G C~AIJGAG X CAP.2762 C3CPG1TIT C COOCAC,FG
AAAAC(70C
95 HSGF.TA6PR1067 C~OOCtTQJ CUC~;Ur~G X QUA 2763 PC~L3CAGT A PC~O003C
ACUOCL1CZT
106 Fi9GF.TA6I~R1068 a;~GAGAG CZJC~1L7C~G X 2764 P~CCT C CI~TCmC
CC~F. AO3COOCU
109 H9GATA6PR 1069 AAPO;~AC~ CtX~G X Q,AA 2765 CGC~PCCr C T'TCCITT
PL~AOOOG
111 H9G4TA6PR 1070 AAAAAG;~. CtJGAL7GAG X 2766 CL'POCIGT C
~ PGFDC~
113 H9GATA6PR 1071 AL7GAAAAAG CL7C'~7G~G X .2767 'mCICICT C CITTTTAT
~ AC~C3GA
116 F~6PR 1072 C7GAAL~AA CLX~LJr;AG X 2768 T~'Lr.'I~GT T
CGAA PL3~GFGp.
ll7 Fi9GATA6PR1073 GUGAAL~A X ~A A~G~G 2769 CIC.'I~CIT T
TIA.TPCAC
118 FZ9C~6PR 1074 aCLX C1~A AAFL3C~P. 2770 T"'ICCTTr T ~C
119 Fi9GATA6PR1075 Ut3C~X"~AAIJ CL7C~LJGAG 2771 CiC~CT~IT T ATI~OCF~.
X CAA AAAAOGFG
120 ~6PR 1076 CtJO(3UGAFa CUGAL7~G X 2772 'PCCITIZT A TIC~1CCF~a
CVAA AAAAF~C~1
122 H9GF.TA6PR1077 UOCUOC~L7G CMG X ~'~AF. 2773 CTZTI'~PaT T
pJ~AAAAG C~OCa.
123 FL9GATA6PR1078 CUOCL~J CUC~G X ~.P. AALIAAAAA2774 TTTT'1'P.ZT C
PG~CpG
152 H9GATA6PR 1079 OC~OOC CT~G X AAA P~003G 2775 CC~ C C~CIOOC
L58 HSG~6PR 1080 CAOO:~ CLOG X O~A AO~OC~G 2776 CI~CT C 0.~CIG
174 H9~.~6PR 1081 GAGAAOCC C<JC~UGAG X CC~A 2777 QOOC~C'GCI' C
PL~f3~C (33CTIL'IC
179 H.9GF.TA6PR1082 0."1'3~G C~JC~TJGF~ X QUA 2778 CCI~'~C~C.T T
AC~GCCAOG Ch(.'IC03C
180 H9C~'A6PR 1083 ~0~ CC~IJGFG X 0.A APC~~AG2779 CI~3CIT C ~Q'3C~
182 H~.6PR 1084 03~ CLJGALJ~G X ~F. PC~AA00~2780 C~30CI~T C 'It~30C~CC
184 F19GA2~.6PR1085 CAOC~00~ CLOG X CAA P~AGC 2781 aCi'IC..'iC.T
C COOOCX.'IG
203 Fi9GATP.6PR1086 C~OOOOCG CMG X CQ~A PL~CU 2782 PGCAL'~!' C ~O~G
216 H9C~'A6PR 1087 ~C~1G CL7~LJ~G X C~A AC~NOC2783 C~3CC~T T CILCAIC3C
217 HS~.6PR 1088 CC3CALJO~r CLOG X CC~1A 2784 COOCC~'iT C ~CG
AA030CCG
219 HSGATA6PR 1089 UO~L7G CLOG X Q~F. AGAAQ33C2785 QO~TI~T C CATCC~OC~CA
246 F~9C~.TA6PR1090 CT~JC CLI~JC~G X CGzIA 2786 GF~t3CT A GAOGICPG
POCTJOGTJC
252 H9GA1~.6PR1091 UCCAkIOaJ CZJGAZ~G X Cr.~F.2787 C~GT C POCTI~.
AOC~COpG
257 H9~6PR 1092 C3C~CT7Ctr CZJC~TJC~ X 2788 ~OCT T aC~0000C
QUA PL~~
285 F~.6PR 1093 OC~JC CMG X CAF. AC30CCATJC2789 GAZC~GCCT T GPCIC~
306 Fi9GF.TA6PR1094 aCfJtJC00C C~iJC~G X O~A 2790 CIC3GI~3CT .
POCACCAG T aCt3JAFL3C
318 H~~TA6PR 1095 COOCCOOG GL7GAIJGFG X O~A 2791 C,i~AC3CL~T T
P~CWC ~30~
319 HSGF.TA6PR1096 C~C~OCCCC CiJGAt~FG X CAF.2792 AAC~CTT C 03C30CCt'3C
AP~OCX3CUIJ
348 H9C~P.6PR 1097 POC~CUCLJG CT2~~1JC~G X 2793 CAG~AGT C C~L~.T
O~A PGUCC~C.ZJG
357 H9C~6PR 1098 QOOCt~ Ci~AIJGFG X ~5A 2794 ACT T 'I~03C
.'903CUC<JG
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
81
Table III. Hammerhead ribozymes targeting GATA transcription factors (1, 2, 3,
4, and
6) and the complementary sequences
358 HSGATA6PR1099 ~CX303CtJ~ CLJGALJGAG X 2795 Pf~CTT T CCPG~
CC~P. APa3CLLLT
359 fISCATA6PR1100 CC~Ci7G CUGAZJGFG X ~ AAPC3C~TJC2796 GAO C CPL3Gn~
375 HSGATA6PR1101 C~3CC~JG CMG X QUA AC30GCLJC~2797 C~GAC~L~C.T C
C~Ct~C
386 HSGATA6PRll02 GAI~~c3C~ CLT~IJr;FG X 2798 CG0.~CCT T C~CCATC
Q~P. AOGCOOC~
387 H9GATA6PR1103 PGAIJt303G CT~FG X CGAA 2799 C3CLaCCIT C CCCCAIrT
APDGC~OC
394 HS~TP.6PR1104 C~OGAAGp. CZJGAUGFG X Qs4P.2800 'I'UC~T C 'I~:.'I'C
ALJOG3GOGA
396 HSrATA6PR1105 ACGAOGAA CZ7C~G X CIA PC~GG2801 CCCCATGT C TICCIr7GT
398 HSGATA6PR1106 (3jACGPI~ CLJCAZ)GpG X 2802 CCAT~T T CCIt'G1LC
C1~A PC~GAL~3G
399 HSC~TA6PR1107 PL3GACGAG C~7CAtJC~G X 2803 CATS C C~G'I~Cr
CGAF. APGAC,ALJG
402 HSGF.TA6PR1108 PDGPL3GAC CTJGAI1GAG X 2804 CPCI'ICCP C GI~Ci~LT
AAA AGGAPGFG
405 HSGATA6PR1109 P~GpDGnG CU~G X CAF. A~OGAA2805 TI'CCIC~T C CI~CI~C.T
408 H9GATP.6PR1110 PI3CAOGFG CLOG X AAA AL3GACC~PG2806 CT~Cr C CI~CT
411 6PR 1111 C33C,FDCPG CLJG~AIJGFG 2807 GI'CC'IC.LT C
X 0.P. PDGAO~C . C~CC
417 H~.6PR 1112 C~C~ CL7GA1JGAG X OC~AA 2808 CI~C'IC~ C C~~
AflQ~GG~G
467 HSGATA6PR1113 GCTOGAGCU CIJ~G X QUA P03CC~JCJC2809 aGACOCx.T C
PL~CPOC~C
472 HSGATA6PR1114 UCOCTJ~JC CTJC~T7GPG X 2810 CC'IC'~OCr C
CGAF. PL3CtJG~G C~~A
507 HSG~6PR 11L5 aCP~OC CC~ALX~G X O~A AOC'3GOCC2811 f30CCl~CT C
CaC'InC'InC
517 HSGATP.6PR1116 LB~OG~1ACV C~JGFTJGFG X 2812 CIC3CT'GCr C
Q~AA PI~OCFG AG'rI'C(.'I'A
521 HSG~TA6PR1117 POQ~lAGG CMG X OG~P. PL~CA2813 'IC'~CIt~GT T
CC~Cr
522 FL9GA~6PR1118 AAG~G CTJCAZ~AG X O~F. 2814 OCm~IT C CTACGCIT
AACUGAOC
525 H9GATA6PR1119 0.~GAAOCu CLJC~ X CGPA 2815 CAGTIC'CT A C~CTr00C
PO~AL~7G
530 H9GATA6PR1120 ~CG CTJGAUG?G X CGAA AGOG 2816 CC~LOGT T CC~CATCCC
531 H9GATA6PR1121 PC~OGAIJC~C CI~G X C1~A 2817 C'~CIT C OCATCLT.T
AAOCCT~G
536 HSGATA6PR1122 CCCuAFaG CT~G X AAA AIJOC~G2818 CTICJ3CAT C CCThC333G
540 Fi9GF:IP.6PR1123 C~AOCC~ C~LJ~G X 0.'i. 2819 C~C'AZCCCT T
PDOGALJOC CGOGC3C'IC
541 HSGATA6PR1124 OGpOCLCC CZJr;FIIJGpG X 2820 CATCCCTr C C3300CTLC
QJAA AP03GAL~
548 H9GATA6PR1125 UC~G CUGALJC~G X QUA PGCC!L~A2821 T~C~.'r C COCOA
560 f~9GATA6PR1126 PL3003COG CT~G X QUA P~C~CT2822 AOOGACC'r T ~G~CCT
561 HSGATA6PR1127 CAOGDOOC CUt~ X Q7AA AP~OG2823 ~CIT C ~CCIG
574 HSGA2A6PR1128 OGGOCCQ.3C Ct7~~FG X O~A 2824 CC~C~3GGr C a~30~
A0.~C~'3G
597 Fi9GATP.6PR1129 OCCAC3CTJC CTJGAIJC~G X 2825 C4PGt:IGT C GAGCIC~
Q~F. AC~1GC~JtJG
612 HSGF.TA6PR1130 PG~CAGC CZ7GAL~AG X OGAA 2826 C3C,~~GACI' T
PC~~Ct70C O~C~T
~ _ O~JG CiJGALJGAG X U~.A 2827 O~G~GT T ~C
~1 PG~C~OC
622 H9GATA6PR1132 A~QJC'9C~7 CMG X CGAA AAC~~OCPG2828 ChGCIGTT C ACI<;AGCT
631 H9GATA6PR1133 aCU~3C~7C ~G X CGAA PC~~JC~J2829 PL~cCT C GnLCAPOC
666 ~.6PR 1134 ~30CZJG CL7GAL7C~G X CGAA 2830 C3CZG~3GT C CA00.?~OG
ALC~C
693 Fi9C~TA6PR1135 ~'~JOOG CUC~IJGFG X O~A 2831 G~CCT T COCAOOC~
PL3000CUC
694 F~.6PR 1136 UO~C CZJGFTJGAG_ X O~A 2832 PL~CL~CTr C aC~CO~.
AF~300~TJ
720 Fi9GATA6PR113'703~G CLOG X CGAA AC~I7r.TJCC2833 O;~GP~G'r A CCFGAOx
730 Fi9C~P.6PR1138 PG~~COOC CC7hAUGAG X Q:~A 2834 CAC~GCL'r C aNOCIrT
POOGtJCZ7G
737 HSGATA6PR1139 OCi~~FGp. CL7~L7C~1G X 2835 'I~OCP C TC'n7Cl~L~C
D~A AOOGOOGA
739 HSGATA6PR1140 L~C30~ Ci7GALIGAG X CAA 2836 C~C~.'ICT C 'I~OOCA
PL~00.'~
741 ~6PR 1141 CCUOGCUG CMG X CAF. PGAGFL~2837 CGCIC.'ICT C
Cl~GCCFC3G
752 H9GA1'A6PRll42 030~CL'~ CMG X OGAA ALCL~3GC2838 C~C~T C ~GCCOC~
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Table III. Hammerhead ribozymes targetin' GATA transcription factors (l, 2, 3,
4, and
6) and the complementary sequences
762 FL9GaT-. ll43 C~CCL~JC~ GTJC~,I1C~G X 2839 ~CX.T a C~A~:C~CG
r ':~ CVAA ACC
783 t-LSGATA6PR1144 Pf~70G~C~ CUG~L~G X QUA 2840 ~C3CP T CxsI~C~C.T
pC~T~C3CCG
784 F~1TA6PR ll45 GAC~JGCAC CIJC~IIC,FG X 2841 Q3CGGCTr C GIC3CAf.'IC
CAF. ACC
792 H9GATA6PR1146 CO~p~, ~C~ X ~ p~7GC~ 2842 CG~CAGT C 'IL3CbOCCG
831 HSC,ATP.6PRll47 3G CIJG~UC~G X OGAP. PL3CL~2843 GOCC'~~C3LT C
~GICT
838 FiSGA~I6PR1148 03CACCT>A CiJGAL~G X CGAA 2844 TCCCCt~T C 'IA~~
AL~GC30GFr
840 H9GATA6PRll49 tJ00C~CACG CTJGaLJ~G X 2845 ~LmGIt='f r7
CGAA PC~L030G CVIGCC1~.
863 HSGATA6PR1150 CP(3CAL7C~ CZfi~AIJC~G 2846 ~C~T T CCA2C3CIG
X CGAA AL~CC~C
864 H9GATA6PR1151 ~CAIJG CIFG X CVAA APL'CC~OG2847 C~GIT C CAZC~3C
880 FL9GATA6PR1152 Z~OG f:LGALJGAG X CGAA 2848 ~pCx.T A CL~!'ACCA
PL30C0.'~
885 FL9GF~~16PR1153 GG~C3C~JOG GLG X 0~1A AOO~L3G2849 CCTAO~T A Cue'
900 H~6PR ll54 CAGLZ3CCC C<JGAZ)GFG X 2850 GCA03C1;T C G03CFGIG
QUA AC!OCCUt3C
956 H9C~P.6PRll55 CGpI3GOCTJ CTJC~UC;pG X 2851 OCICaGGCLT C
QUA PL3GCC~10C AOOC~InG
963 HSGATA6PR1156 L~OOC CtJGAUGFG X CAA P~C30C~A2852 T~CGT C GGCOGACA
977 H9GATA6PRll57 (~CL,~I7G CC~AL7GAG X O~A 2853 AG~3CLL.T C CA'I~L700C
PL33GCL7C~J
981 F~9GATA6PR1158 CGCUC~C.'C~ C(JGAUC~G X 2854 CC~.'mC'AT A
QUA AIX~~AC~3G 033CaDC~ .
1038 H9~~.TA6PR1159 C~03C~LTJ CtJGALJGAG X 2855 ~C~T C P~Q!OOOG
CGAA AC~CCPL~OG
1054 Fi9C~.TA6PR1160 C0~ ~ X CG~A ACC~JC300C 2856 GOOCACXT C T'~3G0~
1056 HSGATA6PR1161 PL~OOOOCC CIJGAIJGAG X 2857 GCACGPL'r C O3Q3Ct3GT
CL~A PGA03JOC
1065 H9GA2~.6PR1162 PQ~3C33s CLJC,AL)G~G X 2858 03CGCOCT T 0.'~CCIACT
CX~A PL30000CC
1066 6PR 1163 GpI~OC~ CC1G~L7G~ X CGAA 2859 GC~CIT C 0.''CI'PL'IC
APL3CZ300C
1071 HSGA~16PR1164 UC~OGAC~G Ci7GALJGpG X 2860 CT'ILCCCr A CICrCCC'A
Q~F. A03GG~AG
1074 H9C~TA6PR1165 GGCOOGC~. CUGAL1GAG X QUA 2861 C~:CCPPLT C '1L2CAOCC
PC~3003
1076 Fi9GATA6PR1166 CGO3CU'3G CLJGAIJGAG X 2862 CCTACnT C O~O00.~
O~A PL~OG
1120 H9Ga.TA6PRll67 GOOOOC~. X Ct;AA PG~OCJC~G2863 0.'~OGGFGT T
'~OOCC~GC
1121 HSGATA6PR1168 CGCt~J CZJGAIJC'~G X CGAA 2864 C13GG~TT T A03~
AACL117CC~G
1122 x~6PR 1169 o~cCGCC cvc~caG x oc~A 2865 GGC~crrr a ~ooc~roG
Ap,~
1172 Fi9C~1TA6PR1170 C~3CCAOOC CZJGAI~.~G X 2866 GCGOC~T A GCCIa'3CG
0.F. PLVO~OC
1206 H~6PR 1171 OOC~~ GLX~LJGFG X CGAA 2867 GC~T A CPL3CIC1~
ACUG~
1212 H9GP.TA6PR1172 OCGAC~DC CZJG~G X Ct~F. 2868 GTACAOCT C GCIG'IC13G
P~L~C
1218 H9GATA6PR1173 GOOOOOC~ C~JC~UGFG X CAA 2869 C'I03C1vT C GGO~C
PC~GOC~G
1245 H9GF.TA6PR1174 G;~7C~ CTJG~G X Ci~Fr ADGr7000G2870 Q33~T A CC~1LC~LC
12'17H9C~TA6PR1175 ~OIJCG CZJGAiJG~G X QG<1A 2871 ALA' C Q~00.'~OC
Acx3C~J
1287 F~.~.6PR 1176 pG~ C'Z~AI7~G X CGAA PflOC~GCt7C2872 GAO~LL'r A CImCLCT
1290 H9CA~6PR llTl OC~33C ~G X QUA PC~3C~ 2873 COL~TPGT C C~Ll~.C'TAOG
1296 Ft~6PR 1178 CCC~ CTJC~G X O~A Pi33G0.;~G2874 CICX~CCT A OGIt3C~
1338 H9C~ATA6pR1179 O3C~JCTJOG CL7GALJC~G X 2875 CC3GAL~T T OC~G~
CGAA A0~
1339 F~.6PR 1180 G33~JrTJC C<JGAI~G X AAA 2876 C~FL'L~CIT C
AAOOCTJOC GAGAL~CC
1387 H9C~,TA6PR1181 OGC90CGG C~IJ~G X Ci;AA 2877 GC0.~OCT C ACC
PL~0003GC
1403 f~,TP.6PR1182 UGC9C~ C<JGALJGAG X OGAA 2878 C~CL1700GT C
PLCCOC~ CC~C'A
1431 ~6PR 1183 GGCUCTJOG CUGAIJC~G X QUA 2879 GGACJCIGr C CGAGFDCC
PL~DC,UOC
1461 H9GATA6PR1184 LJL~GAIJG CL)C,AIJGFG X 2880 C~OCP C C~C~
CGAF. PL3CLOCPG
1465 H~.6PR ll85 GO~JG CL~UC~G X 0.A AUC~OCC2881 OGCIC'~.T C CPC~CC
1503 H~6PR 1186 Ut3C~C~ CZJ~GFG X ~ PL~LJOOOCG2882 OOOOCFLT A CCIG'IC3CA
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Table III. Hammerhead ribozymes targeting GATA transcription factors (I, 2, 3,
4, and
6) and the complementary sequences
1525 H.SCATA6PRll87 LT~CUG~. ~ X O~A r~D~Ca. 2883 'IC3CL3GOCT C
'CAA
1527 HSGATA6PRll88 L~SJtJGCUG CUG~IJC~G X 2884 030GC~C.T A CPDCP~GA
CGAA AC-PLaC~
1546 H9GAW6PR 1189 c3GC~GCT1 CUGAUGAG X Q~,A 2885 rl~C~' C PDC~C
PC~3C'!~7C1
1558 HLSGATA6PR1190 QOCUUGAIJ CRAG X O~A PL330G0.'~2886 Cr C ATCAPDCC
1561 HSGATA6PRll91 UGOGOCUU CtJ~LJGAG X Q~.A 2887 CCCCICAT C APL3C'Q3C'A
AL1~033G
1583 H9G~'A6PR1192 CCGUGAUG ~ X O~A PDGCACDC 2888 C3C~IGCLT T CAICAC7GG
1584 Fi9GATA6PR1193 C3CCl~JGAIl CUGALIGFG X 2889 C~'I~3CCIT C
CG:AA AP133C~CG ATC~3C
1587 F-L9GATA6PR1194 C~0.~7 CL~AUr~G X OGpA 2890 aCC>'ICAT C AG~O~
AIJGAPD3C
1597 H9G?~TA6pR1195 C~9ALK~C CUGALJ~G X 0.;F. 2891 ~G~OLT T C~P.TIGIC
AL~.~OCC~
1602 HS~TA6PR 1196 Ct~OGAC CiJ~tx'~AG X CC~A 2892 ~Ga.T T G'ICC'IGTG
ALJCCAPL3C
1605 F~ATA6PR 1197 C~OC~G CUG'4UGAG X QUA 2893 T3~TI~T C CI~3C~1
AC.~AIJCCA
1619 HSGATA6PR1198 LJ COGAUGAG X CGAF. AC~(JUOG2894 CCA~CIt;T C ACACCFCA
1631 H9f~,TP.6PR1199 UAW Ci7GAUGAG X CVAF. PL~JC~70G2895 ~ACr A CCALCITA
1638 I~GATA6PR1200 UC~CCAII CUGAUGAG X ~a 2896 TP~AL~I' T A'IC~..,OOC~
P~JOC~
1639 H9GF1TA6PR1201 CUl'~CC3CC~1 CUGALJ~G X 2897 PLC~DC~P A 'IC.~3COC~G
QUA AAOC~J
1679 H9GATA6PR1202 C~L~CAC CTJGAL7GAG X CC~A 2898 OCAA'IC1CP T
PC3CAWOC GTnGACIC
1687 F~GAT'A6pR1203 L~9I~ CL~AIJGnG X CGAA 2899 2~'3GACT C '~A'IGAF~
PL~7CCACP.
1689 HSGATA6PR1204 C~JUt7CAI7G CV~IJGAG X 2900 'InG:9CIC.T A
CGAA PC~JCCA CAT:~AAFC
1699 HSGA2'A6PR1205 AG~CCC'PJJG CLJGACJC'a~G 2901 ATZ;AAAGT C CAT<3G3GT
X CG4F. P~LJ
1720 H9G~'A6PR1206 Ut~IL~OC COGALJGAG X CGAA 2902 PC~F~ T Off.
AC~JGGUI.LT
1724 HSGATA6PR1207 Ut~JfA)tJC'A CUGA~FG X 2903 CACITOCP A 'IC~AAAF1A
CC~A AGCAA~
1741 H9C~TA6PR1208 CC7~JWG CUGA1JGFG X CGAA 2904 C'~OO~AT T CAAAG7CFG
ADUC~JC
1742 FZ~6PR 1209 CCUGC~JUfJ CZJ~G X 4~A 2905 PDC~.~"'AATT
AAL)UCC~.tJ C A.~ACCA~
1763 Fi9GATA6PR1210 t~lUrT7UGtT CUGAUr~G X 2906 GAAAACCP A PC,A~.
CQ~A P~~(AJt7C
1771 H9GATA6PR1211 C~1I7U~W CLJ~T~G X CC~A 2907 AAGF~A~.T A AATAAAI~
AL~7UC~tJ
1775 FiSGATA6PR1212 CiJUUGAW CL)GAZ~AG X CGAA 2908 PG~AAT A AATCAAFG
AWC1A~IJ
1779 Fi9GATA6PR1213 AAC~7IJ CL~T~ X CGAA AI~tI~TJC1U2909 AA~TAAAT C P.A~AG'IT
1787 ~6PR 1214 ACCFGPaC CZ~L7C~G X QUA 2910 CAAAGACT T OC~C..'I~T
PC~C.ZJt7UG
1791 HSGa.TP.6P'R1215 UAIJC~OCA CL7~LJGAG X 0.7AF.2911 C~Cl'IC3CP C
.~L3CAAQ7C 2C~TAATPr
1796 H9G~6PR 1216 AWGC(B~LT CL7G~L7GAG X 2912 OCTL'In~T A ATAOCAAT
CGAA P~
1799 H9GATA6PR1217 ALltlAVIx3C CTJGAZ~AG X 2913 CST A OC~ATAAT
C1~A AUtTFL7CAG
1805 H9GATPa6PR1218 AFTJC~GAALT CLOG X CZA, 2914 A'I~AT A ATI'L'~CATI'
A ALx7GCiIAtJ
1808 I-L9C~A6PR~ O3~A~3G CLIra~IIC~G X 0.A 2915 OCAA2~T T C~'I~OC
1219 Ai7~7U0C
1809 ~6PR 1220 UC~OGAAIJG CL~AG X CC~A 2916 CAAT~ATr C COCA
AAt~ItJG
1813 Fi9~6PR 1221 GUC~IJOGG CiJ~LJGi~G X 2917 AATIICAT T OOCAT~C
QUA AvOG?~J
1814 HSG~6PR 1222 P~i7C~ ~G X OC~A AAU~AIJ 2918 ATILCATT C C~ATGPL'r
1823 H9G:4TA6PR1223 OGAF~UG CUGAUC~ X ~P. P~UOG2919 C~ C CAFC1TCC
1829 H9C~.TA6PR1224 PGAO~JC3G CT~iJC~G X CQ~A 2920 CTOC~AGT T ~GC.'IC,T
AC,WGC~G
1830 H9G~6PR 1225 AAG~JG CT~I~ X ~1F. P~AGUC~GA2921 T~AAGTP C CALCICTr
1836 8~.6PR 1226 AL~7C1~AF. CT~G X Q~1A 2922 TICC~Cr C TiC.'1'AACr
POC~C~A
1838 H9GATA6PR1227 tJGW~IC1PG CL1GAUGAG X 2923 CCpLCICT T CrAP~L'I~;A
D~A PGA0~3G
1839 HSGATA6PR1228 C~L~R.IA CMG X ~1A A~JG 2924 CpOC'i~'IT C
'1'AACIC~G
1841 H~'A6PR 1229 AIJCZJGFL~J CLOG X Qi~IF. 2925 CC'I~TICT A PL'IC~T
PLUG
1845 H~6PR 1230 AAL7C~I7CLT CT~IJGpG X 2926 TI~'i'AACT C
CAP. AC~JCmC~IA PGAT~'I'
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Table III. Hammerhead ribozymes tarjeting GATA transcription factors (l, 2, 3,
4, and
6) and the complementary sequences
1853 H9GATP.6PR1231 L'(JCK3C(JCC CVCX CAP. 2927 CAGA'~F~ T ~CAAA
AL7CAUC<JG
1865 F.S~'A6PR1232 0033GAPG CLGn.LIC~G X CAA 2928 C3CAAF1AAT ?
AWtJWOC CITCC~CC
1868 HSGATA6PR1233 tJr~00C3C~ CLOG X CC~A 2929 AAAATPLT T C~'CAC'A
PL~IIUUfJ
1869 HS~TA6PR 1234 DUC~J033G CUGAIJGAG X Ct;~P.2930 AAATACIT C CCCCPCAA
APL~WtJ
1886 HSGATA6PR1235 tJC,PL3C3CiJG CLGAC1GAG 2931 CACHAOCr A CF~GCCIC~1
X CuAA AO~JG
1893 H9GATA6PR1236 CL~CCCCU Ct~ALJC'~G X CLAP.2932 '~CC.T C PL3300QG
PD3CZX~
1940 HSGATA6PR1237 Ql(~TTC3G CZ~PG X ~1A AWOGUOC2933 aCP,CCAAT C COCAGAAC
1957 H~,ATA6PR1238 GAAL~C.W CLK~G X CGAA PL~iJOI~CU2934 AOC~OCr C e~G~ATIC
1962 H9GATA6PR1239 c~Cr~A C~FT~G X o~P. AcUCJGPOC2935 CCI~PGr a TiLOC~
1964 H9GP.TA6PR1240 UIJ~L~CCG CIJC,AZJr;PG 2936 TCAAGrAT T CC3~P.
X OC~AA AI~LVUGA
1965 H~6PR 1241 CUUGACL~ CT~A~G X Cu~P. 2937 CAPGTATr C 03Gn~PG
AAL~~TJUG
1970 fL~ATA6PR1242 C~CPLCTJC1 CLJGAZJr~G X 2938 ATICX~c~T . C
CGAA AC~CL~AZJ ?~1GA'IG3G
1981 ~6PR 1243 CC<JC~UC~G X ~A PG~LJC 2939 GA1~O~CT C '~G
1983 H~'P.6PR 1244 c~CC.tIAtJG cU~G X 0.~P. 2940 2nc30CT~r A CP~G3C~
PGpGOCC~.
1987 F~9C~1TA6PR1245 CUGPCOCC CL~AU~G X CQ~A 2941 C'~T A 030GrG~G
AL7C~IPGAG
1993 H9GATA6PR1246 QOGAGACLT CZJGAUC;PG X 2942 ATPO3GhT C ?G'rCil73C
~ AGGCCC~iJ
1997 FZ~6PR 1247 C~GC~CVA C'VGAUC~G X CG4A 2943 OCGICAGr C 2n3Gt'ICG
PLL~AOOC
1999 H9GA~6PR 1248 03CC~C CUGF~G X CuFA PGACL~AC2944 GPCAGIC.T C aCv'T~CC
2004 H9Gp~.6PR1249 COC~C~OC CL~L~G X CAA PD3~9GF.2945 'I~'~CCT C OCR
2017 H~A6PR 1250 GAO~ACufJ CLJGAIJr~G X 2946 C3C~APGT C AOGI~'1C
Ct;AP. AGtJCI~OC
2022 H9GATA6PR1251 OCPG3C~1G G X Q;AA A~JC~J 2947 PL~'I~T C CTCXJGIC~C
2025 F~9C,ATP.6PR1252 C~CACG CtJGAUC'~AG X 0.A 2948 CAOGn7CT C ~OC~C
PD~JG
2039 H9C;A'L~.6PR1253 aCALCPL3G CT7GFTJ~G X QUA 2949 C~AOmC~T T CCIC3GiL~
AL1000C~JC
2040 H9GATA6PR1254 03CACCAG CLOG X CVAP. AALJCC3GU2950 PL~AT~ C CIt~OG
2095 H9C~TA6PR1255 CWCC~OCG Ct~G X o~.A PGOCCtJCC2951 aGFC~30CT C ooCCaOC~
2108 F~ATA6PR 1256 PL~OG~TJ CTJGAtJ~G X OQ~A 2952 C~C.~'30GOCT
AC~3CCCOC3C C AL'ICCPLT
2112 H~'A6PR 1257 CP,OGAL~7G CZJGAL~AG X 2953 OCCIrPLT C C~'t~~G
~ PC~i7GFGOC
2117 H9GATA6PR1258 OCPGPCAC CMG X CC~1A PGU0.3PGtJ2954 ACDOCACT C GIGTCII'~
2122 FZ9~6PR 1259 CAAAPGCA CLJ~UGAG X ~A 2955 PL~U~T C ZL3CrITIG
A~J
2127 ~6PR 1260 CtJOCACAA CL7GALIGAG X 2956 1G~L~DCT T TTt;i~
OGqA PGG~
2128 H9C~.TA6PR1261 aCU0CPC21 Cu~ILX~G X CAA 2957 Gn'R3CIT T ~CFGC
AP<3CPGAC
2129 H9C~LTA6PR1262 C10COC~CAC CLOG X 0.A AAPGCAGA2958 'I~'IOCITr T
GI~DCA
2140 Fi9C~6PR 1263 ALZJ~TJG C~1UC~G X Ct;APs 2959 a~ C CAC~GT
ALZX3COLaC
2174 F~6PR 1264 QOf~GpG CMG X a.~A AUCAOC~J2960 AAO~T T CI~x
2175 H9C~TP.6PR1265 AC~OCPL1JA Ct~G X QUA AAUC~O~i12961 AOGIC~T C ~CL.T
2177 FZ5~6PR 1266 AAPGOCAC CL7~LX~G X aC~A 2962 GIGATiC.'r C
AC~P~C GTC3CCITL
2184 H9C~TA6PR1267 UCSAAALJ~ CL~~IJC~G X ~ 2963 TOGIC30CT T 'TATS
PGOCAC~
2185 H~2~16PR 1268 L7t~AAAAtJ CtJC~IIGAG X 2964 OGInCGTT T ATITIG~.
aC~IA AP03CAOG
2186 H9GATP.6PR1269 wf.K~AAP. CUGAiJ~G X CVAA 2965 Gil~oci'IT A
AAAC~OC~C TITIGAAA
2188 Fi9GATA6PR1270 LEA CT~G X OGAP. ALmAA00C 2966 aCCTTTAT T TIL~P~Fr
2189 6PR 1271 CLKZJ~P. CLOG X Q~.A AAL~APL~G2967 CCI'ITATr T 'It~AF~G
2190 H9C.~.TA6PR1272 L7CTJCT~ Cu'~LJGpG X CG~P.2968 CTITATTT T G~AAG~
AAPT~APG
2202 F.~GATA6PRL73 W00 ~AAP. CUGAL1GPG X CAA 2969 PG~ T TTfi~P.
PCAI~T
2203 H9C~'A6PR1274 CWC~OGAA CLGAIJGPG X C~~A 2970 CHIT T TIL~CAFG
A~LJC
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Table III. Hammerhead ribozymes targeting GATA transcription factors (l, 2, 3,
4, and
6) and the complementary sequences
2204 fL9GATA6PR1275 C;CL~ C(~~ X pip, ~ 2971 pGA2~ T T~Cpp~
2205 Fi~~TA6pR1276 CUCU(~33 CUC~LIC~G X 0.A 2972 GATr;I2'IT T
AAAACAL7C CCCAPG~
2206 f~LSGATA6PR1277 CrUCUtL3G ~ X CGAF. AAAAAC~IT2973 A~ITITp C C~AGF~G
2217 H9GATA6PR1278 C~7t7C~PC~C ~ X gyp, PLaCCUCW2974 AF~CI' T O~
2269 fi9GATA6PR1279 ?L~~3pCC~ CpGALJGFG X O:~A2975 'IC3pC~~ T ppp~p~,T
PL~C~,
2278 HSG~TA6PR1280 c~CL7~CL7G CLJGALJGFG X 2976 ~C~,T C C~C~
Ct~ PL~JOOC~C
2293 HSGATA6PR1281 C~2~2G CtJGAL7GFG X QUA 2977 ~~T C
papL~pOC
2310 H9GATA6PR1282 L~G~JG ~ X CJ~A pC3C~GOQJ 2978 ACCCIC~T C CACTI~CA
2315 HSGATA6PR1283 aCUtJCtx33 CLJGAL1~G X 2979 OCI~CALT T C'~1GAFG~
CC~A PC~~L3C
2316 H9GATA6PR1284 ~C~ ~ X p~,p, ~~
2331 HSC~1TA6PR1285 OCACC~CC L~AIJGpG X ~A 2981 CCAC~~GACT A
PC~CCLJOG C~ACCIL3G
2344 H~,6PR 1286 tPGCAO(3C LL~AL7GFG X SAP,2982 CIn00CCT T p~'IC~C~
papC~G
2352 HSGATA6PR1287 ALIAWCCA CLOG X QUA AGCAppCA2983 'ItyCCTCC.T
A 'IT3~~AATAT
2359 HSGATA6PR1288 LxTKUCAA Q7GALlGF~ X OC~A 2984 '~e,~,T A ~
AL7CJCCALTA .
2361 Fi9GATP.6PR1289 L~X.UCL~ CUGALJGFG X CC~1F,2985 TAT T
AL~1UUC~C'p,
2371 F~,TA6PR 1290 L~AAA C~X~L7GAG X C~P. 2986 AGpGAGAT T ZTITAAAA
ALXL~J
2372 H9GATA6PR1291 tX~AA CL~I~ X ~F, AAU~UC 2987 GAGAGATT T TITAAAAA
2373 HSGATA6PR1292 G'~JIJIgIA CTJGAIJGFG X 2988 PGAGATTT T T1AP,A~AA
Q;AA AAAIKTJC_TT
2374 H9 CATA6PR1293 CUUt~ CT~L7C~G X OGAA p,AAAL~JC2989 G~GATTIT T TAAAAAFG
2375 HSGATA6PR1294 IJtT CT~G X ~F, AAAAAIJCiJ2990 PGATI'I~T T
AAAAAAGA
2376 H9G?1TA6PR1295 AtJCUWW C~IJGpG X AAA AAAAAAZJC2991 GATITITr A AAAAAC~T
2385 HSGA'I~A6PR1296 AAAL~3CAA CL1GAUGAG X Q,~Fa2992 AAAAAGAT T TtCaCATIT
AL7Ci~JtJ
2386 Fi9C~P,6PR1297 AAAAUOCA CTJGAIX~G X aC~A 2993 AAAFGAZ'r T
AAL7CWW '~,2fiIT
2387 H9G4TA6PR1298 C~AAAI~ CUGAtJGpG X ~F, 2994 AAAGp.TIT T
AAAL7C.UUU O~T1TIG
2392 ~6PR 1299 Uu3 CACAF. L~AL7GFG X QUA 2995 TI~~CAT T T~~,
AL~AAF,
2393 HSGp.TA6PR1300 t)UUC~G~. CT~~I~,G X ~A 2996 T~C'A1T T 'It~CAFA
AAUOCAAA
2394 H~,6PR 1301 UUUtJOGAC LZJGAZ7C~,G X 2997 Ttr'3CATIT T
~A AAALI0CAb1 GILCAAAA
2397 H9C~6PR 1302 C7GALR7UC7G CL7C~I7C~G 2998 CATS C CAAHA'IC~.
X ~A ACAAAAL~
2404 ~.6PR 1303 AAC3CACALJ CT~LJGAG X CC~1A2999 2'L"~CAAAAT
ALIUt7U0~, C p~GIC~CIT
2412 H9Q~TA6PR1304 AL~C~F~ CUC~G X 4;~, paCACAL~3000 CA~G~T T CI~T
2413 H9C~TA6PR1305 GAL~F, CCJI;A(~G X O~A 3001 ATGIC~G'IT C
AAOCACAIJ T~C
2415 F~.TA6PR 1306 t7t7r~G CLOG X ~A AGAAOCAC3002 GIt~CI'IC..'r
T Cue.
2416 H9GATA6PR1307 A~ GL~G X O~A AAGAPDCA 3003 ~CIT~CTr C ZGF~F.T
2421 H9C~,6PR 1308 CCAAAAInJ CTJGAL7r~G X 3004 CI~C.'It~.T
OC~1A AL7CAGAAG C AATT'I~G
2425 H9GATA6PR1309 ACAAGiC~A GZJ~I7GaG X OC~A3005 TGATCAAT T TIL3~T1Z;T
AI~AIJC~
2426 F~,6PR 1310 AA~ACCA CUG11i7GAG X dC~A 3006 GA'It~ATr T
AAL~I7C ~~'IGIT
2427 Fi9GATA6PR1311 GAAC1~AOC CLOG X C1C~1F. 3007 A~ T ~G~C
AAAZ)(~L1
2431 Fi9GATA6PRL312 L7C~X3GAAC CLOG X t3jAA 3008 AT1~:,T T GI'ICJCAGA
AOC~p,AAi1
2434 FZ~,6PR 1313 AAUI~TX~ C~ALJGAG X t1A 3009 TIhGIZG'T T
AC~9ACCAA CCFGAATT
2435 H9C~.TP,6PRL314 AAPL~JG CTJGAZ~G X CGAF, 3010 'n3GI'rGIT C
AF~A~ ~ATIT
2442 FL9GATA6PR1315 L~IJ~AGp. CL~tJ~G X ~F, 3011 ZCCpGAAT T TCIZC~A
AUUCiX3GA
2443 H9C,P~~6PRL316 QIAI~AG CTJGAZ~AG X ~A 3012 Q~,F.~T T CI'IrATPG
AAUU~
2444 HSC'~F.TA6PR1317 O~IJGAA CLIGALIGAG X Q~1A 3013 C~ATIT C T~
AAAI7IJCTJG
2446 H9G4TA6PR7318 AAG~IJG CL~AI7~G X QUA 3014 G~.TI~.T T CATACJCTT
PC~AAiIt7C
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
86
Table III. Hammerhead ribozymes targeting GATA transcription factors (l, 2, 3,
4, and
6) and the complementary sequences
2447 HSGATA6PR1319 PtIAO~LT CC~TJGpG X 0.A 3015 AATI~ C A~~T
P~PC~1AAW
2450 HSC~TA6PR1320 aCAAAPDC CUGALx~FG X OG4P.3016 TI~.'IT~T A CSC
AIJGAPGAF.
2454 HSGATA6PR1321 AL~C70 GAA CUGFItJGpG X 3017 'It'ATAL~.T T
CGAA PD~A ~.T
2455 H9C~TA6PR1322 GAZ7GlJGC A CUGACIGAG X 3018 CATPL~.'I'f T
0.;AA AAOGL1ALJG . 'ILC~C
2456 HSC~TA6PR1323 03 CL1GAL~FG X CAA AAP~L1 3019 ATACCTIT T CCFrATCC
2457 HSCATA6PR1324 UC33GALIG<JG CTJGAL~G X 3020 TAG~I'~iT C CP~CA
~A AAAAO~
2463 HSGATA6PR1325 C~AAAI~L7G CVGAUGFG X OC-AA3021 TICCAC?.T C CPC~2TIC
AUG(JC3~~1A
2469 HSGATA6PR1326 OC.~CAUC~ CUC,AUGAG X O:~F.3022 ATCCAGAT T 2~C
A(JCUOC~IiJ
2470 HSGF.TR6PR1327 ~CAC~IIG CIaC~G X ~A AAI~;~13023 'I~Gr'12'r T
CA:I~IC~~
2471 HSGATA6PR1328 AC~CAU CIJGAtI~G X Cl';F1A3024 C~GA2'IT C A2~~T
AAALTGLJOG
2480 HSGATA6PR1329 LUG CUGAL7GAG X CGF1F. 3025 A2GIDC~T T CATC3GAGA
A~CAC1~LT
2481 FiSGATA6PR1330 UtJC~CAL1 CUGAUGpG X ~A 3026 'I~IL3~IT C ATOGFC~A
AAOOCF1C'A
2493 Ii9GATA6PR1331 CCixAAQJ CZJC~G X CVAA 3027 G~AGAT C ACI'1.C~
AUCt7CJC.TJC
2497 HSGATA6PR1332 AIJC.~OCCUC C<JGAIJC~G 3028 FGA~CT T GFGOCCAT
X QUA PGL~LxU
2506 H9GATA6PR1333 C~1ACCA CtJG~LK~G X OC'~1A3029 G~3C~~.T T ~
AU03LLZJC
2507 Ei9GATA6PR1334 UQJG~CC CiK~G X CGAA AALJGOCCV3030 PGC3CCATT T GSA
2511 HSGATA6PR1335 G~GAU~JG CZ~G X Ct;~A ACCAAFS7G3031 CATi~~T A CACA~C'IC
2517 HS~.TA6PR1336 CCU~Gp. CL~RUGAG X 0.F. 3032 GT C T"IC~C~
AIX~J~C
2519 HSGATA6PR1337 PGCCUC<A CtJGAUGpG X Ct~F.3033 AC~TCr C 2CT
AC,AU~T
2532 H9GATA6PR1338 G~L7GAACC CZJGAIX~G X 0.A 3034 GGCIGFGI' C GSTPCA1G
ACJC~GCC
2536 H9Q~TA6PR1339 ACCt~9I7G CL7GALX~G X C~1A3035 GAGPCC~T T CAZC,FD~T
AC~tJC
2537 FiSGAZ~.6PR1340 CACC(X~iTJ. CL~UGAG X AAA 3036 AGI170G1T C A2L~IC
AAC~J
2545 I~ATA6PR 1341 UGALIAFGA CZJC~JC~G X Q7AA3037 CA2L~G:~T C ZCITA'tC~.
PGCt7CAi7G
2547 HSCATA6PR1342 UUUGAI~1A GTJ~G X CGDA 3038 'IC~C3GI~.T C
AC~1C~A TITP.TC~AA
2549 H9GATA6PR1343 UUUUUGAIJ CLX~X'~FG X Q~1A3039 PGGIC.'It=T T
PGaGACCtJ A'IC~AAAP~
2550 HSC '~6PR1344 A1JC~JUIJGFa Ct.7C"~I7GpG 3040 G~ A 'IC~AAAAT
X ~,AA APGA~C
2552 F~ATA6PR 1345 ALB~UWUU CUGAUGpG X O~A 3041 ZC~L'ITAT C AAAAATAT
AL~AC~
2559 H8GA2'A6PR1346 CAA CC~ItJGFG X 0.;AR PIn7UtJUt3~3042 2~~1AAAAT A TI~L~G
2561 H9C~TA6PR1347 AACiJGF~1 Ct~G X CL~A ALIT3043 AAAAATAT T PCIC~GIT
2562 HSGATA6PR1348 AAALTJC~G CL7GAIJC~G X 3044 AAAATA2T A CTCAGI'IT
CuAA AAL>pT~J(JU
2565 fi9C,ATA6PR1349 UOCAAALU CZJGATJC~G X 0.AA3045 ATAT~ C AGTi~f.~1
AC~ALL9IT
2569 H9GATA6PR1350 GtJ~CA CLOG X CGAA ALA 3046 '1'ACIC.~GT T
TC3CAFL~C
2570 H9C~~6PR 1351 PCB CT~G X CG<9A AACU~J 3047 PL'IC<9GIT T
GCAAt~CT
2583 H9GATA6PR1352 AAFCTJ(mC CLJGAiJGAG X 3048 GAL'lnCAT T GTAACITr
CGAA AIJOC~L~JC
2586 Fi9GATA6PR1353 QJC1~AFQ7 CZ~AI~G X OC~AA 3049 ~C~TIGT A ACIT>AAC
PCAAL70C'A
2590 ~6PR 1354 Qlr CT~TJGAG X CGAF. AAA, 3050 T TAACF~?C
2591 HSC~TA6PR1355 L~L~JIJ CT~G X OC~A AFGtAA3051 Zt;TAACIT T AACA~
2592 H9GATA6PR1356 ~C~IJQT Ci~G X CAA AAPGZJtiFC3052 GTAAGTiT A PAC
2597 Fi~ATA6PR1357 L~JG Q~iJGi~G X CC~1A A1; 3053 W A CPL'IG'Zt;p.
2613 H~6PR 1358 NUUr;F~ X CC~A PDT 3054 ACIL~O~T T TCI~AAG
2614 F~6PR 1359 ALT7UfJC,FG CTJGAUGpG X 3055 CIL;~OGIT T C'I~AFGr
O~A AAOQJt~G
2615 HSGATP.6PR1360 AAGL~~ CtJGALJ~G X (~A 3056 'IGA~TIT C 'ICAAPGZT
AAAC~
2617 H9C'-A'1?A6PR1361 LJGAFL~JtJIT X C?~A AGAAA0313057 PL~TITCT C AAA.
2623 H9GATA6PR1362 AC~1AI1AI7G Clx~iJC~G X 3058 CICAAPGT T Cp.TATIGT
0.3AA G
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
_87
Table III. Hammerhead ribozymes tar?eting GATA transcription factors ( 1, ?,
3, 4, and
6) and the complementary sequences
2624 HSGATA6PR1363 C~L'~,L1ALT CVGAL~ X CL~A 3059 ZCAaAGIT C ATATIGIG
AACmJpGA
i HSGATA6PR1364 CCAC~CAA CUGAZ~FG X C~A 3060 ACT A 2'It;PGTGG
2627 AUGAPLUfI
2629 HSC~2716PR1365 PL~C~C CLC~IIJr:~G X CGAA 3061 GITCp.'I~.T
AI;IAUr~AC T GIG'I~3GT
I HSGATA6PR1366 t, CMG X Q;~A ALTCP~CA 3062 T3GC'~T C T~AGIC~
2641
2648 HSGATA6PR1367 UWCJr'~CLT CLJGAL~ X CCi~P.3063 ~ C a~TCp~A
ACtJUCPGA
2652 HS~i~.TA6PR1368 CP,AaIItJCC CL7C'~JGF~ 3064 AAGICPGr C ~AATrIG
X CGAP. Pd~UGACtnJ
2658 HS~ATA6PR1369 Ur~.ATAC~, CUGALJGAG X 3065 GI'CC~AAT T
QUA AUC7CG~FC TGTPA~
2659 H9GAT~.6PR1370 CUr~JUC~ CL7GAL7GFG X CC,FA3066 'ICC;VAATT T
AAUtJt.~(7;~A G~AAACAG
2662 HSGATA6PR1371 ALCL~x~U CLJGAIJGFG X OC'AP.3067 GAATI~GT a PP~oC~T
ACAAALnJC
2671 H~.TA6PR 1372 LAG CL~7C~ X 0.P. AOCLLJ~IJ3068 A~GGGI' A Cl'3~AACAF.
2683 HSGATA6PR1373 AAG~AP. C~JGAZX~G X Cc~A 3069 AACAP,C~T a
AC~JUQAT TIZ'I'ICIT
2685 HSGATA6PR1374 C~GAr~AAA CLJGALX~G X O~A 3070 CAFGATAT T T~C.'I~C
AtJ~J(JG
2686 H5~6PR 1375 UC~GAFC~1F. CLJGAIJCFG 3071 AAGATA'iT T
X ~A AALIALJC.W TIC.TPCCA
2687 H9GATA6PR1376 AUOC~FGA CUGAU~G X CJ~A 3072 ACATATTT T T~ITCCAT
P~JCV
2688 H9C~6PR 1377 CAL70GAPG CL7C'~G X CC~AP.3073 GATATIZT T CTILCAZG
AAAAL~LJC
2689 H9GATA6PR1378 PCACx3~A CUGAUr~G X CVAA 3074 ATATIZ'IT C
AAAAALI~J TILCA'IGT
2691 H9GF~A6PR1379 AL~LJOG CUGAIJGFG X CG~A 3075 ATIZTICP T O~TAT
PGAAAAALJ
2692 FZSG~6PR 1380 tF~L~CAUG CUGAUGFG X CC~A 3076 TITTTCIT C C
APGAAAAF.
2698 H~TA6PR 1381 L7CU~tnX~ CiJG~~I~FG X 3077 TI~TGP A
CAF. PCACpGAA
2700 HSGp.TP.6PR1382 AAUCL4IJUG CTJGAtJGAG X 3078 OCA'~'PAT A
CGAA AL~03 CAA~F~T
2705 H9GA~.6PR1383 AAAAAAAL1 CLOG X 0~1A 3079 TA'I~AT A ATIfiITTT
2708 H9C~TA6PR1384 W(B~AAAA CZJ~G X CC~1F. 3080 ACAATAAT T 2~TI'I~AFr
AUCL~JaJ
2709 I~.6PR 1385 L~7fJ~AAF. CZ~G X OQ~1A 3081 CAATAAZT T TITTAAAA
AAL)C~AIJUG
2710 ~.6PR 1386 WUU~AA CTJ~G X C'i~A AAAL~1W3082 AATAATTT T TITAAAAA
2711 F~.TA6PR 1387 CUWUCZ~1A CZJC~G X O~A 3083 T T~AAAAFG
AAF,P~I~1C7
2712 F~6PR 1388 PL~R~r CLfi~G X Ct~P. AAHAALIfIF.3084 TAAZ'IZTr T
TAAAAFL~T
2713 H9C~TA6PR1389 CP,GUtJWU GL~ X CGAA AAAAAAIAT3085 AATIZTIT T aAF~AAGTG
2714 HSC~~16PR1390 C3C~T~UU CT.1~IJGAG X QUA 3086 ATrITTI'r A
AAAAAAALT AAF~GIL.3C
2726 F~.TP.6PR1391 aC~CA CUG~G X Q;~A AL1UOCFLU3087 PG'IC~AT T T3CGT1DC
2727 H9GATA6PR1392 UOCAA~ CLOG X Ct~F. AALAJC.1CAC3088 GT3CAAZT T C~ITaCA
2732 Fi9GATA6PR1393 AWC~T~C CLJGAL~FG X ~A 3089 ATI~C3CL~T T
Pa3CAAAIJ O~CAAT
2741 H9GATA6PR1394 WAFGPGTJ CLJ~G X CGAA AI)u3CC7C3C3090 aCFDCAAT C PGIC~'I~A
2747 Fi9CATA6PR1395 AAL~tJU CLOG X ~A PELT 3091 I~AGIGT T AAATCATr
2748 H9C~TA6PR1396 AAAL~1W CLOG X CC~1A AAC~LZJGA3092 2~IGTr A rlATt'Al'IT
2752 F~6PR 1397 AvOCAAAL1 Cite X CC~A AWC~~FCA3093 2~'I'PAAAT C
ATI~C3CAT
2755 Fi~TA6PR 1398 ACA ~G X O;~A AL7G~ 3094 TAAA~T T 'IOCA'IrAOG
2756 FZ~6PR 1399 cJOCLmtxaC ct~G X a~A AAt~AtJtu3095 AAATCATr T O~AOC~A
2761 Ft~.6PR 1400 tJ~AAUCC CLOG X Ct;AA AUOCAAAL13096 ATITIGCAT A
OGATTI~A
2766 F~.6PR 1401 CXlCt Ct7~11UC~G X WAA 3097 CA~GGAT T TAAC~~OC'A
AL70CL~
2767 H9GATA6PR1402 AL7C3~JC~JtJ GUGAiJC~G 3098 AT?C;VATI' T
X CG~A AAIJCCC>ALJ AAI~OCAT
2768 FZ~.~6PR 1403 AAL70CUC'~J CTJGAL7~G X 3099 'I~.TIT A t>~CATT
0.A AAAL)O~
2776 f~.6PR 1404 I~AAA CLlr~i7GFG X CAA 3100 AACpOCAT T TITTATAA
.~L70~T
2777 F~.TA6PR 1405 AIJtI~TmAA GL7~I~AG X O~A 3101 AC~OCATT T TITATAF.T
AAL7C3C~T
2778 I~9C~'P.6PR1406 CAA CLOG X CGAAA AAAZJC3CIJG3102 CAGCaATTT T
TTATAF~G
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
88
'Table III. Hammerhead ribozymes targeting GATA transcription factors ( 1, 2,
3, 4, and
6) and the complementary sequences
2779 HSGF.TA6PR1407 (~UUA11P. CUGALJGF~ X ~A 3103 P~CA'hlTf T
AAAAIZ3CTJ
2780 ~T~GATP.6PR1408 LT~AUCTAI1 ~JG~FG X CAA 3104 C3CATITIT T ATAATGAA
AAAAAL1C~
2781 HSGATA6FR1409 ~ CIJGAtJGpG X CGAF. AAAAPAiJG3105 CATITTIT A '~AA1C,AAT
2783 HSGATA6PR1410 AC~L~tJ CLTGAUGAG X CAA 3106 filfiTTfiAT A
At~AAAA A1GAA~Gr
2792 HSGATA6PR1411 r~AAi7~7tJ CLR;AU~G X O~A 3107 A~GAA2GT A AACATTTT
AC~IJUr3~IJ
2798 HS~TA6PR1412 L~C~JC~SF. CLT~IJGAG X 3108 G'I'AAACAT T
O~A AL~Jt~C T'rAACIT~.
2799 FiSGATA6PR1413 UCIAAaRlA GLG X AAA AP~t~.3109 'I'AAACATr T
'I'AFCITAA
2800 HSGATA6PR1414 AUUAAGU(T CL1GAL7GFL~ X 3ll0 AAACATTT T AP~TTAAT
CAF. AAAL~W
2801 H9GF~'A6PR1415 C~UC~1AG<J CUGAUGHG X C~4A3111 AACATITT A ACTTAA2~
AF~AALJC~fJ
2805 H9C~TA6PR1416 (~C~:AtJU CU~LJGF~G X CG~F.3112 'ITI'1'AACT T
AGUCTAAAP. APOroGGhAC
2806 HSGATA6PR1417 PQ~LCALT CLJGALJGFG X OC~A3113 TI'rAACZT A A'IT3GIPLT
AF~AA
2812 H9GATA6PR1418 AUUUUAFG CUC~ X Cf~IA PGC~TJt~F.3114 TTAATO~T A CITAP,AAT
2815 H9C~1TA6PR1419 AUC~TJUW CUGAUC~G X CGAA 3115 A2C3G~ACI' T
PGi~CAiJ AAAATAAT
2816 HSCATA6PR1420 AAL1UALW CUGAZ7G~G X CGAA 3ll6 'IC~~I'AC'IT
AAC~L~C~. A AAATAATP
2821 H9G'ATA6PR1421 UUUtIAAALJ CUGAUC~G X 0.,F~F.3117 CTTAAAAT A ATITAAAA
P~JUUC~FG
2824 H9C~'A6PR1422 L~K.WUt~1 COC~TX~G X CGAA 3118 AAFATAF.T T '~AAAF~P.
AUt~WJ
2825 HSGATP.6PR1423 UWCWW CUCAUGFG X CC~F. 3119 AAP~'AATr T AAApGAAA
AAU<~I7W
2826 H9C~1TA6PR1424 LJUf~L7IJU CLJGAi7GpG X 3120 AATAATrr A AAFGAAAA
0.F. P.AAUtiAUJ
2839 H9GATA6PR1425 L7Ci~FC~JU ~UGAUCFG X ChAA3121 AHAAA~T T AACI~F.
AC~tnJW
2840 H9GF~2'A6PR1426 ~KT~T CTJGAUt;pG X CC~F. 3122 AAAAZGZT A ACI~C~C
AF~JUW
2844 H9C~1TA6PR1.427 GAAI~TJ Ct~G X ChAA PLTJ~ACA3123 2GTTAAL'r T P~CAT~C
2845 H9CATA6PR1428 P~AAUWC CiJC~G X D~A AAC~C3124 GITAACIT A GACAZTCT
2851 H9C,A'I'A6PR1429 POCAL~FG GL7~G X AAA P 3125 TAT T C~CP
2852 F~6PR 1430 AAC3C'AL~F. C<JG~G X CAA 3126 'TAGA~ATP C TACIT
AAI~JC.~.
2854 H9GATA6PR1431 PC~FL~CA1J CUC~IJGFG X 3127 C~ATIC.T T A'IL3CI~T
C~4A PGAAIJ~JC
2855 H9GATA6PR1432 A~AAOCA C~JG~G X ~F. P.F~AAIJ~J3128 ACATI'CIT A
'IC3CI'i~'IT
2860 H9GATA6PR1433 tX~~P.AFG C<JGAUI;~G X 3129 Ct'~C3CT T C'ITi'~.
CAA PL3CAL~PG
2861 H9C~ATP.6PR1434 Wr;tiAAAF. CLOG X ~A AAOCHZ~A3130 T~3CIT C TTT~F.
2863 H9GP~'A6PR1435 A~F. - CZ7C~LJGAG X SFr 3131 A'I~3CI~GT T
AC~IF~AiJ T~FGT
2864 F~ATA6PR1436 TI~IUCTm CU~i7GAG X ~~Fr 3132 '1C~CT1C'IT T
AFGAAOCA '~A(~ALTA
2865 H9C~TA6PR1437 ~7UC~1 ~G X Q~1A AAAGA~OC 3133 OCT'IC.'TIT T
PC~1ALT.4C
2866 H9~.6PR 1438 LJG ~ X CC~A AAAF~ 3L34 CITi'rlTf A C21ACIACA
2872 H9GA~6PR~ 1439AIX30C~TJG X ~AFr P~7~F~ 3135 T~PGT A CA'IC7CX'AT
2876 HSGp.TA6PR1440 L~AA~JOG GU~G X O~A AL7~C~JtJ3136 AA~ACAT C CC~.TIT~A
2881 H9GATA6PR1441 AAAtI~t~A ~G X 03AA AU03C~LJG3137 CA'IC7~AT T TI'ATA~Tr
2882 H9GATA6PR1442 GAAAL'~L~ Ci~T~G X OQ~A 3138 ATCOCATr T TA~.TTIC
AAU03~LJ
2883 H9C~.TA6P'R1443 ~AAAL~11.1 CZJC~G X Ct;AA 3139 'ILOC~1TIT T
AAAI703~ ATATFICC
2884 H9C~A6PR1444 UOU~AAAL~. CTS X ~9A AAAWJ03G3140 CCCATrTT A TATI'It,CA
2886 H9GATA6PR1445 AU(IO:~~AAA Ct~T~G X OGAA 3141 CAT~T A 'ITIt~AT
AZ~AAAIJG
2888 H9GATA6PR1446 Q~AUCX3Gp. ~G X CGAA AL~i~IAAA3142 TITTATAT T 2CCAATIG
2889 H9GATA6PR1447 ACAAUUC~ CU~tJC~G X CL;AA 3143 TITA~Tr T CQ~ATIGT
P~AI~L~Ap.
2890 H9GATA6PR1448 AP~AF~L1UG CUC~L7G?G X 3144 TTATATTT C CAATI~T
AAA AAAZ~F.
2895 H9GATA6PR1449 L7C.TW~ CZJC~IJ~G X Q~1F. 3145 TTII!CAAT T GI'~AGA
AW3~~AA I
2898 Fi~.6PR 1450 IWJCTJUU CLOG X O~A PLAALR~3U3146 CCAATIGT T AAFGAAAA
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
89
Table llI. Hammerhead ribozymes targeting GATA transcription factors ( 1, 2,
3, 4, and
6) and the complementary sequences
2899 HSGATA6PR1451 LTJtJUtJCiICT CUGAIJGFG 3147 CAATIGTr A AFL~AAAF.
X CLAP. AACAAUtJG
2909 HSGATA6PR1452 t~J~ CLIC~1LI~G X O~A 3148 AGAAAAP.T A TrLCAPGA.
AWUtnKV
2911 HSGATA6PR1453 C~~T7(JGA CVCAL7GPG X 3149 AAAAATAT T TCAAGAAC
QUA ALTAU<7tJUCT
2912 H9C~TA6PR1454 UC~JUCUUG C~L1GAG X OC~P~3150 AAAATATr T Q~PGAACA
AAL~CRJ
2913 HSC~TA6PR1455 UtJC4JUCUU CZJGAUGFG X 3151 AAATATIT C APL~A
OC~P. AAP~UUU
2924 HSGATA6PR1456 UGAGAGAA CUGAL1GAG X CGAA3152 GAACAAAT C TI~'IC~
AUt~t)C
2926 H9GATA6PR1457 CCLJG~FG CiJGAIIGPG X 3153 ACl~AATCT T CI~G
SAP. PGAUUUC~1
2927 H9GATA6PR1458 UCCLJGFC~. CUGALJGPG X 3154 CAAATCTT C T'~~.
O~A AAGAUUUG
2929 H~6PR 1459 UUUC~CT~. CT~G X O~P. 3155 AATCTICr C 'I~GAAP.
P~GAW
2931 HSC~TA6PR1460 AUt7WCCU CLOG X CGAP. 3156 TC'IIC.'.LC.T
PC~PC,P. C POC~AAP.T
2940 H5~6PR 1461 PGHAA03C C<JC~1TJGFG X 3157 PL3~1AP~AT T
Ct~A AI~(7(~LV OCCITIC.T
2945 H9GATA6PR1462 A~C~a CTJ~IJGFG X QUA 3158 AAT'IC3CLT T
AC30CAAW TCn.'PATr
2946 HS~'A6PR 1463 AAALIPC~G CZ~G X (~.A 3159 ATInCCTT T CI~.'fATIT
APL~Cl~P~IJ
2947 HSGATA6PR1464 CAAALZnGA Ci~LIGFG X Q'~4P.3160 TIC3CGTrP C TL'rATI'IG
AAPL30C~F.
2949 HSGATA6PR1465 A~AAL~ C'L7GAC1C~G X OC~1A3161 C3CCITICT C TATI'It;'IT
AGAA~
2951 H9GATA6PR1466 UC~AP. GUG~1JGAG X Q~P. 3162 GZTIC.'IC.'f
PI~GAAAG A TIZGZ'I'AP.
2953 HSGATA6PR1467 L~A~ GTJGAL7~G X ~,~P. 3163 TIC'I~IAT T 'IGTI~APGA
AL~GP~A
2954 H9GATA6PR1468 UUC<JCTAAC CSJGAUC~G X 3164 T"TCI'ATT T GTPHF~A
C1~A AAI~.
2957 HSGATA6PR1469 AAAWCUU CUGAIJC~G X AAA 3165 CTATI~T T A.~ATIT
AC~AAL~G
2958 H9C~.TA6PR1470 P~J CtJGAL7GpG X ~ AAC~AAL~3166 TP.TITGIT A PL~A2fiiT
2964 HSGF.TA6PR1471 i~.lAAF. CTJGAU~G X ~A 3167 TrAAGAAT T
AI7IX.TJtn4A
2965 H9C~TA6PR1472 inJC~L~P. CL7C~LJGpG X 3168 'ITAAGAP.Tr T
~~Pa AAL)CI~r T1~1A
2966 H9GP.TA6PR1473 CTI~I~. CT~L1GAG X CC2~A 3169 AAGAATIT T '~ATAL~PG
AAAt7UCW
2967 H9C~6PR 1474 IJCTJt7C~E1 CZ~G X CC~Pr 3170 PGAA'hI'IT T
AAAAUUCZJ A'~C~PC~
2968 H9C~.TP.6PR1475 L7CCZJGAIJGAG X CAA AAAAPTJfX:3171 C~P~TIZ'IT A
TACAP~AF.
2970 HSGATA6PR1476 L~JUG ~G X OC~A AL~AAAAIJ3172 ATrITI3~T A CAFC~ArA
2984 HSGATA6PR1477 PL.~003C~. C~JGAI~G X 3173 PC~CCAAT A TALC'~,T
SAP. AtftJC3~JC~J
2986 HSC~'P.6PR1478 AAPDOC~ CUGAL~G X 0.'A 3174 PDCAATAT A C0.ZCI'IT
AI~3~J
2993 FiSGATA6PR1479 C~AAAL1A Cu.2~G X CL'~A 3175 '~C7~CCT T TAT!'ITAC
PDOOOC~~a
2994 H9C~a6PR 1480 PI~AAAiT CL1L;AIJGPG X 3176 PGOOCL"IT T ATITT~.T
Q~1F. APDOD~1
2995 H5~6FR 1481 C~AAF. CLX'~AIJC~G X CAA 3177 0.'~~.'~IT A
AAPO~ Ti'1'~ACiG
2997 Fi9GATA6PR1482 CUGAIJ~G X OGAF~ AL~AAOOG3178 OCCi'ITAT T TrPCIGiG
2998 H9~6PR 1483 O~r Ci7C~TJGpG X OC~~A 3179 CC~Tr T TACIGiC~G
AAL1AAAOG
2999 H9~6PR 1484 UOCP~1 CZJ~IJC,PG X CV4A 3180 CITrATIT T PLZG'i~
AAAt~PG
3000 H9GATA6PR1485 WOQ~G CC7GA1.~G X Q'~A 3181 TITATITT A CIGI~AA
AAAAI~APr
3010 H9~6PR 1486 C'~~Q~C''A QJr;AUGPG X 3182 'IGZO~1AT A lGn3CiC~G
~1A AL7C1CCF~.
3025 H~6PR 1487 C~JUC~J~J~C CRAG X aC~P. 3183 CTAAAAAT T 0
AI~C
3037 H9C~TP.6PR1488 P~OQ~ CMG X O~A P~J 3184 PC~AC~CT T 'I~OCT
3038 H~6PR 1489 Lg10~1 CtJGAL~G X ~ A~JIIG3185 CAACAL'IT T PL'~CTA
3039 H9C~6PR 1490 UImD~G CL1GAI7GFG X QUA 3186 APCACIZT A CTPLCTAP.
AHF~J(J
3042 H~6PR 1491 CLOG CL~~1JGAG X QUA PGL~AAGU3187 PL'I'ITPLT A
CCTAAO~
3046 H9~.~6PR 1492 CIB~OGZJ -Ci~AI7GpG X 3188 THL'T~GT A PL7~ATAG
CAA P13~
3053 H9G~.TA6PR1493 PLAAAiIOC CLK~LJGFG X 3189 '~AA~T A OCATI'IGT
UGAA ALJC7~.
3058 H~~TA6PR 1494 L~WITACA CLIGALJ~ X AAA 3190 ~ GA'~T T TG'~AAAT?.
AL~3CT~IJC
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WO 00/61729 PCT/US00/09721
Table III. Hammerhead ribozymes targeting GATA transcription factors (1, 2, 3,
:1, and
6) and the complementary sequences
3059 F~GATA6PR1495 GC~IWCgIC CL~AUC~G X G~.A 3191 ATPG~~T T GPAAA1~C
AAL7C3CL~tJ
I 3062HSC,F1TA6PR1496 p~JAW CTJGAUGFG X CGAA 3192 OC~'I~GT A AATACIC.T
ACAAALpC
3066 HSGF.TA6PR1497 ACCt~9GpG CiI~L7GFG X 0.P.3193 ZTG'~AAAT A
AL~P. CILI'~3G~
3069 HSGATA6PR1498 GAC~1CCLTA CTJGAL~FG X 3194 TAAATACr C T130~TAZC
CVAF. AGi~JUUA
3071 HSGATA6PR1499 Q~C CU~tIG~G X (A PGFG~~t13195 AATACICT A a~TA'IC.'IG
3075 HSGATA6PR1500 tJU~c.~GR C~LJGFG X CC~A 3196 CTCL~GGr A T~AP~A
PrCtI~G
3077 H9GATA6PR1501 U~JUI~CA CZ7GAIJC~G X (>;AA3197 C'1'P,GG'I'AT
Ai.~CCT~G C T~AAAC~.
3081 H9GATA6PR1502 PGAGIJGUU CUGAUC~G X CGAA 3198 GrATCI~T A ~
ACpGAIIAC
3088 HSGATA6PR1503 CZJUG~A CTJGAZJ~ X QUA 3199 TAAACAGT C 'I~2G~PG
PC~JfJC'~.
3098 EZ9GATP.6PR1504 C<JG~IJC,FG X C~A ALZJtK~I7C3200 C~.T~F~T C '1~'ATPGI'
3102 HSGATA6PR1505 IC<JGAtJGAG X O~A PL~GAaAJ3201 AAGIt'IGT A
'IPGIGIGA
3104 HSC~.TA6PR1506 P~C~ CZJC~G X QUA AC~C~C 3202 GMAT A GILT
3113 HS~TA6PR 1507 CLL~~1 C(JGAtJCFG X CAA 3203 GIGI~.'r A PL'CCAC~G
P~UC~C
3128 HSC~'A6PR1508 L~AACC CUGALJGFG X CGAFv 3204 Pa0CAC3GI' T
ALL~X~CU Q
3132 HSGATA6PR1509 UtIAAUC~ Cite X C1~A POCAACCtJ3205 PDGI'IC3Gr T
'~ATI~1P.
3133 H9GATA6PR1510 AUt~.AL7GU Ct7C~AUGFG X 3206 aGIZLaGIT T
Q1AA AFLCAACC PL~2TAAT
3134 HSGATA6PR1511 AAt7t~AALJG CUGAUGpG X 3207 A C71T~AAZT
Q~P. AAACCAAC
3138 HSC~.6PR 1512 AAAAAAW CL~AUGpG X O~A 3208 GrIfiACAT T
AL~AAC AATI~ITr
3139 H~6PR 1513 AAAAAAALJ CLJGAIJGFG X 3209 TI'IrACAIT A
Cs~A FAZ~AA ATrITTTT
3142 F~9GATA6PRL514 AAAAAAAA C~L7GAG X CGAF. 3210 ACATIAAT T TI~TIZT
AUtE~AIJC~J
3143 H9GATA6PR1515 AAAAAAAP. CCK'~ALJGpG X 3211 CATTAAZ'I' T
CGtIA AALA~ALJG TITITl'IT
3144 H9GATP.6PR1516 CAAAAAAA CL7C~UC~G X CIA 3212 ATI~AT1T T TFITITIts
AAAUC~AL1
3145 H9GATA6PR1517 Ut~AAAAA CRAG X 0.~AA AAAAV(~A3213 ThAAZTIT T T~
3146 6PR 1518 Ut~AAAh. LL7C~G X Cu"AA 3214 TAF~'I~'IT T
AAAAALA~1 TITrIC~A
3147 HSG~.6PR 1519 AUUC4AAA C~AUGFG X CAA 3215 AAT~ T TITIC~AT
AAAAAAW
3148 H~6PR 1520 CALnJCAAA C~1I7GFG X CAA 3216 ATIZTI'IT T
AAAAAAAU TrIGAATG
3149 H9GATA6PR1521 CC~ALfi~G X CL~A AAAAAAAA 3217 TTITITIT T TAG
3150 Fi9GAT~.6PR1522 OCCAt)UCA CUt;AL7GFG X 3218 T!'~TTIT T 'IC~A'I~3G
~AFr AAAAAAAA
3151 ~6PR 1523 UCOC~1LAJC CMG X OC~F. 3219 TTI~IZTr T GAATC~3~.
AAAAAAHA
3163 H~6PR 1524 UUOC~L~G CZJ~G X USA AC?~IJCOCA3220 2C33~1TGT C
CTATZ3~1A
3166 H9GATA6PR1525 Q~JUCC'A CLOG X CC~A FD~CAL7C3221 G~iCX.T A 'L~~AACC
3176 FZ9C~6PR 1526 UOf~AAA CU~UC~G X CG9A 3222 aGAAAO; T A
PDaJ(1UC~C TITCpL!CA
3178 H~ATA6PR 1527 tJ~~ ~ X O~A AL~O~JIJtJ 3223 AAACX.'IAAT
T TCACC~
3179 F~r6PR 1528 CUQJOC~JG CT~IJGAG X ~A 3224 AAC<'TAT'T T
AHt~3~JtT CPOCF~G
3180 Fi~.TP.6PRL529 ACUCLx30LT CTJG~ X C~A 3225 PL~GTALZT C
P~AAt~3J ALCM
3189 H~TA6PR 1530 ALnRN~A Cite X O~A PLL~J 3226 ALCPC~G~ T TI~AAAAT
3190 H~.6PR 1531 tC~AtJGFG X Ci~F. AFLi~3 3227 CT TAAAAATA
3191 F~.TA6PR 1532 UC~7tJ CZJC~G X CC.~F~ 3228 CPC,AGTIT T
AAACL~7G AAAHATAF.
3192 H9C~A~'A6PR1533 LJI7I~t7U CTJGALJGpG X 3229 PGAGITIT A AAAATAAA
CAA AAF~J~J
3198 Fi9GATA6FR1534 PGCCUWU CMG X CAA AL7WtA~A3230 TTAAAAAT A AAAFD~T
3207 H9GATA6PR1535 CAP,AACAA C~U~ X GSA AO~TJU(JU3231 AAAFL32uT A
TIt;TITIG
3209 HSC~A6PR 1536 Q~AAAC CT~LJGpG X OCR. 3232 AAOC~'IAT T
AL~L0.~Jt1 Gi~'I'IGIC
3212 FL~6PR 1537 C~PGACAA CLJGAL~G X OQ~A 3233 aGI~TI~T T TI~C.TIC
AC1~AI~1CC
3213 H9GATP.6PR1538 AGAAC~C~~ CLJGAIX~G X cT~A3234 GrATIGIT T T~'1~.T
AACAAI~G
CA 02364577 2001-10-03
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91
Table III. Hammerhead ribozymes tar?etin~ GATA transcription factors (l, 2, 3,
4, and
6) and the complementary sequences
3214 HS~Tp,6PR1539 . ~GX ~, pp~ 3235 'LaTIGTIT T
3217 FiSGATA6PR1540 c~.p,CAGAA CUGAUGAG X Q~, 3236 T~ C
p(~p~A
3219 H5~6PR 1541 C~,CPG CUGF~(7GFG X Q~1P, 3237 T~ T
~AF,A
3220 HSGATA6PR1542 , ~ X ~, ~,~, 3238 TAT C
~
3224 HSGATA6PR1543 PLT~AC.T7G CtIG~IJGAG X 3239 'IC.TICZGT A
Q~,A ACF~4AC,A
3233 H9Q~TA6PR1544 FDOGAAC3G CUGAIJGAG X Q3PA3240 CAGI~',AGT T
pLL~Gi7t; CGTI~CT
3234 H9GATA6PR1545 Pa03GAPG CUGALT~G X O~A 3241 :~It;AGIT C CT~C~
AAC(~T
3237 HSGATA6PR1546 GAAAA03G CUGAL~G X Q;~. 3242 G~CT T CCCITTTC
PDGAACiJC
3238 FL9GATA6PR1547 L7~AAppG ~G X C~A APC~~1PGU3243 ~CIT C C
3242 HSGF.TA6PR1.548 C~CL7C7lJr;AA CUGALTGAG 3244 CrTICCCT T TIrAAAOC
X O:~Fr P~3GAAOG
3243 F~ATA6PR 1549 PC~CUI7pGp, ~JGAL~FG X 3245 CrPCC~CIT T TCAAApCP
CL;AA AFC33GAAG
3244 HSC~.TA6PR1550 AAGCZJUUG CtJGALGHG X ~1A 3246 TI~CGCTIT T CAAAC3CIT
AAF130C~.1A
3245 F~9C~F,6pR1551 AAP~OI7UU CLC~L7GpG X CGAA3247 'IL~ITr C AAFL3CITr
AAAAGp,~F, .
3252 H~6PR 1552 L~AAHPL~, ~ X ~A pGCUI~F, 3248 TC<AAAOCr T A
3253 F~.6PR 1553 AL1AAAAPG CCJCAIJC.~G X 3249 CAA~~T T ~qT
CC~F. AFOCtJtJtJG
3254 H9C~TA6PR1554 C~L~F,AAA CjJ~G X p~A AApOCWU3250 AAAOL'iTT C ZTIT~TG
3256 H9GATA6PR1555 t~LTP,AA C1JGAL~,G X 0.~. 3251 ?L3C1T'IC.T T
PGAAPaCtT T~CP
3257 H9Go.TA61'R1556 CAOCAL~A CTG X CC~1F. AAC~APDC3252 02TI'I~'IT T
TIA~~~'IG
3258 6PR 1557 ~CALg1 CTJ~ X 0.;AA AAFGAAFG3253 CITIC..'ITT T
'IAZC3CIGT
3259 F~A~6PR 1558 LIAC~Ia~IT CL~L~G X Q~P~ 3254 TI~'ITT T .A2C~~
AAAAGAAA
3260 H9GATA6PR1559 AL~C~OC~ CiI~L~C~G X QUA 3255 TI~ITI~IT A 2C3CiGTAT
AAAAPL~A
3267 F~,6PR 1560 L, CL~U~G X 0.~, pI~CAL~. 3256 ~CI~T A 2GIGAC~A
3275 H9GATA6PR1561 AAL~AIJCC~. COC~Ix~G X 3257 A'tGIGACT A ~TATT
Cl'~F. P~C~LT
3277 H~TA6PR 1562 LJGAAZ)AL1C CT~T7G~AG X ~ GPGPL~L'AT A
Q~F, AL~C 3258 ~
3281 HSGATA6PR1563 L~LZ~A CUGALJGAG X 0.~, 3259 CTA~T A TIC~TP:1'A
AL~L1P.I~G
3283 H~TA6PR 1564 WCZAI~LJG Ci7GAUt;pG X 3260 A2~GA'IAT T CATA'hAAA
~A At7AIJC~IT
3284 fi9GATP,6PR1565 L~.L~IT Ct)GAI7~G X CC~A 3261 'IAGATAZT C ATA2AAAA,
AAL1A1;~
3287 H9GA~.6pR1566 I7CJt'~An7t~, CL1GAI~G 3262 ATATICAT A TAAAACAF,
X ~A AZ~AI~IJ
3289 H9C~A6pR 15(', P~JU CL~I~G X 0.~9A AL~AiT3263 ATI~A~T A AAAC~
7
3309 F~.6PR 1568 At~JUfJOCp, CMG X ~9A pGt~,pG3264 C~AGr T 'IC3CAAAAT
3310 F~C~.6PR 1569 CAL1(xR7UC CZJ~G X CAA 3265 GIs T a~IAAAZG
AFDC
3321 H9C~.TA6PR1570 ~tg~, CUG~G X CC~AA PC~AZJI~7tJ3266 AAAA2C~CT T 'TAAOOCCP
3322 F~6PR 1571 AAOOOCW C1~G X CL'~1A AAOC~L~7tT3267 AAA~CIT T AAOC~~OCTr
3323 F~C~.6PR 1572 ~~.TJ CLJ~G X AAA AAAGCAW 3268 AF~C3CITT A P03CCl'IC
3330 H9GATA6PR1573 TA~AAGG C~IJGAG X CGAFr 3269 '1AA03CCr T F,
PO30L~JC~r
3331 I-LC~TA6PR1574 L~AAG CUGAI7C~G X CGAA 3270 AAOC~!CIT C CIT~A
AFf3Ca~tT
3334 H9C~TA6PR1575 UOCI~. C<J~AiJ~IG X 0.;AP.3271 C3CCI~.T T 'IC~AAaCA
P~pOC
3335 HSGATA.6pR1576 ALX3CUUUG C<JGAI~G X AAA 3272 CCI'IICIT T CAAAG~.T
AF1~~A0"
3336 H5~?~6pR 1577 7 CLOG X ~F, AAFDC~AG 3273 CT'inCITr C AA~13CATA
-
3344 H~6PR 1578 AAAFt3GAC CUGAIJC~,G X 3274 CAAF~C~.T A GItzTI'IT
AAA P1JOC<JWG
3347 H,6PR 1579 L7CCAAAAG CT~Ut~ X 0.A 3275 PDCATAGr C CTIT~~1
AL~I70CU
3350 HSGn.TA6PR1580 Q~CAA CUGAUC~G X QUA POC~L't~t13276 ACCT T TIl~00C
3351 HSGATP.6PR1581 ~GCUO(~. C1~G X 03AF, AF~LL~3277 'i'AGInCIT T
~OOOG
3352 Ii9GATA6PR1582 Ac~OCUC~ C:iJ~li)GAG X 3278 PGICCrIT T dGAOLL~T
OC~1A AAAO~J
CA 02364577 2001-10-03
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92
Table III. Hammerhead ribozymes tar5etin~ GATA transcription factors (l, 2, 3,
=~, and
6) and the complementary sequences
3361 HSGATA6PR1583 P~Ci:A CLIGAIx,FG X Ci~A 3279 c~AOCCGT T 2C3GTALtT
AC~JCC
3362 HSGATA6PR1584 AAO~C CUGALTGAG X CGAA 3280 GAC~CC'GIT T
AA~3CUC C3G~AC~CTT
3366 HSGATA6PR1585 ALTAAAAC~G CLIGAIJGPG X 3281 ~DuT A CC~I'ITAT
Q~1A ACCAAACG
3370 FiSGATA6PR1586 POGL1AL1AA CL~AG X Ct~A 3282 TCGT'ACCT T TIATACCT
AC~CCA
3371 H9C~TA6PR1587 Ae~O~ CT~G X CC'~A APC3GC~C.'C3283 ~CIT T TACIT
3372 fLSGATA6PR1588 C~P~U CVGAtJ~G X QUA APPD~3284 GrPLiCTl'r T
ATP~CCI'IG
3373 H~ATA6PR 1589 CCAPL3Gt~ C<JCX ~P. AAAAO~TA3285 TACCTTZT A TALCTIL3G
3375 H9GATA6PR1590 PGCCAPL3u C(Jr;AIJGAG X 3286 CCITITTAT A CCI~3CT
QIAA AL~1AAFL~G
3379 H9GATA6PR1591 AAtJAAOCL CL~FG X Q;AA 3287 TrATAL~.'P T
FC~~L~A 03CITAZT
3384 HSGATA6PR1592 CUU~AALJ CLOG X AAA AOC'CAF~G3288 CCI'IC3GCT T
ATI'IL;AFG
3385 H9C~1TA6PR1593 ACUUCAAP. CTJ~1L1~G X AAA 3289 CI'i~3C.ZT A
APL3CCAF~ TIICAFbT
3387 HS~6PR 1594 CAAC<1UCA C~AL7r~G X CGAA 3290 T33CTITAT T TC~AG1TIG
AL~3C~.
3388 HSGATA6PR1595 UC~AL~JIJC CTX~G X 0~1A 3291 (30CLTAZT T GAAGI'1~
AAL~PDCC
3394 ~6PR 1596 G~L~JC CTJGAI~G X CC~F. 3292 TI'It;AAGr T
PGZRJC~AA GAC~AZG
3407 H9GATP.6PA1597 L~C~AGTJ CMG X O~A ALL~CAI7G3293 CP.~3C~OGT T
PGTI~C1~1
3408 H9GATA6PR1598 G~AC CTJGAI7GAG X 0.A AACCC~tJ3294 AT333G'IT A GITACIAC
3411 F~C~TA6PR1599 PGAC~J C~ALX~G X AAA PLTTAACCC3295 C33GITP~T T PLTACrCr
3412 H9G~TA6PR1600 GANG CiJC'~G X ~A AACi~ACC3296 aGIZPG1T A CrAL'Ir'IC
3415 H9GATA6PR1601 AIJGGAGAG CUGAT~F~ X ~ 3297 'PAGTTACT A CIC.TOCAT
PL~AGL~
3418 H9C~'A6PR1602 CAC1~UC3,3A CU~UGpG X Q~F.3298 TTACTAO.T C 'ILCAZGZG
- PAP.
3420 H9G~6PR 1603 UGCACAL7G CLK~G X OGAA 3299 ACIPCPCT C CA2t~OC~.
A~J
3430 H9C~TA6PR1604 CUCCT~0.'~C QJGAUC~G X 3300 AT~IOCAT T a3GG~G
0.;AA ALJOCAL'?dJ
3440 HSGATA6PR1605 CTJC~L~AA CMG X CGAA AL~C 3301 C30GACAGr T TITATAFG
3441 H9C~ATP.6PR1606 AGT~L~A CZJC~,LJ~G X OGAA 3302 OGAC31GIT T TrATAF~T
AAC~JOC
3442 H9GATA6PR1607 CALTJC~L~. CIJGAZ~G X AAA 3303 C,ACAGTIT T TATA~
AAALZJC~7C
3443 HSC~ATA6PR1608 CCP~C<7C~LT CiJ~G X OC~A 3304 ACP~lZ'IT T ATAAGIbG
AAAACuQT
3444 HS~.TA6PR1609 C'L~CAGTJC~. CUGAIX~G X 3305 CAGZ'ITIT A ~
CuAA AAAAFGTJG
3446 HSGATA6PR1610 UtJ~~~J CTJG~G X CGAF. 3306 GITITTAT A PGICa~AA
AL~IAAApG
3460 FL9GATA6PR1611 AL~ALT~J CTJr~IL~ X CAA 3307 C~FDGAL'r C AGrATI~.T
~~JC.CL7l7C
3464 FI9C~.TA6PR1612 L~ILmALB~F. CUGAL~G X OC~A3308 GAG'I~GT A Tl~ITIATA
FLL~JC
3466 F~6PR 1613 APd;mL~IALT ~ X ~A AL~LL~G3309 CICAGTAT T ATTATATT
3467 F~.TA6PR 1614 AAAT~A CT~G X aC~A AAL~7C~.3310 A Tl~'ATIT
3469 Fi9C~.TA6PR1615 L~AAi~IT CUC~G X CVAA AI~AI~L.V3311 A~'TA~~1'AT T
ATATTIr.~A
3470 ~.6PA 1616 QJCAAAL~. CiJC~L~G X OGAA 3312 G1AT1'ATr A ~G
AAL~AL~1C
3472 H9~.6PR 1617 Ai~1 CLOG X CGAF. AI~AI~ALJ3313 ATI~.TIP~T A
ZTI~T
3474 Fi9GATP.6PR1618 L7CAL~. CTS X CC~P~ AL~F~ 3314 'I~IITATAT T
TG~
3475 F.6PR 1619 AL~AI7~LTJC CLOG X OGAA 3315 ATI~iTAZT T CST
AF1~I~1ALJ
3484 FDG~PR 1620 AAAALIOCU CLfi~UGAG X Of~A3316 CST A PC3CATTIT
P~C7~L7C1JC
3490 H9GATA6PR1621 CCAAFLPA GLfi~G X 0.;AA 3317 ATAAOCAT T TI~G
ALx'3Ct7UAU
3491 ~.6PR 1622 CLCAAACA GZJGAL1GAG X ~F. 3318 TAAOCATT T T'''ITIL3C~
AAL~CtJt~.
3492 F~.TA6PR 1623 tJO~AAC CL~L1GAG X CAA 3319 AAOCATTT T GI'I~GA
AAAI70CUU
3495 ~6PR 1624 UC~~CC'A CZ~I7CPG X ~A 3320 ~'PI~'I~T T T33GAAC~
ACAAAAUG
3496 FiS~.6PR 1625 UtJt'~JC7CC~ CLOG X ~, 3321 AT'ITIGZT T 03~ACAF.
p,~AAIT
3509 H~'A6PR 1626 AL~JIJ CUGAL~G X OC~~A 3322 ACA~C~CP T AAAAATAT
PL3CGIIR~lJ
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93
Table III. Hammerhead ribozymes targeting GATA transcription factors (1, Z, 3,
4, and
6) and the complementary sequences
3510 HSGATA6PR1627 AALTAIJWU CLOG X ~A APDCAU(~3323 CAP~GCTT A AAAATATI'
3516 HSr~ATA6PR1628 WCt~3GAA CUGAUGpG X Q~1A 3324 TTAAAAAT A TILCF~GAA
AW(n7t~F.
3518 HSGATA6PR1629 Cs7UUCU0G CL1GAL7GFG X 3325 AAAAATAT T CL~C',AAFG
03z1A ~
3519 HSGATA6PR1630 ACUC7UCTJG CL~AL~FG X OG4A3326 AAFATA'IT C CpC,AAFGr
AAL~TJWU
3528 HSGATA6PR1631 AAAAIJGLJG CL)C~LI~G X 3327 CAGAAPGT T CF~TITT
AAA ALUUUCUG
3529 HSGATA6PR1632 AAAAALX.ZJ CiJCALIC~G X 3328 PC~AAGIT C PC,A'ITTTT
CGAA A.~JUtXU
3534 H~ATA6PR 1633 PGAAAAAP, Ci~ALJGFG X QUA 3329 GI~C,AT T TIfiT1'IC..T
AIJCiJC,AAC
3535 F19GATH6PR1634 AAGAAAAA CUGAL7~G X cJ3~A 3330 TI~C~.Tr T 'ITIfiTC.'IT
A~LJCLJC~A
3536 HSGATA6PR1635 AAPGAAAA CUGAL7C~G X CG~A 3331 't~'AGATTT T
AAALKi7GA TITIeTIT
3537 H9C~.TA6PR1636 CAAFGAAA CL7GACIGFG X CAA 3332 CpGA2'TTT T TI'IC.'IfiIG
AAAAC7C<7G
3538 HSGATA6PR1637 ACAAAGAA CLJCAIJ~G X CGAF.3333 PGATITIT T T~C,T
AAAAAL~TJ
3539 HSGATA6PR1638 CACAAPC,A CUGAL7C~G X Q~Fr3334 GATITTIT T TC.T!'I~IG
AAAAAAL7C
3540 H9UF.TP.6PR1639 I~AAPG LUGAUGFG X CC~.A 3335 ATI'iTITr T CITIGIGA
AAAAAAALT
3541 H~6PR 1640 uJC~CAAA CUGAL1GFG X O"~AF.3336 TITIfiTTT C T~'~F,F.
AAAAAAAA
3543 H9GATA6PR1641 ~ C<7GAIJ~G X QUA AGAAAAAA3337 TI~TI'I~T T ZG'IC~A2G
3544 H~6PR 1642 L7C~L1C~'PC C~Ai7C~G X 3338 TI'ITIGIT T G'~A~P.
0.,AA AFC~A?~AF~
3556 H9C~TA6PR1643 CCpGAAL~. CTJGAZJGAG X 3339 AA2GAAAT A 'I~Tl'CIC~G
Q';AA AL~UCP~IJCT
3558 H9GATA6PR1644 OOCC2~AA CL~L7GAG X Q~1A 3340 'IC"~AAATAT A
AL~I7(~A T1~3CC
3560 HS~TA6PR 1645 UC1300CFG CUGAUGAG X AAA 3341 AAATATAT T CIG3CQ'A
AC~tI~ILA7CT
3561 H9C;A~6PR1646 COCA C'Z~.LJGFG X Q'~F. 3342 AA'I~.TATr C
AAL~W 'IC330.~C
3582 H9GATA6PR1647 UGAAAOGF. CL7GAI7GAG X 3343 PL~OOOGAT T TCCTZ'IC'A
~ ADOOL~U
3583 H~6PR 1648 CL~1AA03 CL7GAI~G X O~A 3344 0300GATr T C3:TI'It~
AAL1C~7CC
3584 F~9~6PR 1649 ALLJGAAAG CZJGAt~ X CGAFr 3345 O3~ C CITir?Gr
AAALJC30C
3587 fiS~A6PR 1650 AAAFGL7GA ~JC~T~G X CC~A 3346 GATITOCr T 'ILAGIfiIT
PL3:~AAALJC
3588 H9C~A6PR 1651 AAAAFLT~ Ct~G X 0.F. AFD~1AHIJ3347 ATI'Z~C.'IT T
CAGTITIT
3589 H~.6PR 1652 AAAAAALTJ CZJC~IJGAG X 3348 TTIr7CTTT C PGITITtT
Q'~1F. AAFDGAAA
3593 H~.6PR 1653 AAC~'~AAAA Ct7GAt~G X 0.A 3349 C1TICAGr T TITiC7CTT
PGZ7GAAAG
3594 HSC~.TA6PR1654 AAAL3GAAA CZ~AI~G X Q~F. 3350 TITCFGIT T TI'ItXTIT
AAC~AA
3595 HSC~.TA6PR1655 AAAAC3C~A CiJGAIJt~G X 3351 TI~~TIT T TICT,:.'IZTr
Ct;AA AAFL~A
3596 H9 ~ATA6PR1656 CAAAW3~. CT~AI~G X OC~A 3352 2C~GTrIT T TCCITI'IG
P~AAAC<Jt~.
3597 H9G~,6PR 1657 OCAAAF~ C~I7C~G X t3~A 3353 CAGITIZT T CCITI~C
AAAAALZJG
3598 FI~6PR 1658 LOCAAAFG CMG X OGAA AAAAAALZJ3354 AGiTI'ITr C CIrITIGf'A
3601 H9C~6PR ~ 1659CAA CUC~G X Qtr PL3~1AAAA 3355 Tifil'IGrT T
TIGCAAOG
3602 H9GATA6PR1660 PICA Ct~G X ~,AA APL3C~IAFr3356 TTI'IGCIT T 2DCAACuT
3603 FI9C~F.6PR1661 f~JUOC CC~AL~G X CG~A AAFL3C~1AA3357 Ti'I~CTIT T CCAAC~IG
3615 H5~6PR 1662 ~7C C~IX~G X CC~A AOOCF1C~T3358 ACGIC3CX.T T
C~FG'I~IC
3621 H~.6PR 1663 AOCt~. CZ7C~LJGpG X CAA 3359 Cl'IGAAGr C Tr~AAC~CT
PGUC1CAFG
3623 H9GF.TP,6PR1664 LJGAOCWU CTJC~LJ~G X 0.~AA3360 TGAFG~C..T C
PC~LTJUr'A AAFGCIC'A
3630 FL9GF~TA6PR1665 CGi~0~1 CTJC~G X Q'~P. 3361 'IC~AAOCT C PL~IGAOG
PC~C,TJUI~A
3640 H9GATA6PR1666 AOC~JC.T~C CiX~JGAG X QUA 3362 ~C~T T aCpGAC>jT
PDCt7C~OG
3649 FL9GATA6PR1667 UU0033~J CUG~ X 0.~1F. 3363 OC~T T AO~AA
A~X~
3650 H~~TA6PR 1668 BOG CUGAiJC~G X 0.~4A AAO~JQJG3364 CFGFDGIT A 0.'~CC.L~AC
3666 H~6PR 1669 UUtXUACC CZJ~G X O~A AIJC~JUC~JG3365 CAC~FGAT A a~AA
3670 HSGATA6PR1670 ATJCAWUC C~JGAI~G X Q'~A 3366 PGF~'A03T A GAAATG~T
PCCUALJCZJ
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94
Table III. Hammerhead ribozymes targeting GATA transcription factors (1, 2, 3,
4, and
6) and the complementary sequences
3679 F1.SGATP,6PR1671 C~G~Gi70G CL7GAUGAG X 3367 C~AAA~AT T CCAG~C~C
QAA AI7CAUUUrr
3680 fLSGATA6PR1672 03CCPLZJG CUC~J~G X CGFA 3368 AAA2GATT C C
AALR~7IJ
3690 HSGATA6PR1673 AaL~AAF, ~ X p(~A pp3CCAGU3369 PG'InC3CCr C
TTI~TATr
3692 H9GATA6PR1674 AAAAL~C~. CvGAL~G X ~, 3370 ~C~ T ~~p~T
PGAOOCCA
3693 ~6PR 1675 C~AAAI~C ~ X O~A AFG400CC3371 C~pC~T T
3696 fLS~Tp,6PR1676 C~G~p, X CG~A pCA~G 3372 A
3698 H~,6PR 1677 AL~AGFA CLOG X pC~F, At~l'AAF~3373 CTI~CzTAT T
TI~TIC~1T
3699 H~P.6PR 1678 AAL~AAGA Ci~G X ~F, AAL~,AA3374 TT T
3700 FiSGATA6PR1679 ~ X ~ A 3375 TPG~ATIT T C~T~
3701 F~~.~.6PR1680 rY~ALII~A C~7GAUr~G X 3376 TG~ATITT C TIC'ATIL,T
QUA AAAAL~A
3703 H9GF,TA6pR1681 CAAG9AUG CiJGALX',pG X 3377 TAThI~'~ T G4TIGTIG
Q~F. PGAAAALTF,
3704 Fi9GATA6PR1682 L7C.~AC~AiJ CT7C~TJ~G 3378 A2'ITIC.'IT
X Q~ AAC~AAALT C ATIG~L~
3707 HSGATA6PR1683 L~LTJ~AC CL~L~G X O~p, 3379 T ~A
AIJGAFGAA
3710 HSGATA6PR1684 AUCT~T7C CLOG X a~A ACAAUGAF.3380 T ~p~T
3715 F~TA6PR 1685 C~AAAL)C ~L7C~ X pC~l 3381 ~ A
AGt7CAAC~1
3719 H9GATA6PR1686 UUUC~Ci~F, ~G X Q~, AL~7C3382 C~GtAGAT T 'I~GAAF.
3720 ~6PR 1687 AD~7G CL~ALX~ X Ct~p, 3383 FGI~ATT T C~D2AAAT
AAI~TgLU
3721 F~F.TA6PR1688 C~U(~CU CTJC~I~G X ~. 3384 G~'IT C AOGAAA2C
AAALJCC~C
3729 F~1'I'A6PR1689 C~LU C~JC~S7GpG X Cu4A 3385 C~~,T C p~~
AL1C7~JLZ7G
3739W~ATA6PR 1690 L~1W~A Ct~i~G X CC~A AC~QJCC3386 C~C,Ap~T T ,
3740 H9C~TA6PR1691 c~LR7C~JG C~7~G X CC~1F, 3387 GA~hG'~T T ~.F~G
p~lp~L7C
3741 fiSGATA6PR1692 I~(7QT CL~L~ X pQ~, AAA~J3388 AOGIG'ITr C
Ate,
3747 Ft~Tp,6PR1693 I~7G CLOG X UC~F, AI~J~p,3389 A ~,
3762 KgC~pR 1694 CC~ X ~~, p~pC~ 3390 (~,~pp~ T ~
3763 H9GATA6PR1695 UC~1 CLOG X ~F, ApppL~L1 3391 A'IC~pOL~T T
AAC~
3764 F~6PR 1696 IRJ~T Q~J~G X Q~F, AAApO~,3392 ~IL'~pOCI~T
.1L_ A FL'ICIGAA
w nCre -~ - represents stem 11 region of a HH ribozyme (Hertel et al., 1992
Nucleic Acids
Res. 20: 3252). The length of stem II may be ? 2 base-pairs.
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
Table IV. Hammerhead Riboaymes to TR2-9 and TR2-1 I Orphan Receptor Genes
Pos Target SeC- RZ Seq. Substrate
LD. LD.
No. 'No.
9 EICllrIrR2113393 C"'"~ CC~JGi~ X CGAA ACF~CC4172 GGGAC'IGT C
G~OC~
.4 HUNII'R2113394 C~CnCC C(~ALGP~ X C.'~AP.4173 ~CGT C GOC~3CC~
ACC3CGACA
32 HI2'LCR2113395 ..C"'~L"UOCU CL -~' JGt~G4174 CbCnGr'~GT C
X CVAA ACIJ~'~~a Pf.3CF~G3G
52 Ht22IR2113396 C~~UC,ItiC CL'GP1JGPG 4175 APPL3CGGr a
x CZ;AA AL~CUUU GATCA'IL~G
So' E?C1~R2113397 G,T~3CG~tJ CtJGALJG~G 4176 O~T C A~OCAAC
X CGAA ALTC(J~CG
08 HUMCR2113398 r~Lt,~ C 'LuAt7G?G X CGAA4177 GC~~T A GF.~AAAT
AUO~~
'.7 h'IE~RR2113399 L~.IXTJGC CCJGAL~FG X 4178' GpFG?~AAT T
CGAA AUUUC<JUC C3CP~ATGa.
84 E~R211 3400 A?L?AUUU QJCAUGPG X CGAA 4179 TIr3CprAT C
AC7C~JC3CAA AAATTATT
89 fiLM1R2113401 UCZ,'CK'AALT CiJCALJC~G 4180 CA2CAAAT T ATIt;APrA
X O;~AA AUUUGAUG
SO HI.1~R2113402 UC~ZJC~A C(JGACT'.~PG 4181 A~AAATT A TI~C.~P.
X CVAA AAWUGALJ
92 H(ll2LR2113403 UCTJW CvGALIGFG X CGAA 4182 C~APaTAT T GAACAPrA
AL1AAL1UUG
113 HI.&~2~R2113404 L~Pr LZJC~JGpG X CLAP. 4183 GGpGFCAT T GITPCpGA
ALCUC:i7CC
L16 HUMIR2113405 Li7CL~T CUGALJGFG X OGAA 4184 GFGATIGT T P~P~FDCA
PC~F.L~TJC
ll7 HI&~R2113406 CCx3CUCUG CL)C,AUGAG X 4185 AGATTGIT A CPG~3CPG
CuAA AAG'AAUC~T
.43 FitS~R2113407 PL~AIJCUG CC~AG X CGAF. 4186 CPGAAAAT C CPC~F.TIL~'r
AUUC~
'_49 HIll~2IR2113408 GCIhfJCAC CC~PSJGF~ X ~ 4187 AZLCFGAT T GIGFC~L~C
CGAA ALJCTX3GAU
161 I-~~IR2113409 LTu~LJGAUC CUGALJGAG X 4188 AC~10CACT T
CAA PL~JOCtJCTJ GAT<A~A
165 FiL)~2IR2113410 G~C~IJ CUGAL.:~FG X CAA 4189 CPL'rIGAT C
AL7CA~ ATAAT~LC
i68 HIll~21.R2113411 Uf~GC~B~IJ ~ X CGAA P~I7GAUCAF.4190 TAT A ATPLC'CAF.
171 F~S2IR2113412 GCCUUOOG CUC,AIJGF~ X 4191 A2ZP.TAAT A
CGAF. AL1C~SJGAL1 Ci~PD3C
187 HId~IiR2113413 UC~AAUG CUGAUGFG X QUA 4192 CAAC3CAGT T
PLL70CUUG CATIC'IGA
188 FiUNB'R2113414 GUCAGAAIJ CG X CX~A APLTJOCW4193 APDC~T C AWC
91 HIE~~R2113415 LLT~P~G CUGACJGFG X CAA 4194 C~GI'I~AT T
AUGAACLX; CIGFCAAA
~2 H(JMIR2113416 AL~JCA CUGALJG~G X OGAA 4195 PGTIr,ATr C
AP,UGAAGU ~G~AAAT
201 HIRUR2113417 GCCC~JCGLJ CtJGAUGpG X 4196 'I~AC.~AAT C
CGAA AIJC1~JC~. PLGACnGC
211 Fif.~IiR2113418 UtZ3GFl~. CUGAIJGFG X 4197 CGALI30CT C
CGAA PDC~ CAA
213 F~R211 3419 7UOGpG CUGAZ~G X CGAA 4198 ACX~GC'ICT A
PGpDO~~J CILCAPaC
GC(
216 H(~R211 3420 _ 4199 GC'IC,TACr C
UCAJOCUUG ~ X GGAA ~C CF~FDCAAA
227 Ht~R211 3421 G~AIJ GtJGAIJGpG X CGAF. 4200 POCAAAGT C ATIC.'I~3C
PL~3CLT
230 HIH2IR2113422 CUC30CCPG C~ X CGAA ALIT 4201 AAFGIrAT T C203UCPG
231 HI.~2TR2113423 ACA CTJGALJGAG X O~A AAIJG~U4202 P~P~CA2T C ZL~3CCPC~
246 H~R211 3424 G CI~AL~i~G X CGAA AL~CC 4203 GOCAAGAT T CCPL~CG
247 F~.R2ll 3425 G~3~~JG CUGAIJGAG X Ct'~AF.4204 GCAFGATr C CFI.'iOCt3G
AFDC
252 HI~R211 3426 UUUfJCL~'~ CUGALJGAG X 4205 A2'.tLCAGT C
CGAA PL~3~~tJ ~3GAAAA
263 HIH~ffR2113427 c~AOCAF. CZ7C~L7GFG X 4206 GGA~1AACT T
0~1A PLZ7I~JUCC TICCTIPC
264 HIJ~2IR2113428 LJ~AAO~~F. C<.7GAt7GAG 4207 GAF~F.P~IT T
X CGAF. AFLWIRJC 'I~CTTPCA
265 F~ll2IR2113429 UC~FD3 CUGAIJGAG X 0~1F. 4208 AAAAGTIT T CCI~CAF.
AAF~TJUCJCT
266 I~R211 3430 Gt~~PG CC~TJGpG X CAA 4209 AAPG'Ti'IT C
AAAPL't~(J CITPC~C
269 HIb2IR2113431 GC'~JUG<T CUGAL7GpG X 4210 GIT~'T T PC~FCI~
CGAA PC~CAAAPC
270 HI.1~2IR2113432 UOGF~J~JG CUGAIJGpG X 42ll 'IThITCTT A
CGAA APL~AAAA CAPL'~LCA
276 HI.fi2rR2113433 UGCALJC1JG C~JGAiJGAG 4212 ~'i'AC~C~ C
X Ct~P. PGUUC~9P. Cl~2LaC.~.
~
293 HIWiR2113434 Ar~3~Jt1 CUGAUGpG X CGAF.4213 GC~OGIGT C APDCFG'IT
PCPC~CUOC
301 HI~IR2113435 UAAAAAAC1 C~JGAIJG~G X 4214 CAACCFGT T ATrITI'IP.
Ci~A PLU~JUG
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Table IV. Hammerhead Ribozymes to TR2-9 and TR2-11 Orphan Receptor Genes
! :'.t~~:R2113436 CL-~?AAAA CUGAt~G :t 4215 .'-~:C~Tr 3
302 CGAA P?C.TX3GUU T?TT_Tr?r
j ::C~~'R2113437 ;AAA C(~.tJG?~ X CC;AA 4216 CC~'rrAT T TI'rrrlCCA
304 AITAACIJC~
305 HC~IrR2113438 Ctx3G't~AA CUGAUGPG X 4217 CrY~'rrATr T
CAA AAI1AP~ TITP~
306 h'IJ~'R2113439 e~L~Jt3GtJAa C(JGALJGP~ 4218 ?~TLATIT T TTF~:GaLT
X CGAA AAAL~~AGiJ
307 ~'R211 3440 Cz L~JO~JA CtJGAi'C,FG 4219 GIT~ITrIT T
X C~~FA AAAAUAP~C TACC~CtC
308 HC~IIR2113441 GG~~J CI~AL~ X CGAA AAAAAITAA4220 T~TTrrr T POCK
309 E'1~R211 3442 ?D;t~C~OG C(JGAL~P~ X 4221 TATITrIT A CCAL'I~CT
CGAA P~AAAAAL~.
315 h~R211 3443 C~PG C(JGAIJCpG X CGAA 4222 TI:~LCAGT C
PGUO~kIA CI~P.ZLZG
321 hL'NIPR2113444 tT3C.~A CL7~IJGPG X CAA 4223 C~.'UC'1.~AT
AL~GFG C T~.'IGCA
325 h'~R211 3445 G..ZX~'A CCJGAIJGPG X 4224 'I~,iL~T C ~~PC
CGPA AC~GAUCA
344 HCll~2IR2113446 L~.LJGUUPG CUC,PJ.~FG 4225 CT~PDCr C CrAP~GA
X CGAA PL3CU~'P~
347 Hf~R211 3447 LET CCJGAIJGPG X CGAA 4226 C'rL3CI~C.T
PDGFflCUG A rlC~'I:~1
354 HC~R211 3448 LZ3GAGAALT ~ X CGAA ADCL~.4227 TPrG~GAT A ATIL'rCCA
357 E~R211 3449 GC~GGFG C'C~AIJGFG X 4228 C~T.~1AT T CI'L~CPCPC
CGFA AUC1AL~~
358 HC~?IR2113450 C~'~A CCJGAIJGPG X CGAA 4229 ~C~TAATr C 'IC~GACC
AADC~ULZJ
360 H(ll~IR2113451 WGGUCpG CC7GACJGFG X 4230 r~.2'~ATIL'r
CGpA PGAP1A.~J C CP.~CAA
378 HIll'2rR2113452 r~aaAP~IJ CL~RLT'~PG 4231 G~AAT A PDGTTTIT
x CAA AWC~CTJC
383 F~.l~2rR2113453 AAA CUGAC~F~ X OGAA FLCCJUAVU4232 PaTPpflGT T
TrIGAZCT
384 hTJrffR2113454 ~~Ai7CAA CSJGRUGFG X 4233 A2'~PL3GTT T
CGAA AAOCUIJAIJ TIGA~.'IT
385 HIlMTR2113455 Aa?C~A CUGALJGAG X CGAA 4234 TPpDGTiT T 2~A1L'ITT
AAF~LCUC~.
386 HIJ~2IR2113456 C~1PGALC CUGAt)GFG X 4235 P~L~GITIT T
CGAA AAAACC<JU GA'i~'I'rIG
390 HBa2LR2113457 L1~C3CAAA C~IJGF~ X ~A 4236 Tl'lTIGAT C
P1JCAAAAA TI'IL3C~fiA
392 H~TR211 3458 AC(IA03CA C'IJGAL7GAG 4237 T~IGAZC'T T
X OC~F. P~T~AAA 'I~CGTPGT
393 HIJ~R211 3459 L~GC CZ~AZ~FG x CGAA 4238 TI~AW~'r T GCC3rAGTA
ApGAUC~1A
398 HI.ffKI'R2113460 OCP~~AC C~AL~G X CGAA 4239 CTIZC3CGr A
PLOCAApG GTA2GIL3G
401 Hf.~IR2113461 L~.tICCi~CA CI~AL7C'~FG 4240 TGCG'I'AGr A
X CGAA PLL~CA ~GPGA
418 H(JMIR2113462 G?LGUC~T CUGATJGF~ X 4241 CPp~CAT C PDGAL~IC
CAA AL~JtIUG
426 Hfa2rR2113463 LJOCAL~AIJ CTJGAUC,F~ 4242 CPtdGFLGr C
X CGAF. PL1~CUG ATTA~GA
429 HC~t211 3464 UC~CUC~LJ Ct~ATJGF~ X 4243 GFLGIrAT T ATC3C~3CA
~A ALJ~C~JC
430 HI~2IR2113465 CUGCUCCA CtJGAL7GPG X 4244 P~Tr A ~CFG
CGAA AAL~PCQJ
440 E~.~R211 3466 UC~AF~tJ CUGA~G X C;AA 4245 G~OCF~GT A PLTIGIGA
PLLJC~CUGC
444 HIJ1~2IR2113467 GCCfRJC~C CUGAIJGpG X 4246 C~GrAFL'r T
CGAA AC~CLJG G'IGAAC~3C
463 HI~~2IR2113468 UUUt~AAA CZJGATJGpG X 4247 CAAPDGAT T Trl'rAAAP.
OC~1A AL1CLL1(JIJG
464 HI.H2IR2113469 C~P~P. CZJC~TJGAG X CFA 4248 AAFflGATr T
P~AI~CWU TITAAAFG
465 E~.~~2rR2113470 L1~JIJUI~P. CUGAIJGpG 4249 PpDGATIT T TrAAAPGA
X CGAF. AAAiJCCW
466 HI.ll~2IR2113471 Ut~L~JUC~ C:L~AL~G X 4250 Pf~GATITr T
CrAA AAAAL7CCU TAAAFGAA
467 F~J~2IR2113472 FG X CGAA AAP~AAL70C 4251 GG ATITIT T
CTJUCWtItJ CZJGAL7:~ AAAFGAF~
468 I-B.E~R2113473 _ 4252 C,AZ'rITZT A
aLZJUCUVU CTJC,PTJGFG AAPC~1FDC
X Q~1A AAAAAALJC
479 HC~IlR2113474. UUUUUUOG CZJGAL~ X QUA 4253 PGAAOCAT C OGAAAAAA
AIJOCI~.TJ
489 FiIR2rR2113475 AI~ITPLL1A QJGAUGAG X 4254 GAAAAAAT T TpGIP.TAT
O~F. Atl~lA7C
490 F~R211 3476 AF1L~I~iJ CZJGAiJGAG 4255 AAAAAATT T PG'TATA2T
X CAA AAIJUUUInJ
491 HI.~R211 3477 GAP~I7AL~C Ct.7,~AtJ~G 4256 AAAPATI'T A
X AAA AAAWCJW GTA'I~TIC
494 fB~2iR2113478 CAL~AAL~ C~7GAIJGFG X 4257 APTrr.~T A 'rAT'LCAZG
OGAF. AC~1AALW
496 F~R211 3479 C'~FCPTJGAA CZJGAL~ X 4258 TITF~7rP.T A
CAF. AL~:~1AF. TItA2~
498 HI~IR211 3480 LJC~AC~JG CUGAL~ X CCAA 4259 TPGrA'~T T CATG'I~GA
AI~L~
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97
Table IV. Hammerhead Ribozymes to TR2-9 and TR?-1 I Orphan Receptor Genes
i99 T.~R211 3481 CUC~ACAU C<.~,AL~G X CC~ 4260 e~',TATATr C
PAL~1 A~'IC:PG
~u4 i-IL~ffTt2113482 C~~UC CCCA.tJGFC, X ~A 4261 AT:C~'I~'I' C
AG~LJGAALJ GAC~Fv'I~A
! HG'N11R2113483 Pe~T~LTJUU Ci~A(JGAG X 4262 TCC~33GAT C AAPt3
5i1 CAA AL~~A CATr '
5i9 HUhITR2113484 P~1LTRAL~C CCJGAIJGPG X 4263 CRAr~AT T GTATTAZT
Ct;AP. ALICCt~
522 F~R211 3485 AL'C~AUAA CC7GAl;JGPG X 4264 PL~aT'I~T a TTATI71AT
CC,AA ACAAUCCU
524 H(JMIR2113486 L~AAU C'CJGALJGPG X CC~A 4265 GATIC~'rAT T
PJ~PCAAIJC ATrAATAA
525 I~2IR2113487 CUC~UC~A CUGAL1G~ X CAA 4266 ATICTATr A TTPATAP~
AALTPCAAIJ
527 H(llKIR2113488 UC3C.T~W CUGAL~PG X Ci~A 4267 TGTATIAT T AA'~AP~C~.
AL~L.~.
j HCll~R2113489 c~JGCU(JALT CUGA(~G X CC,AA4268 GT~T~P,TT A ATAFOG~C
528 AAt~AL~C
531 Eitll~I~R2113490 GUC~O~J C~,AI~AG X CGAA 4269 TTATTAAT A PI3CACCPC
AWAAITAA
j HUhIIR2113491 OC~I(1 CIJGAI~P~ X CG~A 4270 PL'CC3CIGT C
552 P~C'~DL'C~U PATP~lL3C
556 HC~R211 3492 AC~X3CPG CUGAUGPG X Ct;AA 4271 C'I~IrAAT A C'I~CAL3'~T
AWGACpG
565 HI~IR2113493 AL~UC~tJ CLJGAUGFG X CLAP.4272 C'IL'3~CPl~T
ACCZJOCPG T AC~GPCAT
56f FiC~R2113494 CALICiJCUG C(JGALJGPG X 4273 'IOC~IT A CF~AZG
CC~A AP~LJC33CA
I I-~R211 3495 Aa?L13CAA CUGP1~PG X CCAA 4274 PST A TIC3~IT
576 ACAUCiJCU
578 HfJ~2TR2113496 CCAAPC3C CUGAC~PG X CGAA 4275 PGAZ~:f T Q~G
A~IJCU
583 I-~IR2113497 L~CA CUGAI~G X Cu~A L1A 4276 'L~L3CGT T T~AATVA
584 HI.ll~2TR2113498 L'IJC'AIJUCC CUGAIJGPG 4277 ATIGCVTT T aGAA2t;AP.
X CAA APLY3CAALJ
i HI.~IIR2113499 AL~3~P. C'C~PTJGFG X CG~P.4278 OC~1PGAGT C T"IDCAAT
001 AC~JCTnJOC
0'05 Fi~2rR2113500 L~C.~J;IUG CUGAZJGPG X 4279 GPCIr=7~GT C
CAA PC~UC G~A~IG~A
526 HtR41R2113501 GEC CIJGAL~PG X CC,AA- 4280 AAACCCAT T CAPGTA2tr
ALJGG~JUtJ
632 f-BJMCR2113502 LZTJCGtJGP. CUGAIJGpG X 4281 ATIGAPGT A TCPLGPGA
CAA PLUJCAAL1
634 HC~CR2113503 t~CCT CUC,ALJGF~ X CGAP. 4282 TC~PGTAT C PLGF~AAA
PTTF~Jr'A
046 HI~2IR2113504 A~GAA C~ALJGpG X Cu~A AI)fJUWCtJ4283 PC~4AAAAT C TILCAPGT
648 HI~~IR2113505 PC~IJUGG ~ X AAA P~AUUtJIJU4284 AAAAAICr T CG~PL'IG~
049 HIJ~2IR2113506 C~JtJG CtJGAIJGPG X C~1A 4285 AAAP~C.'IT C
A~AJt~T CAPCI~IG
663 H~R211 3507 UtJCUGIJUG CIJGAL1GAG X 4286 G'IL~C~.'T T
CAA PL3CL3~C ChPCpGAA
664 fB~IR2113508 UIJUC~JCT CUGAZ7GFG X Q~P.4287 'IC~~C.'IT C
AP~CnGCA APC1~GAAA
077 HIR2TR2113509 CL3CALTAI1A CZJC,AIJGPG 4288 GAAAAAP.T C '~ATAZCCG
X CAA AUCxJUtJtJC
679 I~R211 3510 WCOGAL~ CUC~1UGPG X QUA 4289 AAAAATC'I' A
PGAL)WUU TP~2GAP.
681 Hl.~2IR2113511 CUL1IJWGA CTJGAIJC~G X 4290 AAP~T.'~F1T A
aGAA P1~C-A~AJ 'IL17GAAPG
683 HI.d~2PR2113512 tJ~JUUCG CZJGAL7GPG X CGAA4291 AZCTp:~AT C OGAAAC~GA
AL~Ll~iJ
695 HI~R211 3513 (303CI7PLG CTJGAUC,F~ X 4292 APL3GALC.T T
O~P. PaC~CW CvTPflCCC
696 HI~~iIR2ll3514 UC~30CC~C CUC~FG X AAA 4293 PC~CIT C GI~C'A
APaC~CU
699 F~R2ll 3515 t~l~C CZ7GPTJGpG X CLAP. 4294 PLC'hICGT A C3CCCATI~A
ALGAAO~LT
706 FR~2rR2113516 UC~GUU CTJGAL:~FG X AAA 4295 'I~l3CCCAT T
At7G30Ct~. AF~L_iDCAA
707 HI~2TR2113517 CZAJOG~T CUGAL7~ X CAA 4296 PL~CCCATT A ACI~C~AC
AALJO30CU
717 HI~TR2113518 AAAP~~JtJG CtJGAI7GAG X 4297 C1L3CAPLT C CP~PL.'ITiT
aC~A AC~JUOCP~
723 HI~2IR2113519 t~A~CAA CZJGAIJGPG X aC,AP.4298 C~CPACI' T TIG'TAACA
PL~fJOG~G
724 HI~2IR2113520 C~C~. C(JGAIJGF~ X CHAP. 4299 'I~CAACTr T
AP~JUOGF1
725 HI~2IR2113521 UCUC~C CUGAUGPG X CGAA 4300 CC~PLTZ'~ T G~APCpGp.
AAPhTlUOG
j H~2TR2113522 Ci~J CLJ~tJGPG X CCAA PCAAAPGU4301 ACTrI'7~GT A
728 PCpGF~TPG
735 HIa2IR2113523 PLC CLJGAUGPG X C~1A AUCT~UUA4302 TAPCpGAT A GIGAP,PL~T
744 FiIa2IR2ll3524 LJGACCCnJG CUGALJGF~ X 4303 GTC,AAPL,T A
CGAA PLLnJUCPC CAPL~ICa.
751 HL~2rR2113525 GUCCL7C~JU CUG~JGpG X CCAA4304 2~1CFPI3Gr C
PDT APCPDGPC
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Table IV. Hammerhead Ribozymes to TR?-9 and TR2-I 1 Orphan Receptor Genes
763 iiG~R211 3526 CL~_AALLV C(JGAUGP.G X 4305 nDGPL'IGT =
CAA AC~Q1 ~TIC?G
764 hL'MIR2113527 C~GAAL~ C~AL~P~ X CAA Ap~JC~4306 OGACI~'TT _.
~T1~C~
768 I'l~ffR2113528 CAUWCL~ C.L~ALJC,FG X ~2. 4307 2~TP,GAT = =C~,A~~G
AUCL~ACA
769 E~R211 3529 ?~IJtJCCLT CUGAL~AG X ~A 4308 GTTPGAZT C ~3C-AAT~T
AAL1CTTAF~C
778 h'Cff~2rR2113530 UAU(JCALJG CtJGAUGPli X 4309 AO~AA~T = ~2GAATA
CG~A ACATJC~CU
779 HI~IPR2113531 A(JAUUC~LT CCJGAUGpG X 4310 GGAATvIT C ~'TGApTAT
CAF, APCALJIJCC
786 Fi~R211 3532 UOGALGAA CLJGAL~G X CC~A 4311 I~ATGAp,T _.
PLRJCAUGA ACA
788 HI.1MIR2113533 CAUt3GAUG CUGAUGFG X AAA 4312 A~AATAT =
AL~IT(~?LJ
789 T.-1~2IR2113534 ?GAIJC7GALT C(JGAI~GFG 4313 T~AATATT C _'~C'A'IC.T
X CHAP. ApSJAI~JCA
792 HI.1MIR2113535 G~G~.DG CUGA13GFG X CGAA 4314 ATA~ICAT C
pTJGAAL~1LJ
796 H(~IR211 3536 UC~;A CC~AL)GpG X Cl~, 4315 T._AT'rAT C
ALJOGAUGA _~CPG'L~1A
803 HIa?rR2113537 L~IUUU C<.JGAUGPG X Ct;AA 4316 TC'IL~GAGT :.
pLiJC~CPGA :: ?FL'tGA
814 HI.a2rR2113538 OCACF~L~CLI CC~~A(JGPG 4317 AACI~T C :i~Clv'IDC
X CGAF. PCC~Jtl
832 Fifa2I1~2113539 CC~U Q7GAUGpG X C1~A AUGLJCAUC4318 GA2~~PCAT C
: GATAPC~
837 1211 3540 UUCPGCCU C<.JGAUGPG X CLAP.4319 CATCPGAT ?_
~ ~IG1A
847 HI.1MIR2113541 CCI~CACT CUGALJGFG X ~A 4320 C3C~I~AAT C
AUCICPaCC _"~IC~C3G
852 HIJC2IR2113542 AUCTJCCCU . CUGAtJGFG X 4321 AA2CATvT C ~C~FC~AT
CGAA PC~1IJGAUIJ
861 HCn2TR2113543 Ul'~LTJUA CvGAUGpG X CGAA 4322 PflOGPGAT ~'
At~CCZJ ==~GTP~A
862 Hf.~R211 3544 ACJGZ~LW CL7GAIJGPG X CLAP.4323 C30GPGATT =
AAL7C~CC =~ACAT
863 HUNlTR2113545 AALJGCJACTJ CC~IJGAG X 4324 0=. ~CATT
CGAA AAAL~C
867 FifE~?IR2113546 OOCl~AIJG CC~AL~AG X OC~F.4325 ATITAAGT .'-_
PLTJ(~AALJ C~GCC
871 FiC~KIR2113547 CAUCJG3CC CUGAIJGAG X CAA 4326 APG1ACAT _ 33CCAATG
AIJC~LW
884 Fi~R211 3548 AAtJGAIJC~J CtJGAUGAG X 4327 AA'I~IC3G'P
AAA PLCPCAU<J T
885 HI.ll41'R2113549 LTAAL7GALJG Ct7GAL;~FG 4328 AT~GTT ? C~.TCAT.~A
X Q~1A APLCACALT
889 HIJ~R211 3550 U ~CLB~ALT C.T~I7GFL~ X 4329 OGITACAT C -"'IpDC~A
O~A AL~AC'~
892 F~R211 3551 GAUU0.~CU WGALJGpG X Q~F. 4330 TPCAZrAT ~ ~30GAP~
AIJGAiJGT~.
893 HI.aKIR2113552 P~AUUL~C CIJGAIJGFG X O~A 4331 P~ATLATr =.
AAL1C,AIJa1 ~GAp.TI.T
900 HL~ffR2113553 UfJIJUCCAA CC~AL7GFG X 4332 '~PDCGAAT C
CL's. AL~CLg1 ~GAAAA
902 HIa2IR2113554 ~C Ci7C,AIJGFG X CAA AGAWCOC4333 oCGAF~CT ~ 3~AAAFt
912 HI.BKTR2113555 AF~ALJCW C<.~AL7C,FG X 4334 GAAP~F,ACr .'-.
CAF. PC~J~JC .'-~A2C.'IT
918 F~.~IR2113556 UUGpGAAA C1JGAUGt~G X O~A 4335 C~AAPGAT C ITI~IC~A
AUCUUUpG
920 F~.R211 3557 LEA CTJGAI7GFG X ~F, ~TJC~J4336 AApGATC.T T
1C~C~AAF,
921 HL~R211 3558 AL~G CL)GALJGpG X O~A AFC~LJ~IJ4337 APGF.TLIT ~
CIC9AAAT
922 X11 ~ 3559L~IJCAJUGA CiJGALJGAG X 4338 P~,'ITT C ?~AAAP.TA
CGAA AAAGFTJCTJ
924 HI.~IIR2113560 PLAT C<JGAL~GpG X AAA PGAAPGAIJ4339 AZL'IfiIC.'r
C ?~l~AT.~L~T
930 F~L~LR2113561 UUC~C CUGAU;'~AG X 0.3AA 4340 C'IZ,AAAAT ?.
AIJfJCEJG~G ~
933 HI.~?IR2113562 C31IA.AJC~IJ CiJGWJGpG 4341 AAAATAGr .'-.
X CGAA pI:T.TFTJUW .'-~AAF:IG
943 HC~IIR2113563 CAAIJ~UA Ci7GAUGPG X O~A 4342 'IC'~AAATuT
PCpT~7IJCp. C '~.2G~.TIG
945 HI~2IR2113564 (n7CP,AL7~A Ci~AL7C,FG 4343 A~I~ ?. A
X C~Ap, ~AC~J
950 HIa~2IR2113565 AFOCUUUC CtJGAL7GAG X CGAA4344 ZL'rAA~GAT ~
AL7~GA GAAAGCIT
958 I~~R211 3566 CALnZ3CW CUGALJGPG X OGPA 4345 'I~AAFL3CT ~
AOCUInJC'A ??l3CA,~7.G
959 I3f.S~2IR2113567 LJCAUUGCU C(~AL~G X QUA 4346 C,AAAGCZT ~3CAA'IGA
APL3CT~
972 F-B.d~ITR2113568 CAAPf~3G CLJGAUGFG X OGAA 4347 AZGATuAT CCZLTTIG
AIJCAIJC~1LT
976 HtB~R211 3569 CACACAAA CUGAL7GPG X CGaA 4348 TC,ATPCC'r C
Afl~ ~I~IG
978 H~2IR211 3570 UU~C~. CZJGALGFG X CG~A 4349 ATPLC'IC.T T
PG~~1IJ ~IGAA
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Table IV. Hammerhead Ribozymes to TR?-9 and TR2-11 Orphan Receptor Genes
979 hLMIR2113571 ?i~C C'UGAL~ Y CAA APIA 4350 TPLCT~.'IT
T GI~IGAt~T
I ::'C~ITR2113572 LT.IKUIJGA CUGAL1G~G 4351 GIGIGPAT T
988 X C~1A AWCACP~ 'IC~F~1
989 .zi~R2113573 .'-i,TJUCUGG C(.~ALJGPG 4352 T~IGA2.Tr T
X CAA PA(JUCACA CAr~CA~tIT
990 E~TR211 3574 C.'-IJ()IJCW C(7GAL3,~FG4353 GIGAATTT C
X ~A PAALIUCPC AP~APA'LG
1016 FTJrIrR2113575 CZCCCnJGA CZJGAIJGPG 4354 OG~A'IGT T
X CC,AA PCALJCPL~C WAPL30~
1017 FiL~2IR2113576 Ct3CCC~JCJG CUGALJGP~ 4355 GIGA'I~Tr T
X AAA .AACAUCAC CAPD30CA
1018 I-~R211 3577 ?.L'~C~CU(J CUGAIJGP~ 4356 ~GATGIZT C
X CAA AAFC~1IJCA ?PL303CAT
1027 HI.H~2rR2113578 GL~JCA ~ X ~A AIX3C2"T)U4357 AF1300CAT T
'I~ACAC'iC
1028 F~.~2LR2113579 CtJGPJpGFG X CAA AAIJC3C2i14358 PL30G~ATr T
GACACI~T
1035 F-1~R2113580 LL'WGCAA C(JGAL7GFG X 4359 'IZGP~Cr C
~A PL~JCAA TII~AAaA
1037 HI.ll2CR2113581 C~CW()(X3C CiJGP~LJGPG 4360 Cl~ACfif T
X CAA PGPL~JC GCAAAPDC .
1048 EiC~t2113582 C-0GAUC~ CLJGAtJG~ X 4361 PAAAC~AT T
CAA AUGCUUCAJ GAr~CIG
1053 t~t211 3583 Ct7Ct~C~ Cv~t7GpG x ~. 4362 T C cl~C~
Ant~AAtJG
1081 E~2IR2113584 CCC3CC~TJ CUGAL~FG X 4363 CCAGFGCr C
AAA POCLJCUGG PL~'IPL3CL~
1085 HCll2IR2113585 aIJOCCL~C CTJGALJGFG 4364 ~L3CT~PGT A
X CG~A PC(JGFflCU OCC~CAT
1106 HCE~2rR2113586 ?LZ~OC~JG CUGF~,UGFG 4365 CaGAFGIGr A
X CAA AG~.L7UOC CACCrAaT
1112 F-B.~IR2113587 CC~tJGAtJ CUGAUGF~ X 4366 GTACAOCT A
QUA PD~C ATCPL'iL3G
1115 HIa2IR2113588 ~CFL~J CL~AIJGFG X CGAA 4367 CPLCTAAT C
AIn~C3~JG ACiC~Gr~.
1125 HIll2TR2113589 i.T~C3CUUG C<JGALJGFG 4368 CIC~GPGAT T
X CAA AIJC.iJCCFG CAPfCATA
1126.Eit.~IIR2113590 LT~UOCW CT.7GAZ)GFG X 4369 2C3C~FGp.Tr
CGAF. AALK.tJCCA C APL3CAT.AA
133 E~.H~ITR2113591 C~lIUtJ CUGALJGFG X CGAA4370 'ICAP:C~AT
AUOCLnJGA A AATrP~C
1137 HI~21.R2113592 UUCOC:TJQT CLJGAUGpG 4371 OCATAAAT T
X CAA AUC~C PC~C:CGPA
1138 F~~~2IR2113593 Wtx70GfJG CfJGAI~1G X 4372 CP~T~AATr A
O~A AAWtmL~ CPL~AAA
1160 HIWIR2113594 LJC~CIJC~G CZ7GAIJGpG 4373 030CCPL'r T
X GJAA AC(7C~3~ C'IrPI3CGF.
1161 I~'R211 3595 AL~'C'3CUGA C~AZ)GF~ 4374 03CCPLZT C
X AAA ACC 2C~C9CGAT
ll63 HCll~2IIR'lll3596 C~CU CLJGAL~FG X ~A PGAPGUOG4375 CCACI'iC'T
C PDC~F.TIC
1170 Ev.~TR2113597 L~~JG CCJGAL7GFG X AAA 4376 ~PDCGP.T T
ALJCL~CZJC'~A CP~CP~~TP.
1171 F~R2ll 3598 CL~C~LJaT C~JGF~JG~G 4377 CPC3C~T C PCA~IPG
X (AAA AALJCC~C.ZJG
1178 F~211 3599 CLJGAAFOC CZJGAIJC~G 43?8 ~r A GCrrIC~
X ~1F. PCAL~(JGp.
1182 E~R211 3600 GM3CL~<JGF. C.~UGPG X 4379 AZG'rPL3CT
CG~A PDC1~L'PTJ T ~C'IC
1183 F~R211 3601 tJGFL30LTJG cTJGAi'G~G 4380 '~I~OCTr T
x c~A AFOCt7PCA CPD3CTCA
1184 HIa4iR2113602 C,Z~AOC~(J CUGALJG~3 4381 GCTIT C PC~GC~C~C
X CZ;AA AAFOCI~C
1190 HI~2IR2113603 aOCALJ03J C(J~IJGpG X 4382 TI~30CT C PLCATO~
OG~A PC3CX.TJGAA
1200 HI~uR2ll3604 CI~DGaG CtJGALJGpG X 4383 CCAZL3CCT T
CGAA PD3C~t~G C'I'L~CrATG
1201 F-~.~2LR2113605 OCAI~3GA CZJGALI~!G X 4384 CAZC3CC.'IT
OGpA AFI33~I7G C 'IL'~C~C
1203 H(~2IR2113606 ?D3CALipG CZ.~AL~FG X 4385 'IC3CCTICT
CGAF. PGAAC30CA C C'rAWCT
1206 Hf~.R2113607 C(7C~OC3CA CvGALJC,F~ 4386 CTICZCCT A
X OGAA P13;~AAG ZC3CC'IL~G
1216 F~211 3608 CAiJtJ~C3G C(JGFJJGPG 4387 C3CCI~CGT A
X CGAA PGUCAOGC CCIGAAZG
1231 HIa~ITR2113609 CL2CAALJG CLx'~AIJGPG 4388 ~CACr A CATIC303G
X C~F. PLTJJ3rI~L'A
1235 HI.d2tR2113610 C,~GUCCOC CzJGAIJC~G 4389 CACTPCAT T
X aGAA AI~JG 030GFGIC
1243 HI~2LR21136ll L~CA CL~PG X CG?1A PLL7GLLCA4390 'IL30GGFGr
C TDCL'IL~A
1249 FB~fIR2113612 OCF~iJG CUC~FG X Ci~A 4391 GIC'IC3CCT
P~O~C C ~C
1261 HI~R211 36L3 CItJGAImPG CTJGAIJGt~ 4392 PL'n3Clv'r
X ~A .~C~OCFGU T Cr~T~A
1262 HI~R211 3614 A(~IAA CUGADGpG X CGAF. 4393 C'IDC~IT C
AFL~DCaG T~AAT
1264 HIJ~2IR2113615 C~T7C1GAIJ CUC,AIJGFG 4394 GC~TIC.T T
X CGAA PGAFC~OC AWA1DC
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Table IV. Hammerhead Ribozymes to TR?-9 and TR2-11 Orphan Receptor Genes
~65 X211 3616 Cz3CAL'C~ CCJGACJGPV X 4395 A ~~
CGAA PEG
1267 YCll~R2113617 AGCJOCAW CCJGALJGAG X 4396 GTIC.'ITAT C
CGAA AIJApGAAC AA2L~CT
1283 h'C~211 3618 GG?r~LICGA CUGAL~ X C~'~AF.4397 'Ip30C~C.T T
PL~~3CL~'A 'IC~;~ATmC
u?84 HC~t211 3619 ?D;~AAIJCG CUGAIJGpG X 4398 GC~CACIT T CGATI~'~
CGAA A.~IJGC~C
1285 HI~R211 3620 ?.~f3GAALIC CUGALJGPG 4399 GOCAL'ITr C GATE
X CGAA AAAC~OCC
1289 HCll~R2113621 a?~C3G CL~AC7GAG X CGAA 4400 CTI'I~~.T T CChI~'hIT
PTJCt;AAFG
1290 E~.ll~2IR2113622 CAr~P~APG CUGPJ~FG X CGAP.4401 TTI'CGATT C
CTI~'I'I'IC
AA(JC~uAAA
1293 F~2I'R2113623 CU3GAAFG CC~P,C~G X CGAA 4402 CGATICCr T C'rITCCFG
PC3GAAL~
1294 HU~211 3624 C~JC~GAAA C<JGAIJGAG X 4403 GATIL~;.Tr ,C
CAA AFL3CAALJC TTI'L~CFC~
1296 HCJMIR2113625 ~.LZJC3GA CCJGAL7GPG X 4404 TIL~'ITL'r T
CC,AA PGAPI~AF. 'IL'iCPC~'!'
1297 HC~21'R2113626 G?L~CCt~ CUGFT~FG X CGAA 4405 TCCT1L'IT T CCPDOCIC
AP~IFaGA
1298 F~R211 3627 PC~OCCTJG CCJGA(T~PG X 4406 OCITCTIT C CPL3C~CIr.T
CGAA AAF~APL~
1305 E~~2IR2113628 UU3CCCTlA CUGAUGAG X CAF.4407 T'1~OC3CT C TAOC30CAA
PDCGL~
1307 HIA~R2113629 L~TJIJOCt~ CC~ALJGAG X 4408 CPC~7.LT A 033CAPGA
CVAA P~FC3CCOG
1325 HU~2rR2113630 ALCFL~JGF. Ci7GALJGPG 4409 APC~~L3CAT A
X CGAA ALJOCCx~JCT 2~L'IC3;,T
1327 F~.~'R2113631 L7~CpL~J CC7GAIJGAG X 4410 CPL~CATAT C PL'IZ3GIGA
~A ALIAiJOC(~
1341 Iit~R2113632 AL'UCCPQT CUGAUGFG X C1JAF.4411 TC,AAPaCT T PL'IL3;~AAT
PGCt7UUCA
1342 HI.a21'R2113633 C~LIGCt,PG CUGAUGFG X ' 4412GAAFC~CIT A CIl'~AAZG
CC~A AP(3CUUUC
1355 F~1?iR2113634 AAA CC~AUGFG X CAA P~JUCAUT4413 AATGAALT T TITPCl~.'r
1356 HI.~L'R2113635 AP~PL~P. C<JGAL.i~FG X 4414 AZGAACTr T TI~tT
~A AP~L1
1357 Hf~II'R2113636 CAAGFGUA CIJGALJGFG X 4415 TGAACTTT T TACIL'riG
CGAA AAP~JrA
1358 fifll~2l'RZll3637 CCAPC,AC~CT C.~LJGF~ X 4416 GAACrIZT T PLZC'I~3G
QUA AAAFL~tJC
1359 HIll~~R2113638 PLCAPGpG ~ X Ct'~AF. AAAAFG(1(J4417 APC:CfiIZT A
CIL'i~D3T
1362 HlllKiR2113639 APGFLCAA CtJGAUG~G X CGAA4418 C T'IL3GICTT
PG<mAAAA
1364 HI~2IR2113640 GCAPf~C CUC~IJGFG X CUAF~4419 TT~L.'IC.'r T
P~A~. GGIt'I~'3C
1368 E~tR211 3641 CUGC~OCAA CCJGAUGFG X 4420 CT"rn3GT C TInCCCPG
CGAF. PC~ApGFG
1370 HI~?IR2113642 CPLLJOC~3C CUGALIG~G X 4421 CTIr'~~IC.T T
CGAA PC~CAAG GCCC~L~'IG
1397 HIB~R2113643 AL~3C Ci7GAUGFG X CGAA 4422 A'IGAF~G'r A
PCAIJ~7~IT GCAACIPT
1404 HL~R211 3644 UC3CZ~ALTP. C<JGAIJGpG 4423 TAOCAACT A TATTPDCA
X QUA PGUtJOCtg1
1406 f~IIR2ll3645 C~A~C(~A ~ X Ct.~A AL~C 4424 GCA~(.'~AT A
T'1POCAPC
1408 fB~2IR2113646 P~L~CtT CIJGALJC~G X ~1A 4425 AACTATAT T PDCAFCAT
AImLp~UIJ
1409 I~R211 3647 AAL~7UOC CL7GAL7 ~G X 4426 PLTATA~T A OCAACATr
Q.~F. AAL~I~J
1417 HI~R211 3648 APTAJG~1CA CUGALJGpG X 4427 PC3CAFrAT T 2GDCAATT
Q~F. Af~IJOCU
1418 F~R211 3649 CAALA7GAC CUGAZ)GpG X 4428 GCAF~T T G'IZ~AATIG
QUA AAI~C
1421 HI~2iR2ll3650 PG~AInJ CL~AUGPG X O~,A 4429 ACATIZG'I' C
PCAAAUQJ AATIGZt'T
1425 F~R211 3651 ~C CtJGAUGFG X CGAF. ALnJGFCAA4430 TIG'It,AP.T T
GIC'rICl~C
1428 F-B.R~I'R2ll3652 AixJGUGAA CvGAUGF~ X CGAA4431 TCAA~'Its'r C
PCAAI)IJGA TI~PC~T
1430 HI~t211 3653 CL~LJUCTJG CUGALfi~ X 4432 AATIGIC.'r T
CGAA PG~~AtxT C~C~P.'I~
1431 F~R211 3654 PL~IJIJCZJ CUGALJC~G X 4433 ATiI3IL'IT C
CGAA AP~AC~AiT ACAATAGr
1437 F~~~2IR2113655 t~C,AC CUGAL7~~ X CGAA 4434 2'ICACAAT A G'IC.'i~A
AUC7CTJGAA
1440 HI~R211 3656 UUC~~JGAA CLJGFTJGFG X 4435 ACAAT?GT C TI~'APC1~A
OC~AA
1442 E~.~?IR2ll3657 LX.T~JUG Ct~At~AG X QUA 4436 P~ATPGILT T CAFCAPGA
PC~W
1443 ~R211 3658 AI~JC1 C<7GAL7GpG X Ci.~IA4437 A'~IC'IT C AACAFGF:r
APGFLZ~IJ
1452 HI.~IR2113659 LJGFCAI~7~T CUGAiJGFG 4438 AACAF~AT A P~AA2~
X CGAF. AI~J
1459 HI~2IR2113660 L~JG<JU CCJGAU'~FG X CGAF.4439 TAAAATCr C APGnGAAA
ACPTJUtJI~.
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Table IV. Hammerhead Ribozymes to TR2-9 and TR2-1 I Orphan Receptor Genes
14 M?C~f'B2113661 C~~:ALJC'AA(J CUGALJC,~.~ 4440 aPG'~AT T ~TI~,A2nG
i'i X CT~AA AL~JC~.W
14 iutlL'~2113 662 UCC~CC,nA CL7G~JCd~ X CGAF.4441 PGAP,AATT A TIGA~Ca~
7 AAL~Tl
8
i4&0 i-If~L"'Q2113663 GCCJCC~ CUGAIJGFG X Cr~AA 4442 AAAATTAT T GAMC~C
ACIAAUUW
1493 HGrLP72113664 ~JInJGAA CUGF~PG X CAA 4443 GPGCACAT C TICAAACI'
AIJG~CUC
1495 I~LR211 3665 GC~L~JUC~ Ct~ALJC~G X CGpA4444 GCACAZLT T CAArY'I~C
P~ALJC~JOC
1496 I-1C~LTR2113666 LJ~L~I C(JGAL~PG X CFA 4445 CPCA'IC.'IT C
A1~GALJGZJG aAPCTPCA
1502 Fif.IMIR2113667 ~PL~CCUG C~JGAUGPG X CAA 4446 Z'IC~AAC.T A
PL~I~IUGAA C~~~FGIT
1510 f~R211 3668 L~CAP. CC7GAI~ X CuAA PLZJCCUGCT4447 ACP13GF~T T
TIGTAPC.A
1511 H(~QR211 3669 C(~A CCJGAIJGFG X AAA AACUCCUG4448 CFL3GF~IT T '1~'AP~nG
1512 EiG~211 3670 GCIJGCI~T~ C,UGAI)GF~ X 4449 PL~PGTIT T GI'APCPflC
CLAP. AAPGUCCU
1515 FiC~L'~2113671 CALJGCUGI1 C(~~TJG~ X Cx;FA4450 P~'IZ'1~'I' A
PCAAAACU PCPDCAZG
1526 Ht~IiR2113672 CPGr~JUIJ CC~ALJGPG X CGAA4451 PL3CAAT~ T PAAL'I~.'IG
PG~~~TJOCLT
1527 h'C~2IR2113673 GCpGPGUCT CUGAUGFG X C1,;AA4452 GCATOGTt A r'Ie~CICIDC
AACCAL7GC
1532 HI~IIR2113674 LCA CiJGAIJGFG X CGAA PGUUtTAFC4453 GTTAAALT C 'IGCATI~A
1538 HI~2Ift2113675 LTF~CAtJC CZJGAI7G~G X 4454 CIC~CAT T GAS
CAA AL1GCPGFG
1546 Fif.E2I~2113676 CACT~G CUGAL)GFG X CC,AA 4455 2~AZGGAT A CGAATAZG
AL1CCAL~P.
1552 HI.~L'tt2113677 G~OCA CCJGALJC'~ X QUA 4456 ATACGAAT A 'IGCt'rPCC
AUUO~iJ
1558 HI~TR211 3678 CCUfJCPC~G Cu~IJGPG X cGAA4457 ATATGCCT A C~APC3G
Pc30CP~t~IJ
1571 F~Ti.~t2113679 ~PGPQJAC CC7GFTJC'~FG X 4458 AF~C3CAAT A G.i'PCICIT
CGAA PJJtJC3L'C<7CT
1574 F~IIR211 3680 CUGAFGFG CC7GAUL~G X CAA 4459 G~~1ATPGT A CILTIC~G
PGi~UC~C
1577 I-~LTI?2113681 0~~CUGAA CpGACIGAG X CGAA 4460 A'IPL~'rACr C
PGL~LiI~J TIC
1579 HI~R211 3682 CUOCFCUG CZJC,AUGAG X OGAA4461 PG~ACICT T CPG'mCFG
PGPL~J
1580 HI~'h~R2113683 (JCL7C33GFLT,T CSJGALJGFG 4462 GTACILTr C PG'I~CpGA
X ~ AP~C~C
1584 HI~2IR2ll3684 ALJGAUCUG CUGALJG~G X OGAA4463 1C..'I~GT C C1~C~.~AT
PLZJGAFL~F.
1590 HI~hIIR2113685 GCUUOGALT CUC~LJGAG X C1;~A4464 G'ICCAGAT C A'IOCAPflC
AL1C.LJOGPC
1593 Fif.S~2LR2113686 t~C~GCIJUG C<.7~JGFG X 4465 G~GATCAT C CAFDCC~A
~F. AUGALJCLJG
1601 HL2~R211 3687 AL~JIJC CUGAi.'GFG X AAA 4466 CCAPL~!CT A GAAApGAT
PDGCUCX~G
1619 HI~211 3688 AAUUUCTJC C<JGAtIGPt~ X 4467 GAACIGAT A c~AAAZT
SAP. PTJC~IJC
1627 HI~R211 3689 L~JGA CUGAiJGpG X AAA AIIII(JC~JCZJ4468 PGpGAAAT T
2rPaGAAA
1628 HI.~2IR2113690 UtJIJ(JC~7G C<JGAL~ X ~A 4469 GpC-~AAAZT T
AALJ(~TJC CPaC,AAAA
1629 F-~R211 3691 CUCII~CiJ CUGAIJC~G X AAA 4470 PGAAATI'r C PDGzIAAAG
AAALJIAJCTJ
1641 HI~211 3692 LJCIC~CP~AiJ CZJGAZ~G X 4471 AAAP03CT T P~G~A
~A POCCtJ~J
1642 I~R211 3693 ALxJ~CA CvGAL~AG X CAF. 4472 AAAC~C~C.'IT
AAOCCUW A 2~'iOC,AAT
1651 F3LE~IR2113694 AAIJCWOG CUGAIUGpG X CAF. 4473 ~GAAT T CC~PGATr
AUUOCPCA
1652 HI.~21R2113695 t~ALICTJUG CLOG X ~'~F. 4474 G'IC3GAATT C
AAIJ~JC~1C CAF~1T~A
1659 HI~ttR2113696 GQJ~L~IJ CTJGAUGpG X QUA 4475 'IOCAPGAT T P~POC
AL~J~3C-A
1660 F~R211 3697 UO~JC~ItB1 ~ X OQ~A AAL1CTJUGG4476 CC'APC~A2'T A
TATAPDCA
1662 F~R211 3698 t1~3~. CtJGFTJGAG X CVAA 4477 P~ATTAT A TP.FCCAAA
AL~AI~.W
1664 HIE~R211 3699 C~~JO;dT CiTPTJ".~G X ~A 4478 GAT~~TAT A ACCAAAPC
AI~L~AIJC
1675 F~.d2IR2113700 CAL~T~3;~F. C(7GF~LIGaG 4479 CAAAACAT A ~GAZG
X Q~F. AL7C~JI7C1~1G
1677 HI.~ffR2113701 QJ~iJCI:JG ~ X CAA AL~AJC14480 AAP~CP.~~.T C
CPGA~FC
1690 ~B~2IR2113702 AI~ACCtJG CUC~1IJC,FG X 4481 ZGFCPCCT A CAOGITAT
CVAA PO~JCA
1696 HI~R211 3703 GUCUO;~AIJ CUGAIJGpG X 4482 CITAC~OGT T A~'~C
0.3AF. PGC~
1697 HIaZIR2113704 P~;~F: CT~AI~FG X O~A AFLCIX~4483 '~ACPL3GTT A
TLCF~GFLT
1699 HI.~~2IR2113705 G(~I~JG CZJC,ALJGAG X CuAA4484 CAOGTrAT C CpGFL'rPC
AI1AFDCUG
CA 02364577 2001-10-03
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Table IV: Hammerhead Ribozymes to TR2-9 and TR2-11 Orphan Receptor Genes
1706 HC~IR2113706 CUC~G CZJGALJGFG X CAA 4485 'ICCPC,FLT A
?L~LC'UG;~FL CTPLI~G
1709 :?t~R2113707 a?CZJGPI~GFG X CGr~A 4486 aGALTFLT A CPC~GAZT
rLT
171? FiLNBR2113708 GGC2AUCCT CC7GF~I!?PG 4487 CTAG'~ACZ' C
X CGAA Au<~L~G PGATIC3CC
1717 HI~R211 3709 ArGCUG3C CCJGAIJGFG X 4488 A~i~'FC,AT T
CFA ?~(JGP~1 ACTT
1725 HUMIR2113710 CC(G X CC,AA PGCL703CA 4489 2C3CCPGCT T
'~APC,PLTG
1726 HtJ~R2113711 UCr~,LU C~JGAt~G X CAA 4490 GCCPL3CIT T
APGCUO3C PAGACIGF.
1727 fil.~2~R2113712 AUCPGUC(I CUGALJGFG X 4491 C~PGCITT A PGACIGFT
.- CGFA AAPDCtX3G
1743 E~JNRR21137L3 PLUG CtJGAUGFG X CGAA 4492 2UAA2C~CT A
POCP.InJCA CCAZ~CT
1748 HI.R~?rR2113714 L'CLJtJCPC~tJ CUGAL1GPG 4493 GCI~LCAT C PL~APGA
X CGAA AUGC~DC
1759 E~R211 3715 LGAAAP~AC Ct~ALGPG X 4494 'I~PC,F~AT T
CGAF. PLUCCIt~'A GTifit'~1~1
1762 H(~IR2113716 CUU(JGAAP. COGAUGFG X 4495 PGAATI~T T TrIrAAFG
CAA P~AP~LJUCZJ
1763 HCB~R2113717 CC~J(JGAA CUGALJGFG X 4496 GAATIGIT T TI~APDG
CUFA AP~AIJfJC
1764 Fif.Q?rR2113718 ACCiJUIJC,~. CZ.JGAI7GFG4497 AATIG~IT T '~AFDGT
X CGAA AAFCAAIJCT
1765 H(1~R2113719 GALCiJUtJG CUGAIJGPG 4498 PIT T CAAPC~IC
X CGAA P,AAPCAAL1
1766 HCll~R2113720 PG~CUUU CUCF~IJGFG X 4499 'I~TIZ'rT C
CGDA AAAAACAA AAPflGILT
1773 HUMrR2113721 GCCAAIJGA CiJGALIGAG ~ 4500 'ICAAPC~T C
X CGAA PLCWIJGA 2C'ATn3GC
1775 HI.~2I~2113722 UUC3CCAAU CL~AUGAG X 4501 AAPC3GTC.T C
CC,pA P!'.~G~ ATIL~;CAA
1778 E~.BKIR2113723 AC~L1UC3C~ CUGPT~FG X 4502 G~I~AT T GGCAATAT
CGAA AIJC,FC,~C
1785 F~R211 3724 AAUfJC~ CZJGAUGpG X ~A 4503 TI03GaAT A TAL;~AFITr
AUtJOCCAA
1787 f~211 3725 LJCAATJUCG CUGAIT~FG 4504 GOCAATAT A CGAATI~
X CGAA AUAUUGCC
1793 HI.~2IR2113726 CUGAUGFG X CG~P. AL7UO~L14505 ATALGAAT T C~C~G'IGT
1802 F~R211 3727 UCTJOOGAIJ CUGWJGFG X 4506 GET T ATCCCPL'A
CVAA P~LLJG<JC
1803 I-B~IR2113728 AC7C~3GA CtJCA~JC~G X 4507 PC~IGT~ A 'I~CC~CAT
Ci~AF. AAC~Ja1
1805 HI.~2rR2113729 AC~G CL~A~G X AAA AL1AFCPLU4508 PG~'I'!AT C
CCPCATAT
1812 HI.~IIR2113730 WUCAAAA CUGAL~PG X OGAA 4509 'ICCC~L'AT A
ALJ~JOCdGA TITIGAAA
1814 HC~ITR2113731 AUWtJ~A CUGALGAG X CGFA 4510 O~CATAT T TIGF,AAP.T
AC~1UC~JOG
1815 HI.~IR2ll3732 CAWCItJC'A CUGALJGpG 4511 C~ITATr T '~AAAP~G
X CC~AF. AAL~JG
1816 HI~IIR2113733 C~AIJIJUtJC CUGAL~FG 4512 PCATATIT T C~AAAA2n3
X CGAA AAAL~IJQT
1836 HI.~2iR2113734 PG~IJ Ci~T~FG X O~A AUCiZ3CPG4513 CIOCPGAT T
ATApL'IC.'T
1837 HI~IIR2113735 Cue. CL7C'~AL".~'G X 4514 'IL3CFGATr A
~A AFTJCL7GCA 'I~PG'IC~C
1839 HI.~R2113736 UUG~J C~ X 0.A AL~AilCZ7G4515 G~AT~AT A PG'~P.
1843 HIa~tIR2113737 U(~WUGA C~JC-AiJ~~FG 4516 TTA~FLT C 'IrAAATAA
X QUA Pf~L~IA
1845 I~R211 3738 AA(~JfJ CU~LJGFG X O~A 4517 ATAACI~T C AAATP,A~'T
AGF~JC~IJ
1850 HB~2I'R2113739 (~CAPdJ CZJC~JGAG X CGAA4518 TCTrAAAT A ATIL3~.
AIJUUGpGA
1853 HI.~II'R2113740 C~IIGF~C CZJGAIJGAG X 4519 CAAATAAT T aG'~G
AAA AU(~WUG
1857 f~'R211 3741 AA1~3~C1 C~JGAIJGpG X 4520 '~AFTIL3sT C
CVAA FLCAALA.~ PCAOCATr
1865 F~l'~R2113742 PI~JUtnJCa. CUGAUG~G 4521 CACPGCAT T ZGAAAFLT
X 0.~AA AUOCLIGtJG
1866 HI~2IR2113743 CAL~AJUC C1JGAUGFG X 4522 PGPDC~.TT T
O;~AA AAL1C3CUCZJ C,AAAFL'IG
1890 HI.~IIR2113744 QA~JU CUGALJGAG X CAA 4523 PG~t3C~GT A
PCPLL~G~LU AACh!'AFC
1895 HCR4IR2ll3745 GAAC~fJ C1JC,AOGFG X 4524 'IGTAAALT T
CGpA PGtJ(JC~CA AACiGI~C
1896 HC~?I'R2ll3746 PGAACP~J C~JC~G X CAA 4525 G'IAP~AL'i'I'
APL~PC A PL'~TI~T
1902 X11 3747 UC~3CAAPG CtJC,ALT~FG 4526 TrAACIC~'r T
X O~A PEA CT~IDTA
1903 HI.~2IR2113748 CIJOOC~AA QJGALJ~G X 4527 '~APL'IGZT C
CGAF. AFCX~C~. ThIL~CC~G I
1905 I-8.~1'R2113749 UCJC3GC'.a. CUGAL~PG 4528 PCIGIZCT T 'I~AF'
X CFA PG~FC1~J
1906 HI.~Ii'R2113750 GUC1CT7D3C CUGAIJGFG 4529 CIV'I'iLTT T
X OGFA AFC~C~G GCCAGAFC
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Table IV. Hammerhead Ribozymes to TR2-9 and TRZ-11 Orphan Receptor Genes
929 : T.24TR2113751 GUGPL~JG'C CC~PIG X C~a 4530 CACCAAAT , ~=.~'IG-~
A.UIJLJOGtJG
1935 i-~ITR2113752 ??L3~~=SCI CT~ALJC=F~, 4531 ATIGr~.aL'r
X CC~A PaJCJC'AALJ C ?~3C'I'IT
19:2 :-~Iu'~R2113753 (~3CCC1CAA CI)GALGe.~G 4532 ~'~3Cr T TIGPflGG~.
X CFA PDCFL~(JGA
1943 X11 3754 ALJGCCtXA CL~A(~P~ X ~A 4533 CACIC3CTr T
APC~CPL~ 'I~~OCAT
1944 fiC~R211 3755 GAIX3C'CLC C<JGAL7GFG X 4534 AC~L'3CITr T
CAA AAPldCFQJ G~l30CA1C
1952 h'C~uR2113756 AAUUC1CCA CL)GALJGAG X 4535 'ICFC30CAT C
CAA AL10CZTJ~A 2L~P~ATr
1960 hLrn~211 3757 ate, cc~AUCpc x cr,,~A 4536 croGAAAT ~ TrrACTZT
AwCC~~
1961 t~Jh~R2113758 LTAAPL~A CL7GACJG~G X CC~A4537 'Ir3GAAP.Tr
AAL~CA T TTAGTITA
1962 FifB~R2113759 CJC~AAC~1 CUGAI3.~FG X 4538 G~AAATIT T T?L'rITAA
CC,F~A AAALJUIJCC
1963 H(n?IR2113760 L'VUAAFQT CUGALJGFG X ~A 4539 GAAATTTT ~ ?L'ITTAAA
AAP~AIJtnJC
1964 F:CJMIR2113761 L~AP~ CiJGALJGFG X CGFA 4540 AAATTITr A CTTTAAAA
AAAAAIRJU
1967 F~R211 3762 ACL~1WCIA Q7GA(7C,FG X 4541 TrI'I~CT ':'
CAA PL~AAAA 'T~"~AFG~
1968 HCaMIR2113763 CIAGUfJIJUI1 CLJGAIJGpG 4542 TITTAGTT T aAAAF~TA
X CGAA API~AAF.
1969 H(Q2TR2113764 UCIAGiIWU CUGAIJC,PG X 4543 TITPL~T A AAAPG1AA
CGAA AAPL~JAAA
1976 HC1~2~R2113765 AL~GU C.'C~AIJGFG X ~1A 4544 TAAAAPGr A ACCPGAAT
PLU(JCJUI~.
1985 f-1C1~2IR2113766 aL~CCUC7G C<JGAUGAG X CGAF.4545 PCCPGAAT C CAPD~~TAT
AI~GU
1992 HCllKIR2113767 AALIAAAAA C37GALJGFG X 4546 'PCC~PL3GT A
CAA A0.~JIJGGA TTITrATP
1994 fBa2rR2113768 PAAAZJAAA CUGAUGAG X O,~AA4547 CAAOGTAT T TITATITT
ALgILCUUG
1995 HCa2IR2113769 ;.~P~AAtIAA CTJGAIJGP~G 4548 AAC~ITr T TrATI~TA
X CGAA AAII~Ct)U
1996 HC~'R211 3770 CZ~AAAIJP. CCIGAL~AG X 4549 PC3GrATIT T
CGAA AAAt~aLCU TATIZTPG
1997 Fit.l~2rR2113771 C3CL~AAAL1 CCJGAZJGAG X 4550 OG~'I~.T T ATITrPL~
CGAA AAAAUFLC
1998 HIJMIR2113772 ?L3Ci~AAA CT.JGAIJGpG X 4551 G~ATITTI' A
CGAA AAAP~AL~C TITTPDCT
2000 F~R211 3773 GAFY3CCmA C~AZ~FG X CGAA 4552 ATrrITAT T 2TAGCTIC
ALTAAAAATJ
2001 HI3~R211 3774 GGAAGCLgI C<JGAUGpG X CGAA4553 2'~2'I' T 2'~DCrIC~C
AAL~AAA~1
2002 HI.E~R2113775 GOGAP~CU ~ X CFA AAAI~AAA 4554 TW'I'T T ?DCTIL~C
2003 F~uR211 3776 PL30GAFGC C:iJG~AiJGpG 4555 TTTATITT A GCrICCCT
X CGAA AAAAL~AA
2007 Fif.~IIR2113777 Ct7UAP~3G CC~AIJGF~G X 4556 TIT~CT T CCCT>'APG
CGAA AC~1P~AA
2008 F~2IR211 3778 L~TJC~,FC3G CUGAUGAG X 4557 TITPD'Cl'r C
CC~A APOCC~AA CCZ'~APC~F.
2012 HUMIR211 3779 P~AAI7UCUtJ ~ X ~ POO~ 4558 GCTTC'CCT T
AP~1ATIT
2013 HCQ~R211 3780 AAAAC1~J C(JGALJGpG X CAA 4559 CI~CTT A ~
AAOOGAAG
2019 HI~IR211 3781 ACUUCAAA C~AL~G X O;~AA 4560 TI~1PGAAT T
AUUCU~A TI~APG'T
2020 HI.d~R2113782 CpLZIUCAA C<JGAZJGpG X 4561 TAAGAATT T TI~1F~G'TG
CGAF. AAtA~T~
2021 F~.R~2IR2113783 LX~JCA CtJGAL7CFG X ~A 4562 AP~AATIT T '~AFGTGP.
AAAIJU'W
2022 F~R2ll ~ 3784C~JCAGLAJC C~~IIGpG X Q~1A4563 PC~ATrIT T GAFGIG~C
AAAALRJCU
2049 Fif.EKIR2113785 AIAJG~WU CUGAL7GpG X ~1A 4564 OCpCT T AAATGAAT
AIItJ(JCUOC
2050 HI1~R211 3786 AAL~J~J(J CtJGAtG'~ X O~A 4565 CpGAAATr A AATuAF.ZT
AAI~JCUG
2058 HI~R211 3787 GGAAGAAA CUGAIJGFG X QUA 4566 AAATGAAT T 2T~'~C
AiIUC~JW
2059 HI.~R211 3788 PDGAAL~AA C<JGAUGpG X CGAA4567 AATGAATT T TI~'hICLT
AALJC~1W
2060 HIR~.R2113789 CPL3GAAGA CTJGAIJC~G X 4568 A~AATI'r T 2C'hILC'IG
QUA AAAVUCALT
2061 HIa2tR2113790 UCH GAFG CZJGALJGAG X Q~F.4569 'IGAP.TIZT T
AAAAWCA CTILCIGF.
2062 HI.a2rR2113791 AT.7Ci~C~AP. WGAUGAG X 4570 GAATl'~IT C
CAF. AAAAAL1~JC TmC'iGAT
2064 HI.JMIR2113792 GAAL~ CUGAIJGFG X CGAA 4571 A'~T T CCIGATIC
PGAAAAALJ
2065 I~~2IR2113793 GGAAUCpG C(JGALJGFG X aGAA4572 TTT'IZ~.'IT
AFC~~AAAA C CIGATIOC
2071 HI~R211 3794 UI~A~3G CUGALJGFG X CGAA 4573 TI~C'IGAT T
A1.JC~D;~A QI
2072 HIa~2IR2113795 AIJfJCZsIAFG CTJGAIJGAG 4574 'IC~CIGATr C
X AAA AAUCFOGA CTITAAAT 'i
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Table IV. Hammerhead Ribozymes to TR2-9 and TR2-11 Orphan Receptor Genes
20 : L'1~R2113796 LLZAWUA CvGeIL7Gp~ X CGAF.4575 '1~ATILC.T
7 ~fl:~AAUC'A T TPpA'IGAA
2076 :'.CllKLR2113797 ?L't~AlJtJfJ CUGALJC~G 4576 GATTCC.TP T
X AAA Ax3;~AALJC AAATGPAT
2077 F?t~IR2113798 L~.~1IJ(I CIJGAIJGP~ X 4577 ATILCIZT A
CuA1 AAPflGAAU AA2~AATA
2085 HC~'R2113799 C1JGUUUCA CUGAUGFG X CGAA4578 AAA2~AP~ A
AI~J(T 'IGAAACAC
2095 :IUrII'R2113800 t~AAUUUG CiJGALuPG X CAA 4579 GAAACPLT a
PL~~JUUC CAPATTTP.
2101 HUM~R2113801 C~PGAALTA Ct7GALJGPG X 4580 CTPCAAAT T
C~3AA AUUUC~G 'ITATIC.'rIG
2102 I~f.~IIR2113802 CCAPGAALT CCJGAI~FG X 4581 TACAAATr T
CGAA AAUUCX~ ATICI~
2103 Fi~irR2113803 ?LiCAFGAA CUGAUGAG X CGAA4582 PCAAATIT A
AFAIJUUGLT 2'ICIZC~GT
2105 HUMLR2113804 L~CAAG CZJGAC~FG X CGAF. 4583 AAATTIP.T T
P11PAALJUCT CI'IL3GIGd~.
2106 HCll~LR2113805 LZJCACC~1A CUGAUGAG X 4584 AA2TrA'1'f
CC~A AAI~AAW C TIDGIGAP.
2108 HI~IR2113806 LZ.U(JCACC C~AUGAG X CC~A4585 TTIATICf T
AGAAIIAAA aGIGAP~F.
2121 h'U~R2113807 OCUUCFDG CC~A(JC'r'~G 4586 AP~ATC,AT A
X Ci~A ALJCAULW CCIGAPOC
2133 HUL~'R2113808 CAPC~.~L3GU CUGAL~ X CuAA4587 GAPDC'It's'I'
~CtJCJC .C PLCIC.'rI~
2138 HI~2rR2113809 AL~AUC'~,A ~AI~G X CCAA 4588 ACT C TIGAT~AT
AOGUGFCA
2140 HIfi2IR2113810 ?C,ALIAAIJC CiJGAUGFG 4589 2C~CIr.T T
X CGBF. PGFL3~ GATrA~I'
2144 HC~R211 3811 Ct~U C(JGAUGpG X CGAA 4590 C'IL'rI~AT
AUG'~PC,F~ T A2CTAAPC
2145 FiUT2rR2113812 X~JC~1FGA CLJC~:F~G X 4591 ZC'rIGA~T A
CGAA AAIJCAPGA TCTAAACT
2147 FiC~KIR2113813 LCUGAL~FG X ~A ALTAALJCAA4592 TIt;A2'TAT
C TAAACI7~A
2149 f4JMIR2113814 C~CZJC1~JU CT.~iJGpG X 4593 GAT~A2CT A
CVAA P~ALB~PZ7C AACTAPDC
2154 HI.a2IR2113815 _ 4594 'IC.'TAAFL'1'
i~DCC~CZJ CUGAUGpG ~X A PDC~.'IC~
CVAA
2161 F~.~'R2113816 aAL~C~AAIJ CUGAL)GAG X 4595 '~P~Ct~'I'
CC,AA P13C3CTJC~. C ATIL'fA2T
2164 WR211 3817 UAAAAIJPG CU GAIJGAG X 4596 C3CGC2~.T T
Ci~IA AL~~C CFATI~'TA
2165 F~R211 3818 AimAAALIP. CUGAUGFG X 4597 CC3CI~'AZT
dC~AF. AAL~D~ C TATITI~aT
2167 ~MIR211 3819 LR~9LmAAF. CZJGAIGaG X 4598 ~ A TTTTATAF.
OGAA PC~1AL1GFG
2169 F~R211 3820 (~AtIAP. CUGF~I;JGAG X 4599 CATICTAT T
CGAA ALTFGAATJG T~TAAAP.
2170 HI.R~2IR2113821 C~JI7UC~L~, CUGAUGFG X 4600 AZZCTAZT T
QUA AALTPGAAIJ '~'AAAAC
2171 Hf.B~2PR2113822 L~JUC~IJ CUGAL7GAG X 0~1P.4601 22L'TATTr T
AAAVAGAA A'CAAAACA
2172 F~R211 3823 UUC~JC1U~~. Ci~AL7GFG 4602 'IC'rATITT
X C~A AAAAL~. A TAAAAL~F~
2174 F~.~2LR2113824 At~UU CUGHIJ~G X CO;AA 4603 '~ATITmT A
AL1AAAAi~ AP~FCAAAT
2183 Fita?lR2113825 GACUAAUfJ CC7GALJGpG X 4604 AAHC~AAT A
CAA AUtJ~AJfJ AAZTpGIC
2187 F~R211 3826 APGAGFLTJ CUGAtJGFG X 4605 AAATAAAT T
O~F. AUUUAL7UU PG'ILICIT
2188 EB~2TR2113827 AAAG~GAC CUGAIJGpG X CGAA4606 AATAAA2T A
AAIJUCmW GIC'ILTTT
2191 HIll~'R2113828 AAAAAFGA CUG~7GAG X CC~A 4607 AAAZTP~T C
ACUAAIJ(JfJ ZL'ITrIZT
2193 HI~R211 3829 AC~AAAaAA CI~AL~G~G X 4608 ATrPGIL'r C
OGAA PC,FLL~AIJ TI~'~I~CT
H(~~'R293830 AC~APOOC CTJGA1~FG X Q~F.4609 C300~T C 03CTrICT
PL~3COC
Fil.~R293831 CTAJGAFI~A CLJGALJG~G 4610 CfiILD3CT T
X CAF. PC3~ ZCTIC~FC
21 I~'R29 3832 O~APG CUGAL~G X ~. AP~CL~C4611 GIL~3CIT T
CI~AACC
22 F~R29 3833 OO~JGAA CUGAI~G X ~A AAPD~4612 'I~CTIT C TICAAOCC
24 H(~9 3834 GAOGaC~JfJG CUGA~ X CAA 46L3 aGCTTICT T
AGAAFL~CC CAAOC~'IC
HI~2IR293835 PGPO3GW ~ X ~A APC~3C 4614 CX.'lTIL'iT
C APL
32 HI.EKL'R293836 CD~HFGp. CZJGAUG~ X CuAA 4615 TCAFLi~Cr C
PD3C~IJ~. ZCTICC~;.G
34 FiCb~2i'R293837 L7~3GAP, CUGAUGAG X Q~ 4616 AAOCL'IC'~
PGpD3GW C TIC~~A
36 HC~R29 3838 ~~GG CiJGALJG~G X CGAA 4617 CCC~'IL'T T
PGFGF~3G C~CC~OC
37 HC~R'Z9 3839 C'3CUCCt3G Ci~AL:~PG X 4618 CCTt~IC2T C
AAA APC~OG C~.C3;~AC~
54 HI.fi2fR293840 CPLZJC~JG CUGAt~ X CAA 4619 C~'CAAT C CpLGFGI~
AUC~OG
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Table IV. Hammerhead Ribozymes to TR2-9 and TR2-11 Orphan Receptor Genes
79 HCMrR29 3841 CL'~L~c cvGACJGP~ x ~a 4620 o3GFL'I~T c GC~C
?Ljf~~C
4 i-1G'hITR293842 CCCC CCJGAf~PG X_C~A ?.LbCGACA4621 'IGIC.GCGl C
G3C~
102 H_C~R29 3843 ECU CCTGAU.~G X CGAA ?.LTJCCOCG4622 CC~GPGT C ?DCFL~~
iy2 H1~R29 3844 CCCiJGALJGPG X CVAA P~3CUUU4623 AAPL~LT A G2~A'It;~
126 iiC~a'R293845 C~.T~T3C~aiT CiJGALJC~G 4624 CC3~T~.T C ~3C3CAF~
X CAA rIL~.T~CG
138 HCll~R293846 rILU~JtIC C(~AC~Pf., X 4625 C3CAAC~AT A Gat~GAAP;r
CAA e~L~~3C
147 HCBKIR293847 L~JGC CT.JGAIJGF~ X CFA 4626 GAPGAP.AT T OC~CA~C'A
AUCRJC.TnJC
154 HCll~2IR293848 AAC1AAUUCT CtJGALJGAG 4627 TIC3CPCAT C ?pr>~TA2T
X CHAP. PI~CAA
159 H(a2IR293849 UI~J~ALT CUGALJGPG X CGAA4628 CA2~AAT T TIGAACA
AL7C1C~AI~
i60 HI.~L'R293850 L'~UCAA CCJGAL~AG X CZ=,AA4629 A~LAAATr A WACAA
P~IJUUGAIJ
162 HtJMIR293851 LC(JGALJGP13 X CGAA ACTAAWUG4630 CAAAThAT T C=~PC~1ACR
183 HCBKIR293852 L~i~P~C C(JGALJGPG X (AAA4631 c~C~GPGAT T
e~l~C
186 HI.~2tR293853 UOCUCL7GCT CC1GAUGpG X 4632 GPGATI~'I' T
CGAA PCAALJCLJC >~CA
187 HIB~IR293854 CUOCUCTJG CUGALJGF~ X 4633 PGAT'IGIT A C~t~FDCP~
CGAA A~AP~LICtJ
2L3 HI.llKIR293855 ACAAIJC~JG CCJGAIJGPG 4634 CPGAAP.AT C CPC,ATI~T
X CGAA AUWtJCTJG
219 HC~R29 3856 GCUGtJCFC CLIGAIUGPG X 4635 ASCGaGAT T GIGPCpL3C
AAA AL~T~3GALT
231 HtH~'~R293857 I~AL1C CUGALJGAG X AAA 4636 ACPGCPGT T CA'~P~AA
e~LJOCUCTJ
235 FiL~IR293858 O~lt~llJ CUGALJGpG X CGAA' 4637CPL'I'~AT C ATAATPLC
PLtAPQJG
238 HI.&~2TR293859 L'CZ30~1IJ CUGAIJGAG X 4638 TIGATrAT A ATAL~CAA
CLAP. e~UGAIJCAA
241 HC~R29 3860 C2UUG3G CUGAIJCPG X CHAP.4639 A'I~ATAAT A C~CAAOOC
AUUAIJGAIT
257 HI.B~'R293861 L~'~AAUG CiJGAL~PG X SAP.4640 CAPL3CPGT T CAT1Z'I~A
PCUOCUUG
258 F~?I'R293862 C~J~GAP.U CUC,AIJ'.~PG 4641 APL3CPG1T C ATIC.'IGAC
. X SAP. AFLZJOCUU
261 HI~IR29 3863 WU~JCPG CL~AI7GPG X CuAA 4642 CPGI'IrAT T CTG~AA
AL7G~P~JG
262 HId2IR293864 AIJUIX~TJCP. CC7C~TJGP~ 4643 PG~ATT C ~ACp.AP.T
X CGAA AP~L1GAALiT
271 HI~2IR293865 GCL~J CT~ALJGPG X AAA 4644 ~ACP~AAT C PC
AL7CI~tJCA GA003C
281 HI7MIR293866 UUC3G~k1 C~7GAIJGAG X 4645 CGACC~CT C TAL'IOCAA
CLAP. PGC~JCG
283 Fit~2IR293867 GCUU3GPG CC~F~LJGFG X 4646 PDOOC'IC'T A
f3JAP. ~C~T CTCCAPDC
286 F~R29 3868 UtJUOCUUG CZJGALJGPG X 4647 GC'IC.'TPCr C
QUA PC~GAOC CAPDCAAA
297 HI~t29 3869 OCCAGAAiT Ct~AIJGpG X 4648 AQCAAPGT C ATIC'n30C
CVAP. PL1JC7UOCU
300 f~R29 3870 CUO3CCAG CZJGALi~FG X 4649 AAPG~AT T C'IO3CCPG
Q~P. AIJGACi~IJ
301 HI~2IR293871 CCU300CA CTJGALJGpG X 4650 APGlC2ITr C Z~CPL3G
OGAA AP~JGPLW
316 HIb~2IR293872 CGGF~C~G Ci~ALJ~G X C1JAA4651 dGCA.~AT T CCPL'I'L~~
AtJCiJUGOC
317 HI~R29 3873 C~~JG CZJGAIJC~ X AAA 4652 ~1PGATT C Ct~'ICCGG
AACJCTJ~3C
322 ' HI~IIR293874 UtAJUC2C~ CL~4IJGF~ X 4653 ATI~C~.T C WC~AAAA
AAA PGUO GAALT
333 F~.B4ZR293875 (~PaG?~A CL7GALJGAG X 4654 aGAAAPGT T TILCTTAC
CGAP. PLZJ(7WCC
334 FiC~29 3876 LJ~FOGA CZ7GAUGFG X ~A 4655 GAAAPGIT T 'ILCTTPCA
APL1JUUUC
335 Ht~9 3877 UC~OG CvC,AI7GpG X Q~P. 4656 AAAAGTIT T 0~'1~CAA
AAAGi~W
336 HI.~2IR293878 C~7GUAPG CLJGAIJGAG X 4657 AAAGrl'IT C CI'TACAPC
C~1P. AAAALTJfJtJ
339 I~R29 3879 T CZJGAUGpG X CGAA PflGAAAPC4658. GTI~1',:T T PC~PL'I~C
340 HIHKIR293880 UO GF~tJG Ci~AI~fiG X 4659 'ITI~CTT A CAPL'ILCA
GL'~P. APC3 GAAAA
346 Hf~2IR293881 UOCATJCTJG CCJG~ALJGpG 4660 T~ACPIPCr C CPC,PfIC3CA
X 0~1A PL~P~
363 Fi~R29 3882 APLLK3~JtJ CUGAIa'.',PG 4661 C~CPC~GZGT C
X O,~AA PCpLCT)3C APDCPGIT
371 HCHKIR293883 L1AAAAAAU CUGAL~PG X CGAA4662 CAPL~?GT T ATrITITA
PLL)C3~JUG
372 HI.b~?IR293884 GUAAAAAA CZJC,ALJGPG X 4663 APLCPGIT A TIZ'~I'TPC
Q~AP. APCL~U
374 Htll~2IR293885 UOC~JAAAA CUC~ALJGpG X 4664 CC~T T TTITPDCA
CGAA AL~PLL10G
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Table IV. Hammerhead Ribozymes to TR2-9 and TR2-11 Orphan Receptor Genes
375 dC~KrR293886 C~.~C~ArIA ~L~i~?~ X CCAA 4665 G~ITATT T TI'T'.rLC~C
PALlAPI.TJG
376 i:LMTR293887 ~.'-L~3CTTt~. CIJC~I~ X 4666 ~ITATIT T TTALZ~LT
CAA AAe~I~ACU
377 iiCR~R293888 G'~3~JA CL~i~G X CGAA AAAAUAPC4667 GITATTTP T TPLC~LZC
378 I~'1~?IR293889 OC~JOGU CUGACJGAG X Ct'~A 4668 TTATTITf T ACCaL'IL~
P~AAAALIAA
379 hC~IR29 3890 .'-DCA~3 ~ X CGAA AAAAAAL~14669' TATI~'~IT A
OCP~L'I'L~:.T
385 h'I~R29 3891 C'-GAUr'~ C(JGAI~AG X CGAA4670 TTAL~LT C C'I~2L'IG
PC~~A
391 I~R29 3892 C7C~C?~'A CUGAL7GPG X CGAA4671 CIL~GAT C ~C2L~CA
AL~ACaaFG
395 HC~I'R293893 GL'C~(JOCP, C(~ALJC,AG 4672 'IGATC'IGT C
X CCAA PCpC,AIJCA 'IL~CC~L~1PG
414 HCll~2IR293894 L~JUP~ CC~AIJ~::PG X CGAA 4673 CTC~L3CT C C~GA
Pl3CipCPG
417 H~R29 3895 LJ C(JGALJGAG X CGAA PL3GFGCUG4674 CPGC'I~C.T A
~~TAA
424 F~R29 3896 UGCPGAAU Ct~ACJGpG X CGAA 4675 'I~1ACPGAT A
ALA ATIr'IO;A
427 HLRKIR293897 GL~'~G CL~AG X CGAA AU(~AL~iJG4676 CPGATAAT T Ci'UG'~C~PC
428 HtE~R29 3898 GC~C.TJOGA CC~ALJG~G X 4677 PC~ATPATT C
CAA AAfJC~IiJCIJ ~CpGACC
430 Hf.~21R293899 UUO~TJG CC~FG X CGAA PGAALlt~74678 ATAP.TICT C
CFG?GC4A
948 HC~.R29 3900 ASCU CUGALJGPG X AAA AL)UUGCZJC4679 GAOCAAAT A rY3GTITIT
453 I-~R29 3901 ?~~L~'AAA CUGALGPG X CGAA 4680 AATAPDGr T '1'i'IGA'IC.T
PL>'UCTAW
454 F~.R~IIR293902 A?~AL7CAA CC~AUC3AG X CGAP.4681 ATP~F~L3GIT
AFLCUOALT T TIGA~'IT
455 HInMTR293903 Aa?GAC~'A C(~AIJGFG X CGAA4682 TAAGGTTT T 'I~A2C~'IT
AAFLC(~TA
456 HCllKIR293904 C~GAZJC CvGAUGF~ X CFA 4683 AFDGTIZT T GATC.'ITI~
AAAPDCW
460 HCb2IR293905 LpLGCAAA CiJGAL~FG X CGAA 4684 '~I'ITIt;AT
AL1C'PAAAA C TI~.'GfA
462 Elf~?IR293906 ACC~CA CIJGALJGFG X CGAA 4685 TTTGATG'r T
AGAIJCAAA 'I~rAGt
463 HCd~R29 3907 eU~GT~OC CL1G~AL1G~G X 4686 TIGAZL'IT T
CL~A APGAI~A GOGrAG'fA
468 fifll~2tR293908 0~~CAL~C CUGFT~FG X CGAA 4687 CThIC3CX~T A
PLX3CAAAG GTA2~3G
471 HCll~IIR293909 LJCTRCACA CTJGAL7GPG X 4688 n30GT~T A 2GIL3~~!GA
OJAA PLi~OCA
488 HI.~t29 3910 G~CU CUGAUGAG X CGAF. AIJOCUIAJG4689 CAAPL3CAT C
PD~~It
496 HI.~R29 3911 L70CALAALT CL7GAIJGpG X 4690 CAOGFtGT C ATTATOGA
OGAA P~CTJG
499 F~'R29 3912 UOCtJCI''AU CUGALJGpG X 4691 GAOGIZ=AT T
CC,AA AUGFL~JC A~3GFflCA
500 HUMIR29 3913 CUOCUCCP. CZJGALJC'~FG 4692 PLV'ICAZT A
X O~A AALJ~GU ZDGFOCPG
510 E-B~2IR293914 UCACAFQ7 C<.~AL~FG X OGAA 4693 GGFaCPGT A ACrIGI~.
PL'i~~CL7CC
514 Fit.&~'R293915 C3CCUfJC~C CtJGALJGAG X 4694 CaGTAPLT T GTL~FD3C
CGAF. PL~JfJ~
533 HIH2IR293916 L~AAP. CLJGAIJGpG X CGAA 4695 CAAPD~~F.T T
Ai~ftJUG Th!'~AAAA
534 I~~2IR293917 CL~~AA C1~FG X ~ AAL~CUUtJ4696 AAFL~GATT' T
TITAAAFG
535 HI~R29 3918 ULUtlC7~F. CtJGAL~AG X 4697 AAL3GATIT T
QUA AAF~IJC~CLAJ T~1AF~
536 F~R29 3919 UUC~ CZJGAL~G X CAA AAAAiX7CU4698 PL3GATITT T
TAP~AFC~A
537 I~.MIR293920 C<JC7CL~JUU CZJGAIJGFG 4699 GGATITiT T AAAFGAFG
X CGAA AAAAAIJUC
538 E~.R29 3921 GLTJUC~W CTJCAL~FG X CGAA 4700 GATI~t'IT A
AAAAAALJC AAPGAFDC
549 HI~~2IR293922 WU(IUUCG C<JGP~I~AG X CGAF.4701 PGAPC3CAT C
P~L7C3Ctn7C~J CGAAAAAA
559 Fit~2i'R293923 At~li~. C:UGAL7GpG X CG~A 4702 GAAAAAAT T '~PG~ATP.T
AWtAJCAJC
560 F~t29 3924 AAL~1I~LLJ CUGAZ~3~G X 4703 AAAAAATr T PL~TATAZ'r
CGAA P.A~WJU
561 HI~R29 3925 GAAL1ALTAC CUGAIX~FG X 4704 PAAAP.TIT A
CGAA AAAL7WW ~'It=
564 HI.~R29 3926 CALJGAALJF. Ci~G X CGAA 4705 AATI'TAGr A
PL~AAW TATPCA7.G
566 H(E~2IR293927 G?CAL~AA CZ7GAUGF~ X CGAA 4706 TTT~TAT A ~
P~~AP.
568 E~iR29 3928 LJCGpC~IJG CZJGALJGpG X 4707 TP~T T CAS
C1~A AUAT~
569 HI~'R29 3929 CtJL~AC~1L1 ~ X Q~1F. AAi~L~J4708 PGTP~'r C AZG~LC~G
574 I-~.~?IR293930 C~~JC CTJGFJJGpG X AAA 4709 AT'IC'A'IG'T
PCAUGAALT C GF~;~.
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Table IV. Hammerhead Ribozymes to TR2-9 and TR2-11 Orphan Receptor Genes
i ~~9 3931 ~~UU CIGALJG~G X CGAA AL~C.L'CGe'14710 ~L33~T C P~3'
j~l GATT
X89 :1~R29 3932 ?~ALT~ CU_GAIJGr~G X CGFA 4711 CAAPDGAT T GTATTATT
AL~."iCi~
592 :1.~'R29 3933 ALJUAAIJAA CUGAUGAG X CGAA4712 PDGATIGI' A
ACAALICLU 1TATTAAT
594 f~iC~2rR293934 ~'~IJ(TAAI1 CUGAIJGPG X 4713 GATIG'~T T ATTAATAA
CGAA ALJPrAAIJC
595 e-:I~'R293935 CLTJAUC~1A CUGAUGFG X CAF.4714 ATI~Tr A TTAATP.~
AAC~1CAAIJ
597 E~tllKIR293936 IX3CtnIAW CiJGAIJGPG X 4715 'I~TATrAT T
CGAA AIJAATJPCA AATAPGCA
598. F,'I~R29.3937 GUGCtJUAU CTJGAI)GP~ X 4716 GTAT~aTr a ATAPI'3G~
CGAA AALTAALZnC
601 h-cn~29 3938 Gt~CCr cvG~ x cr~A ~ 4717 TrATrAaT a Fcacpccac
622 Y.C~R29 3939 OCAC~LJCJ QJGALJGPG X CGAA4718 FL~CGCIGr C
AGnOCnC~T AATPC,'n3C
626 ~-:C~2IR293940 r',LCUGCAG (ZJGALJGAG X 4719 CI~IC'P.~.T
CGAA ACl(JGACAG A CIOCAC3G2'
035 H?t~2IR293941 AL'CiJC~J C(JGAIJGPG X 4720 CIGCFL~GI' T
CAA PCC~JGGaG ACpC~AT
636 H:t~R29 3942 C~C~.LXZJG CTJGAUGP~ X 4721 TGC~I' A CPGFCA~
CGAA AAC2~CA
646 HIl~TTR293943 AAAGGCAA C(~AIJGPG X CGAA 4722 PGP~'r A TIGC~TIT
ACALJCUC(T
648 Hf7~2rR293944 CCAAP~3C CLJCAIJGAG X CGAA4723 PC~F.~LAT T
AI1.~JUCZJ OCR
653 9 3945 UCAIJCJCCA CUGPTX~AG X 4724 TATIGCtsT T
QUA ACr3CAAL~. n3C,AAZGA
654 HIa4rR29 3946 C CZJGAI7GAG X CGAA AACX3CAALT~ 4725ATIDCC~'IT T
GGAAWA
671 F~Cd~'R293947 AI~3;ACA C~A27GAG X OGAA 4726 GCAPC,ACT C
AC~7C.TJ(~C ~CAAT
6~i5 F~'R29 3948 (~CP~JUG C~LJC~G X CGAA 4727 Gi~C.'IC'IC~T
PCAGF?GtJC C C~A'It;IGA
696 fi(~IR29 3949 GaLIAL~Jtfi C~A~ X CGAF. 4728 AAACCCAT T GAFG7;A2C
AIJGOGtJUU
702 F~R29 3950 Cx.T70Gi1GF1 CL~AI7C~G 4729 ATI~A~GT A 'ICACGpGP.
X aGAp. PLTJUC~ALJ
704 HI~2rR29 3951 UUIJCTJCGU CUGAtJGAG X 4730 1C~AT C AOGpC,~AA
CGAA. AL~CUtJr'A
716 HI.~2rR293952 PL~~OGAA CUGALGAG X ~A_ 4731 PGAAAAAT C TILCAACT
AWUUt~TJ
718 HIauR29 3953 PCPL~JI703 CC7GAIJGAG X 4732 AAAAA2C.T T
Q~F. PGAIAJtJC7tJ C~AACitsT
719 HI~IR29 3954 C~C~7G CUGAiJGAG X ~F. 4733 AAAATC'IT C
APGAWW c~NC,'Its'iG
733 HCa2rR29 3955 UCJCiIGtJIJG C~JGFG X ~ 4734 G~3C~CT T CApC~GAP.
AC~3CFC
734 HI.~uR29 3956 UU(~JtJ CUGALJGAG X C<~~AA4735 'IC3COOC'IT
APL3~OCA C AP~1AA
747 E~LHK!'R293957 C~0~~ILmLTA CUGALIGAG X 4736 GAAAAAAT C TATAOLTG
CGAF. ALIIAIWUC
749 T.-i29 3958 C~GALIA LiJGAI7GpG X QUA 4737 AAAAA~C.T A
PGAUUUCAJ TAZL1~AA
751 Ht~2iR29 3959 CL~GA C<.~TJG~AG X ~A 4738 AAA7CTAT A 'I'UCGAAFG
A
L~AL~T
753 HI.a2PR293960 _ 4739 ATL'~T C C~AAFL~GF.
_
UO~JIJUC~;~ CUGALJGpG X
~A AL~C~IJ
765 Fita2IR293961 G03CL~LG CtJGAtJGAG X CGAA4740 AAC3C,FCCT T
PC~C~.UU C~'i~D2lr
766 HI.n2TR293962 Lx.130CL~C C(JGAIJGAG X 4741 AC3GACCTT C
O:~A AFO~JCLLT GTPDCCrA
769 HI3~R29 3963 LmA1J003C CUC~TJGpG X CGAA4742 PDCTI~r A GCLTATTA
A~GU
776 HI.B~R29 3964 L1C~CFL~JU CiJUAIT'.~G 4743 TPDCLTAT T AAGZr3CAA
X CGAA AIJ000~
777 F~A~IIR293965 GIJ~CpLTJ CUGAIJGAG X QUA 4744 PL3CCCATT A
AAL~OOCU PCI~3G~
787 HI7~R29 3966 AAAPG~JG CTJGAI)GpG X ~1F.4745 CIC3CAPL'T C
PL~JtJOC~G CAPL'ITZT
793 Fitd~2TR293967 L7C~1C~CAA CiJGAC~ X AAA 4746 CIC~CAACr T
AC~JUO~~G TIVTAACA
794 E~2IR29 3968 COCA CL~AI~ X O~A ALGA 4747 ~CAFL'1'~ T
'IG'~AACPG
795 H(~2IR29 3969 L7CTJ~R1AC CSJGALJGpG X 4748 CCAACI~T T G~AFCAGp.
Ct.~AA AAPt~JtJ03
798 HI.~IR29 3970 C~J CIJGAUGpG X CC~1A . 4749 PL'IT~IGP A
ACAAAFGU PC~ATPG
805 F~R29 3971 PL'LIIJUCAC CLJC~tJGpG 4750 TAACpC,AT A
X OGAA AtJCUC~J~. GTZ;AAPGT
814 HI~~2iR293972 LUG CTJGF~LGAG X CGAA ALVUUG1C4751 GI~AAFGr A CAFa~.
821 I-~.~tR293973 GC~iT~UU CIJGAIJGFG X ~A 4752 '~AG~P~3T C
AOCC~ AACPL3GpC
833 HI~2TR29 3974 CUC~AAZJC1T C17GAL7GpG 4753. PL3~~1CIC~'r
X CGAA PC~CU T PGF.TiC~G
834 HC~R29 3975 CQJGAAUC CLJGALJGFG X C3;FA4754 GGAL'IG'IT A
AFCPGUCZ GATICPC~3
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Table IV. Hammerhead Ribozymes to TR?-9 and TR2-I I Orphan Receptor Genes
I 838 I-iG~T~R293976 CAL7UOCtJG CL~1~ X CGAA 4755 'I~.T~GAT . C~DGAA?G
?t~IPCA
839 i-WffR293977 ~C~UCJC~IJ C~IJGAG X CAA 4756 GITAGATr C ~AP~GT
PtltiCUAPC
348 HI3yIrR293978 tJAUUCAUG CUGaLJG~G X CGAA4757 rY3GAA~GT T CATGAATA
ACALJUCCU
849 I~R29 3979 AIJ CiJG~L~PG X Ci~IA AACAUUCC4758 GGAA'IGIT C A2GAATAT
856 FiC'~hIrR293980 IX3GALJGAA CC~ALJGRG X 4759 TCATGAAT A TmA~;A
CC;AA AUU~IJGA
858 HOMTR29 3981 GAUGGALJG C(~AUGF~ X CC,AA4760 ATGAATAT T CA'fiCA~
ALZ~JC'PTJ
859 I~R29 3982 PGAZJOGAU CTJGP~AG X CGAA 4761 2Z;AATATT C A~ATCT
AALTAI1UC'A
862 Ht~LR29 3983 fX!CPGAIJG CIJGALJGFG X 4762 ATAT'ICAT C CAZt'Il3GA
CGAA AUGAAI~LJ
866 HC~2I~293984 C~~A CC7GALT~ X C~'~P. 4763 'I~ATLCAT C TC3GrIGTAA
AL10;~ALJGA
873 HC2~R29 3985 L1CPC~JIJUU CTJC,AIJC~G 4764 ~~C3GAGT A ~r~pClTA
X ~1A ALZJC!CFGp.
884 HI~RR29 3986 OCAC1~CU CUGALJGFG X CGAF.4765 AAC'It;PGT C
PCUCPGLJIJ ~GC'IGIC3C
902 Htll~2IR293987 CCLJ(TAUCiJ CZJG<'1L~FG 4766 GAZuFrAT C ?~ATAFDG
X CGAA PIJC~JCAUC
907 HC~IR29 3988 UUCPDCCU CtJGAIJGAG X CGAA4767 CA'1~GAT A P~OCIGHA
ALA
917 HIa2PR293989 C~JGPrAtJ CUGALJGPG X CGAA4768 GOC'IGAAT C A2GIt'1~L3G
ALnJCPC~CC
922 HI~2rR293990 AL7CTJCCC.U CLJC~AIJGPG 4769 AA'IG~T C a03GFGAT
X CGAF. PCAL~AIUU
931 I~ffR29 3991 (~.ZJCTP. CUCAI7CFG X AAA 4770 PD3GFGF.T T TAPGI~A
AtJCZJCCCTJ
932 F~R~R29 3992 AC7C~)U CZJC,AiJGFG X a~P.4771 GC3C~GATT T Ar~PCAT
AAL7CL~C1'
933 HI~R29 3993 AALJC~~CtJ CLJGALJGFG X 4772 GC,?GATIT ~ r'GI'PCATr
CC~F. AAP~JCC
937 HI~2IR293994 GOCCAAUG CC~ALJGAG X CGAA 4773 ATI'TAPV'r A
PLL7(7AAALJ CATIL~
941 Fif.IMTR293995 CAUUC30CC CUGAL~G X CGAA 4774 APGI'ACAT T GI~C!CAAZG
AUC~LW
954 F~NRR29 3996 AAL)C,AU~J CTJGAIJGF~ X 4775 AA'IGIOGT T ~
CVAA PLCpCAIA.1
955 I~2rR29 3997 ~ALJC~IJG CUGALJGpG x Ci.~F.4776 ATGIt3GTT a CA~.TI'P.
AAOC~u
959 HC1KIR293998 LJ~CLTAALJ CC~AL~FG X CGAA4777 GGrI~CAT C AT~OGA
AL~.AGC
962 F~R29 3999 GAUtJ~CU CUGAIJGFG X O~F. 4778 'IPCA~AT T PC~C~AA~
AL7GAUC~.
963 Fi(ll~R294000 PGAIJC~C CtJC~IIJGAG X 4779 ACA'IC'ATr A
Q~AA AAtJG~i1 GCGAAZ~:T
970 FiC~R29 4001 WU~'~A C~7C'~PG X CGAA 4780 Tp<3CGAAT C T1C3GAAAA
AWOGCCZA
972 Fif.~IIR294002 GEC CUGALJGPG X O;~AF. 4781 GCGAA'IC.'f T
AGAL~C C~AAAAFC
982 I-iU~R294003 ApC,AUC.W CZJGAL7GpG X 4782 GAAAAACT A AP~A'iCIT
CC,AA PCWCJU<7C
988 F-BE~t294004 UC7GFGAAA CZJGA1~31G X 4783 CTAAFGAT C TI't~iG~A
CGAA ALA
990 I~.~2tR294005 UC~C~A CZJGAIJG~ X 0.;AA 4784 AAFGAZCT T 2~.'~?.
PGAZJCtIUfJ
991 HI~~2PR294006 AWUUGAG ~T~AG X CGAF. AAGAL~JU4785 AP~AZ~.'IT T
C~AP~AT
992 HIdZIF294007 L~LJWUGF~ C~IGAIJGAG X 4786 PGATC.,'1'IT
CC~A F~AFG~J C ~C'AAAF.TP.
994 HI~R29 4008 AC~L~fJ CZJGA~AG X CGAA 4787 ATCITIC.T C AAAATPGT
PGAAFGATJ
1000 F~R2IR294009 UC~1C CL~T~FG X CGAA AWUfI;pG4788 CTCAAAAT A GSA
1003 HI.~t29 4010 CAWIICALJ CTJC~iJGpG X 4789 AAAAT~T A ATGAAA1G
CGAF. ALT~JIJ
1013 HI~R29 4011 Q~AL~Ii~. CUGAIL~lG X CGAA4790 T~AAF~GT C '~4TC,~AT'IG
P~L~'A
1015 HI.ll~2IR294012 UUCAAL1CA CTJGALJGFG X 4791 AAA2~GIC.T A
CC~A PC,FC~JUCT 'I~Ti~AA
1020 HI~R29 4013 APaCZJUUC CZJGAIJC,FG X 4792 TCTP~F1T T GAAFDCZT
CC~A AUCAi~.
1028 HI.b~2IR294014 CAtJU01TJt1 CUGAIJGFG X 4793 TGAAFL3CT T AAOCAA2G
QUA PDCU(nJCA
1029 HI.~R29 4015 UCP~I~CU CU~~,LJC~G X AAA 4794 GAAFC3CTP A PLI,_AA2Gp.
AAOCCIlJ(JC
1042 I-B~ffR294016 CPAPC-~G CUGAUGFG X CGAA 4795 A'IGp.'IGAT A
C~.'ICTPIG
1046 HI.a~2IR294017 C~CACAAA CUGAIJGAG X O~A 4796 TGATPLCT C TI'I~I~IG
PL3~LJCP.
1048 FiU~.R294018 LI~PCpCA CTJC~AIJGpG X 4797 ATPCCTL=T T 'I~TGICAA
0~1F. PC,~IJ
1049 HI~R29 4019 AUUCP~C CZ~IJGpG X CGAA 4798 TPLCICZT T GIGIGAF.T
AAGpDC~.
1058 HIaTTR294020 ZJIJ~JCVUGF. CUC~tJC,~G 4799 GIG'IGAAT T Ti:~PGAAP.
X CAA AU(JCACpC
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Table IV. Hammerhead Ribozymes to TR2-9 and TR2-1 I Orphan Receptor Genes
1059 ~-~f.lMIR294021 ADUI~ CUGF1JGPG X Cue. 4800 'IGIC,AATT
AAL)UCACA T C~AAAT
060 I-~ffR294022 CAC~JCW C(JGALJG_r~G 4801 GICAaTTT C
X CC~A AAAUUCP~ APC~PA'IG
'_086i~29 4023 GQCCU(JGA C<JGAL~PG X 4802 C3GI~A_'TGT
CC-AA _~~At~~ T TCAFDOOC
? I~L~2IR294024 UOC~JIJG CtJGAIJGAG X 4803 GIGAT"'IT T
087 CGAA AACAUCAC CAPa30CA
1u88 h~BR29 4025 AIZ'3CCC:W CO~ALJGFG 4804 'I~'I~I'IT
X CGAA AAPC~JCA C ?PL~CAT
1097 EitJhIrR294026 GF~'A C(.JGAI~ X CC,aA 4805 A_~DOOCP.T
/1C10C~JIJ T 'IGFCrY'i~
1098 I-B.~LIR294027 CZJGAIJGr~G X C>;AA AAL702~LT4806 PD30CATT T
GFCPL'ILT
1105 I~f.ll~IR294028 WC1C~3CAA CTJGAL~F~ X 4807 TI~PCPLT C
CAA PLT~A TILCAaAP.
1107 HCllKIR294029 GCUtJWOC CUGALJGAG X 4808 CP~P~ICT T
CVAA PGF~7C OCAAAPDC
1118 E~R29 4030 G=~L3GAWC CUGAIJC~G X 4809 P~L~C',AT T
CGAA ALL~JIJW CAF.T"CIG
1123 HIJ~'R294031 CtJC.LJCCPG Ci7GPSJGFG 4810 CA'I'I~AAT
X CC,AA AU(JCAALJG C C1C3GPGFh
1151 HCH~2TR294032 C~CCTACCJ CT~AIJGFG X 4811 CCP~=GCT C
CGAA POC~X..LJC~ ?GTPOOGG
1155 HC~?IR294033 ALK3CCCOC CiJGAUC~G X 4812 AOCTrPGT A
CGAF. A~iJC~DCU a~330CAT
1176 HI>N11R294034 AUt>FL3G<JG CUGAUGFG 4813 OGAPG'i~T A
X CGAF. C CACCTAAT
1182 HI.>MIR294035 CC~JGALJ CUGALJGAG X 4814 G'~C~LLT A
CG'AA POGt~ A1~1C~3G
135 H(~R29 4036 LJCUCCPC;(J CUGAL~FG 4815 CPLCI'AAT C
X CC~A AI7UPD~JG ACIl3C,FGA
1195 HL~'R29 4037 C1AUOCUUG CUG~AL~ X CvAA4816 CIL3GFGF.T
AL7CL7CCFG T G~PflCATA
1196 EB.>HIl'R294038 UCIFTX3CW CTJGAUGFG X 4817 'IC~FC,ATT
Ci~AA AALJCTJCCA C AFL3CATAP.
203 HIlc2IR294039 C~AUU CUGALJC,AG X CC~A 4818 TCAAOCAT n
ALJOCZJUGF. AAT~PC
1207 HC~'R29 4040 UIJC3Q.K~fJ CUGAL'GpG 4819 GCATAAAT T
X CGAF. AI~C e~CCGAA
1208 I-~~fR294041 L~'OGiJG ~ X CGAA AAWClAI7G4820 CATFIAATr ~.
CPLOGAAA
1230 F~.~IR294042 UCr.ICLJGFJi CUGALJGFG 4821 QOGCCACl? T
X OGAA PC~J03CCC CI~GA
1231 HB1NZIR294043 AIJCI3CiJGA CTJGAUGFh 4822 C30CCPLTr C
X CGAA AAQJGv3CC ~D~AT
1233 I-B.~.R294044 GAPT)CGCZT C(~AL~AG X 4823 C~ C PO~F:CItr
aGAA PGAPQJOG
1240 HI.~fR294045 C~CpTJGfJG CUGAIJGAG 4824 TCPL3C~GAT
X CuAA AL7C~~T~JGA T CACAZG't~.
1241 F~29 4046 Cil~C~T CUGPSJGFG X CGAA4825 CpL3CGATr C
AAt7~CZJG AL'ATuT?G
1248 F~R29 4047 CUGAAFaC CUGAL~G X QUA 4826 r ? OCITi~G
PG~JGA
1252 Fifa2rR294048 GFCICCtIGp. CT~AI~G X 4827 A2~'I~CT T
CGAA PDQI~IJ ~CIC
X53 HIaK1R294049 U~L~LLTJG CLJC~LJGAG 4828 22;~TPDCTT
X CGAA AFDCL1ACA T CPOGCIC~.
1254 HC7~'R294050 CTJGAOCCU CX CGAA AA~DCT~C4829 GTPL3CTI'T
C PD3C~C'AC
1260 HIZC2rR294051 C30C~IJO~T CL~itJGpG 4830 TI~30CT C PJ=C'AZL3CC
X CAA AOCCUGAF.
1270 HI~R29 4052 CAL1~L1GAG CUGAtT'.~FG 4831 ACT T CILCTAZG
X 0.A PflO~
1271 HIR29 4053 OCALiFDGA CL~AZ~FG X 4832 CA'IL3CCTT
CGAF. AF~GC~IJG C Tl7~C
1273 HI3~'R294054 PDGCPLIAG Ct7GALJGpG 4833 T32TILT C CZ~OCCT
X aGFA PGAFL33C~
1276 HI.>NIrR294055 CUC~G~. CTJGAt7t;pG X 4834 CTIC.'lCCT
OGFA PL3~~GA~ A 'IC~CIGPG
1286 I-X29 4056 CALJUCpOG CUGAIJGAG X 4835 DOCi~FGr A
O~A PL~OOC CCI~AZG
1301 HII~R29 4057 CCCCAAL7G CiJGAZ~G X 4836 ~UIDCAGT A
OGAA Pf~(~CA CATTCl~
L305 F~R29 4058 GpLTJWOC CZJGAIJGF:G 4837 C~LTFL'AT T
X QUA AL)C~C~JG 03C1''~'C
1313 F~R29 4059 L~P03CA CvGAUGFG X CGAA 4838 'Zn3GC,FGr
AGI~CrA C 'IO~hCTA
1319 HI.d21~~294060 OC~.TJG CUGAL~CPG X CG~A4839 G~CCT C G~CIDC
PO3CPGAC
1331 HI.it~'R294061 UI~AtIAPG CUGAZ~FG X 4840 PGZDCIG'T T
CGAA PC~OCPQJ CIA
1332 F3LTR29 4062 AU(JGAI>AA CUGAIJGpG 4841 C'InC'IGTI'
X CGAA APC~OC~G C T1~AAT
1334 HC~R29 4063 OCAL~J CZJGAIJGpG X CC,AA4842 aCIGTIC.'1'
PGAFC.~L~ T A~A~3C
1335 Fl~'R29 4064 UOCF~I~F. CtJGAIJGpG 4843 C'IG'IZLTI'
X CZ;AF. AF~AAC~ A 'IC'i~
1337 HI.1~R294065 PQJOCAW CZJGHIJGFG X 4844 G'I~.LTT.~'
CGAF. ALmPhAFC C AATGCPLT
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Table IV. Hammerhead Ribozymes to TR2-9 and TR2-11 Orphan Receptor Genes
1353 hL'N~R294006 GC~GA CLDaL7Cr~G X CGAA 4845 'In00C~Cr - ~._LC~TICC
~U'C~C~~
1354 fL'NL~294067 :~3GAAGCG CLZALD?D a CLAP.4846 GGGC~L.Tr = -'3GATICC.'T_'
APL~CC
1355 :~IIF29 4068 A?L3GaACTC CL'CACDPG X 4847 GGC~CrIT .: CATICC~.'r
CGAA AAPL~
1359 HC~'RR294069 PAAGAPDG CLX CTFA AC7~',AAr~D4848 C2fitL~AT _ C~TIC.TIT
1360 HUrIrR294070 C_rlApL'-t~PD CLOG X CFA 4849 TI'IDGATr C Cr~TC
AAt~GAPA
1363 HG'L~R294071 CTZ3GAAPG CtJGAi~GPG X 4850 CGAT'I~CT C CITICG~
CC~A PDGAAC7C~
1364 HC~2IR294072 C'CUOGPAA CUCptT,~FG X 4851 GATID'Tr C TI'ICG~
CLAP. APl,3GAALJC
1366 I~t.~'R294073 PDC'CT)C3GA CUCYV~Gr~i'~ 4852 TIL~'r = TL'cPDGCT
X CT~AA PGAAGGAA
1367 HI~2IR294074 GPL~CL~3G CL~ALJC,~1G X 4853 'l~CrI~rT '_
CGAA APC,APO;~P. ;.~A(30CI~
1368 F~R~IR294075 ~GCCCJG CCDALJGFG X CLAP. 4854 CC.TICITr C 10~r
AAPGAPDG
1375 EB.~1R294076 UUOCCCiJA CUCAL~D X CGAA 4855 TCCPDGCr 2 T~OCnA
PL3C~.
1377 HCHKrR294077 UCZJLt~CC CL~IUGFG X CLAP.4856 CPL~C'I~' _'-_
PGPGCCZJG GGOCpr~
1395 HC~IR29 4078 ALCPI~JGA C(JGAI~PG X CRAP.4857 AA.AOCAT _'-_
ALZ3CtJ~J(J ?~PL~T3GT
1397 F~.~2IR294079 tK'ACCPDC1 ~ X CDAA AL1ALDCUG4858 CFC~CATAT C ?L'IL~I~
1411 F~'R29 4080 AvUL<'~IJ CUGAUGPG X CGAA 4859 'IGAAPDCr ~ ?L'~3C~AT
PL3CUtiUCP.
1412 HIa~2IR294081 CAUCK.'CFG CCJGALJGpG X 4860 GAAAOCTT =. C'lt3GAAZG
CGAA APDCUUUC
1425 HCll~2IR294082 SAP. CLtALJGPD X CLAP. 4861 AA~GAP~CT _ 'TTTPL'ICT
P~JC~f.T
1426 HCH~LI'R294083 ~GUAA CCJGA1:7GAG X CGAA ' 4862A'IGAACTT = TrACPClT
AAGUC~'ALJ
1427 FiUMiR294084 CAPDPL~ CUGALT3FG X CDAA 4863 ZGAAL'ITT = T~CIL''IZG
AAPGU'~JC'A
1428 I~R29 4085 C'CApDPL~T CTJGAIJGPG X 4864 GAAL'ITIT = ?LZCTILaG
CDAA AAAPGWC
1429 H~?IR29 4086 ACC.~1PGFG CC1GALJGFD X 4865 AAL'ITTIT . _
CDAA AAAAPL~J~J CT~~T
1432 HI~IIR294087 APGACCAA CZJGAUC,AG X CGAA4866 TTZTrPLT C TIC3GILZT
PGUAAAAA
1434 f~R29 4088 OCAPGPLC CZJGAUGFG X CGAA 4867 TITACiCT '~ GGIC~C
PGPG~AP.
1438 HI.BKIR294089 CT~OCAA CZJGAZJC,PG X CuAA4868 CT'TIDGT C TIC~CC~G
AO~~PC~1G
1440 I~'R29 4090 CPGTJC3C~OC C'UGF~IUGAG 4869 CTIC~GTLT C C~CPGIG
X CDAA PGALI~e~G
1467 Fif~R29 4091 AC~)UOC C~JGAIJGAG X CDAA 4870 A~A~T _'-_ CDAACTPT
ACAU(JG~LT
1474 HI~2PR294092 UOCUAALm CUGALD~G X Ct~PA 4871 TPL~CAACr _'-_
AC~JtJGCUA TATrP<3CA
1476 E~B~?IR294093 GUUOCUAA CLJGALJC~G X CDAA4872 GCAPLTAT _'-_
ALi~JUOC TrPDCAPC
1478 HI.&2i'R294094 AL~JUOCU CUGALJGF~ X CGAA 4873 APCrATAT C ?L3CAPCAT
P~LAL~JIJ
1479 HI~R29 4095 AALJGWOC CCJGAI~ X CJGpA 4874 PCrATP.Tr _'-_
AAT.~L~CT G~PCP.Tr
1487 F~&~R29 4096 AAL1UGACA CCJ~TJG~G X ~A 4875 P~3CAACAT T ~'I~AZT
AL)C~Ix3C<T
1488 I~R29 4097 CAAWGAC CLJGAUC,FG X CGAA 4876 GCAACF.TT T GICAP.TTG
AAUC~UOC
1491 F~R29 4098 .ArACI~A1J~J CZJGF~C X 4877 ACATt'IGT C AATIGZLT
~ PCP~AA~1
1495 ' I~R29 4099 C~~AAGpC CTJC~AG X O~A 4878 TIC~'ICAAT ~
AWC~AA GEC
1498 HI~1R29 4100 AIJIJGIJGAP. CZJGALJGPG 4879 'IC'AATIG'T C
X CJGAA PL~.AiJUC~1 TI~1CAAT
1500 HI~R29 4101 CiJG CUGAL7GPG X CDPA PGACAAW4880 AATI~'I~T = CACAATPG
1501 F~R29 4102 PLL~TJtJQT CUGALJGPG X 4881 AT1~I~.'IT C
CGAA A~CP~ALI PDAATPGT
1507 F-B~~?iR294103 UUGAPGAC C13JF~G X CRAP. 4882 TIC~AT = GZCTI~P.
ALJUDUC~P.
1510 F~R29 4104 UUGUUGAP. CTJGAIJ~G X CDAA4883 ACAATPGr C TICAACAA
PLL~1L1UQ1
1512 Fff.~~lR294105 OCZJUClI(JG CUGAIJGPD X 4884 PATP~IC'T T CAACAPpC
CDAA PDPLI:kITJU
1513 HUMIR29 4106 UOL~JfJ CU~LJGpG X GGAA 4885 ATPGICTr C AACAPDCA
~
1529 E~d~R29 4107 APL3~AU CUGAUGAG X CRAP. 4886 Ac~FD3~r ? A2rPGC.'IT
PLC~CLiJCZJ
1532 HI.E2IR294108 .UtJC~PO~J CL7GAL~FG X 4887 G33;TAAT C PG~CTTAAA
CGAA AUt~CCC
1537 E1UMIR294109 GACAWUU CUGAIJC~G X O~A 4888 AATCPLCT T AAAP~GI~
PaCZJGAW
1538 HL~IR29 4110 ~~FCAUU<J cUGAI7GpG X al~A4889 AZCI~LIriT a
APD~JGATJ PAAIGIrA
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111
Table IV. Hammerhead Ribozymes to TR2-9 and TR2-11 Orphan Receptor Genes
1545 f-T~2TR294111 LLZ1U(~AU CC~UGPG X CGaA 4890 TAAF,p~f C ?~C~?AAA
nG~UUUUA
_542 F:C~t29 4112 CC~PJGU(JI7IJ CIJGAC7GAG 4891 AA'IGIZ,AT C
X CGAA ALR;ACAIJ(J AAAAA'I:rG
1555 HtI~ITR294113 ~GI~9GAUC CUGALJGFG X CGAA4892 TCAAF.AAT A GATCTAGT
AUUI~J~A
1559 H~R29 4114_ U(JCl'~ CUGALJGAG X CGAA 4893 AAATI~GAT C TACr.~A
ALICCTAZ)(nJ
1561 HCMfR29 4ll5 CCtnKVPG C(~LJGF~ X ~ PGAIJC.'~LJ4894 A'I~GF~.T A
CrPGAPDG
1564 ~R29 4ll6 CUOCCWC CUGPTJGAG X CGAA 4895 GA'1~'AL~T A
PL~GAIJC GAPD3CF~
1576 HC~R29 4117 GOGAALJGLJ CUGAU'.~P~ X 4896 OOCPDCAT C ~ATI~CC
CGAA ALJG<.TJC3CC
1581 HC~RR29 4118 AP~AL)OC~ CUGAUGPG X SAP. 4897 CATLF~CAT T OCCAT~IT
AUGUGALJG
1582 F~R29 4119 UAPGAUGG CUGAUGAG X CGAA 4898 A2G~C'ATT C CrA2~
AALJaJGALJ
1587 HI~2rR294120 aLIAAAC~A CI~AC~AG X CGAA 4899 ATILCCAT C TTAL'ITAT
AC103GAALJ
1589 FiLll~2IR294121 CCUGPdJGPG X CAA PGAIX~GGA4900 TCCCA2~T T ACTrA'InG
1590 Eif.R~fCR294122 CLCALTAPG CL7GALJGAG X 4901 CCrA2C~T A CTrA2C3~~
CGAA AAGALJC30G
1593 IifB~R294123 G~CATJ CUGAL~i'~G X CGAA 4902 A~1'tACT T A~3
P~FC~1IJ GACIC
1594 HCU.~2IR294124 GC~CA CUGAIJGpG X CGAF. 4903 T'TI'ACiT A TGGAL'IL.C
AF~FGA
1601 HC~uR29 4125 PC330GUr~ CC~AL~GpG X CGAA4904 TAZC3GpLT C C~CT
PL~CCPTIA
1604 I~2IR29 4126 ?~OGG CUGALJGpG X CGAF. 4905 GGAG'I~CT A CCCCTC~
PO~JCC
1613 fi(~R29 4127 AP~ACAZ7G ~ X CGAA PLCPD33G4906 C~.'1C3GT T CA'I~PC
1614 F~R29 4128 LTAAC,ACPdJ CCJGAtJGF~ 4907 CCCT3GIT C AZGIC.'ITA
X CGAA AALG'~D~ .
1619 HI.llKIR294129 GCAITAI:IAA C~JGAL~AG X 4908 CTLt,A2~'f C
CGAF. A6'AIJGHAC ZTA'~C
1621 F~R29 4130 ?DGCAL~tJ CUGAUGFG X CGAA 4909 'IC'4TGIrT T
P~FCAUGp. ATATGCCT
1622 HI~IR29 4131 C~DGCAL7P. C<.1GAL~FG X 4910 CA'IL~'iC.'IT
CGAP. P~AC~ICpTJG A T~CCTG
1624 Ht~.R29 4132 I>PCPaGCA CUGAUGAG X CGAA 4911 ~T A 'It;CCTGTA
AL1AFGACA
1632 HI.1~R294133 At~CALT CUGAIJGPG X C<'~AF.4912 ATaCL'mT A ATGGTI'AT
PCPL3GCAtT
1638 F~.~R29 4134 GG~LJ ~ X CGAA PCCAiI~C 4913 C~GT T ATAAFOCC
1639 Fif.~IR294135 PQOCin7(TP. CZJGAIJGPG 4914 TAAZDGTr A TAAFDCCT
X CVAA APOCAL1C1A
1641 HC~IIR294136 C~DOCW CUGAUGpG X CGAA 4915 ATt3G'ITAT A
AL1AAOCAtJ AFOCC7~
1648 HUMIR29 4137 CL1~AP~3 CUGAIl:~PG X CGAA4916 TAAPL3C'CT A
PD3CL~ CCI'ICpL3G
1652 HI,~~IR294138 CtIIJ~IG CpGAI7GFG X CGAA 4917 GCCTPLCT T CAOGAAPG
Pl3QIpDC~
1653 FiC~2iR294139 OCT~CU CUGAL)GFG X AAA 4918 CCTACCTr C PC3GAAM3C
AAO~
1663 I-B1~2IR294140 GUCAPD~A CC)GAiJGP~ X QUA 4919 GGAAFflCT A ZO~ITuFC
PDCU(JIJC~
1668 HIll~11R294141 A_F~LJ~GUC ~ X ~A PGCAL~OC4920 GCTP.'IC~~ T
GFL'I'AATr
1673 HI~t29 4142 LiJ ~ X CGAA AC~JC~AGC 4921 G~I~LT A ATIPChAF.
1676 HId~R29 4143 0~C~1~1 C~F~JC~ X CAA AL~JCPr4922 'IGFL'73~AT T
PL'1'AA~C3G
1677 HLllKiR294144 LJ~LICg~G CUGAL~FG X QUA 4923 GACrAAZT A CTAA'IC~GA
A~JC
1680 HI&IIR294145 CCAL7CCAIT CUGAIJGpI~ X 4924 TAATI'P~C.'r
QUA f~1 A A2nC~TOG
1691 F~t29 4146 AL~JU~P. C(JGALJGpG X CAF.4925 GGATOOGT T TTAi9FCAT
PLC
1692 HI~It'R294147 C~U~U~~. CUGAIJGFG X (1;AF.4926 GAZC30GTT T TAAACATG
APCCCAIJC
1693 FiC~2IR294148 PCALJC~J~T CLJGACJ~ X CGAA4927 A'n33C~Ti'r T
AAPL~CALT AAF~A2GT
1694 F~R29 4149 G~JtJ CiJGAIJGP~ X CGAA 4928 Ta3GTTIT A ApG'4~GIC
~ AAAPL~CA
1702 E~R29 4150 LJ~GFL3G CC~AIJGFG X CGAA 4929 AAACAZGT C CC.'!C'I~A
PC~W
1706 Fit$2IR294151 tC(JGALJGpG X ~F. PC33GAC~J4930 ATG'IrJCCT C
TACAATAA
1708 HI.~IiR294152 AWC~IJUG CZJGAUGAG X CGAA 4931 GTCCCZLT A CAATAAAT
P~32AC
1713 Ii~R29 4153 tJW(JAAW CUGAL1GAG X CAA 4932 'I~.'I~AT A PA7.'TAAAF.
AUI~GA I
1717 HI~R29 4154 APGAL7WtI CUGALJC'~AG X 4933 C.~ATAAAT T AAAF~LTT
CGAA AIAAIAZA7G
1718 HI.d~2IR294155 AAF~AWtJ CL~ALI;AG X CGAA 4934 AATAAATr A AAA1LTIT
AAIJUCTAW
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
Table IV. Hammerhead Ribozymes to TR2-92and TR2-11 Orphan Receptor Genes
1723 H(~TR29 4156 _CAU(~'~AAA Ci~AL~G X CC~P.4935 ATTAAAAT C TrIrP.~.~G
AUUUUAAtJ
1725 t~&IrR294157 AACAInJGA CUGAC,v,FG X 4936 TAAAA'IC.'r
CGAA P~AWUIIA T 2~A~Tr
1726 i~R29 4158 AAACAUUG CL~At~ X CGAF. 4937 AAAAZ~TT T G~A~C,'I~T
AFCAt~JfJU
1727 I-lL~2TR294159 CAAACAUCT CUGAUGF~ X CGAA 4938 AAAT'TTT C AAZGTTIG
AAPG~L~J(T
1733 HI.~21'R294160 c~IlAU<JCA CZJGAIJGPG X 4939 TIC~ATuT T ~GAATATA
CGAA PCAUUVAA
1734 HI&ITR294161 L~L1AUUC C<JGALJG~ X CGAA 4940 TCAA'IGZT T
APCPTJUG~. GAATATAA
1739 Fif.E~IR294162 CCACAU(lA CLJG~IJGFG X 4941 GITIGAAT A ~P~D3
. CGAF. AUUG~APC
1741 HI.~21'R294163 CUCCACAL1 CUGAUGF~ X CC~A 4942 TIGAATAT A ATv~It3GPG
P~LTATJUCAA
1754 FiC~R29 4164 C(JCPD~ C<JGAL~FG X CGAF. 4943 aGAOG'ICzT T
AC~LC'CJCC TAL~C.'ltl~
1755 F~R29 4165 C'L~JC~~1 CUC,AL7GPG X 4944 GAC~GIGIT T
Q~F. AP~1!CUC PL~CIGPflG
1756 F~uR29 4166 C'~''C.ZJCPf3G Ct~ALJGpG 4945 P~GIGITT A CMG
X CGAA AAFCPDCU
1768 HI~IR29 4167 GP~At~C,P. CC1GALJGAG X 4946 C~C~3CrT C ZLTA2C.'IC
CVAP. P03CLCZJC
1770 HI~2rR294168 O3GP~. CLJGALJGAG X CGAA 4947 OOGCCIC.'r C
PGF~3C~C TA~IL'~
1772 I-1~2IR294169 ~pp~ C~7GAD:~G X CC~A PGFGAOOC4948 DO'1'IC.'1LT
A 'IC'IC~OG
1774 FiC~R29 4170 UfJ~3A CUGAZ)GF~ X CGAA 4949 CZC~TAT C TCCCCGAA
AL~C,~GFG
1776 HCd~~R294171 AP~IJCJ~33 CUGALJGpG X . 4950CDCrA'IC,T C
CAF. PGF1J~ C~C~AATr
Where "X" represents stem II region of a HH ribozyme (Hertel et al., 1992
Nucleic Acids
Res. 20: 322). The length of stem II may be >_ 2 base-pairs.
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
Table V. Hammerhea, ~ozymes to EAR3/COUP-TF-1
113
hCS Seq. - ~. LD. Stibetrate
LD.
ND.
16 4951 AAACX;p~, C~L~ X C;~lp, 5248 ~C<,T T ~
AL7C~3CACA
17 4952 AAAALK'pG C~7C~T~G X Q~p,5249 p~C~ T
AAiX'~0~1C
18 4953 CAAAAIJCA C(~AI~G X QG~A 5250 'IGCX'ATTT'
AAALJt33CA C 'IG~,TIfilG
23 4954 P~CAA ~G X AAA AL~AF. 5251 TI'IC~.T T TIL3CAACr
24 4955 AAl3J~3CA C(JGAUC~G X 5252 TIC'IC~Tr T
QG~A AAL7CPC~A 'IC3CAAGTr
25 4956 C.~FGUtbC Q~G X CAA A~AI~5253 ~ T p
32 4957 C7CUtJC0..C CZ~G X CC~A 5254 TIC3CAACT T
PL~UOCp,F. 030GAFGF.
CGOC~ CZJG~G X CC.~F, 5255 ACI~~C3CT T
pl3~J C~CICC30CG
69 4959 CCCOOCI~ CTX~L~G X CGAp, 5256 PL3C~Ir3CT C
AOCAFOCU C3COOOOOG
1.54 4960 ACC CTJ~G X CGAA PL~LOCCU5257 pl3~T T 033;30336
275 4961 C~C~3CCXI: C~AI7GF~ X 5258 C~3CPGr A ~003C
CIF. PLIJ0~7C
317 4962 ~OOG CUC~L~Gd~G X AAA 5259 pC~I' C ~OC'IL~
PL~003C
323 4963 ~C~OCLZ Q7G~L7GFG X QG~F.5260 ~~ C 033CIC13i
PL~73~C
329 4964 CAOGAOCC Q~G X CJ~A POOCC1~G5261 C'ICJ0066Cr
C 6CL'ICJ6IG
334 4965 Q~C~G C~AI~G X CGAA PG~COGapC5262 pCIC70C~C.T
C CIC30GFL~
373 4966 X36 CC~T~G X CGAA PL~3000G5263 C6~.T C CSC
379 4967 GAFp3Q36 ~G X QUA P~GpG 5264 CI'~CCr C ~CIZC
386 4968 ~3s CMG X C1;AA P030~F. 5265 'I~C~.T T CCO''hIC~
387 4969 03GAAG3G CUGAL~G X O~A 5266 C~C~'IT C COC'hI~CC
AF~3J
392 4970 C~AAC~30G ~G X CC~A A000",~AG5267 CTIC'L~0.,T
T O~.TICJC
393 4971 O3G~FL~3G Q~JG~ X OGpA 5268 TI'0.2CTT C
AFO33GAF~ OCCTICX7C
398 4972 p6GAC.3~ QJG~J~G X CGAA 5269 CTIL~CCT T ONL~OCC
PD03GAAG
399 4973 UOC~OOG Q~G X OI.;AA AAOOQ~A5270 TI~!CTT C NC'I~TA
404 4974 ~~G CL~LJC~G X CGAA ApmG~5271 CTI~CC~T C ~COOCG
433 4975 UGCtJ~30C Q7G~LX~ X CIA 5272 p030CC~T C 03~AOCTA
PO300~3C
445 4976 pO~AOOC QJ~LX~G X QUA 5273 C~GT C t33CIC17CC
P1.1C~JOQJC
49~ p~ CL~L~AG X CC~A PC?~7GF1~5274 ~~OOCr C OCL~CFL~C
462 4978 a30Ca0C~ ~G X CGAA PL~3~ 5275 Q~CT C Cm0330C
478 4979 CAUX3CtA Q~ X OGAA AL~7t7llC~5276 CCAAAGF1C A
2n3CAA~
489 4980 CU6~FG ~G X ~ P~'AL7~C 52T1 OCAAn33r A GTTAOCFG
492 4981 C~10CC1C~TJ ~G X CGAA . 5278 ATOGTAGr T P~AO~G
PL~~1LT
493 4982 Q2~3~3C QJGWJGpG X CGAA ~9 ,roG~G~T A pC~DCICaG
_ AAC~OCA
508 4983 Q~OG CUGAix~ X a~pA AL~OC5280 c3GOGAGAT C
CGCt~c
~4 '1984 ~CL.Z ~G X Qtr .~00.!Q3CC5281 pO~I' C C300000.7C
706 4985 Ct~CC~ G X QUA P~?3CG 5282 0300CGGT T O~G
707 4986 UQJOOCCC QJG~LX~G X QUA 5283 pC003GIT C (333CC~r
AApC030C
729 4987 PL70CALZJC CTX~L~G X QUA 5284 CAOCACAT C G~GT
AL~CIJG
755 4988 L~CUC ~G X Q.;AA ACC 5285 pGACAFGT C C~f3006CA
770 4989 .~33~G CZ7GAZX~G X CG4A 5286 CA~1CT A ~~AT
PL~~
779 4990 CL~CP~CTXi CC~IJC~G X 5287 ~GC!'~1AT T
~. AIJt700C<Xi CAO(.'IDOG
780 4991 LJ~G31 Q7GAZ~G X Q~1A 5288 03C(~.TT C ALL.~OC~
AAUUG32
802 4992 CL~F~1 CT~t~G X QUA PL1~JOC5289 pCAAAFGr T ZC'I~AG
803 4993 L7CWGApG ~G X C~1A AFL~UUUG5290 CAAAAGTr T CTl~
8~ 4994 CL~F~ Q~G X ~A AAACCJtJUtJ5291 AAAAGrIT C TI~AAGAG
806 4995 UCCtJCL~JG CC7G~TJGpG 5292 APGri~r T C71FC~'3GA
X Q~AA PL~AAWtT
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
Table V. Hammerhea~ .,~bozymes to EAR3/COUP-TF-1
11d
807 4996 CUCCUCUU C~'~AL)GaG X CAA 5293 PGTrIC.'IT C
ppC~AACTJ APC~~G
819 4997 WC1~ CTJGX CGAF. P03'~LJCC.ZJ5294 PDC~D~ C CGC~DGAA
830 4998 CJCT CL~I)~G X ~ PGUUOQJG 5295 CAOGAACT T APG'ITprA
831 4999 ~FQT CTJGAZJC~G X ~ AFCTJCJOCU5296 PflC~AACt'I'
A ACITAC'F~C
835 5000 GCAL7C~~1 Ct~I7C~G X OGa,P.5297 ACrrAAGT T ACC
PL~AQT
836 5001 C~CAL7CZJG CLOG X CGAA ApGUC~IPG5298 CTTAACIT A CACAZDCC
862 5002 Q1~L7C.~ CT~I~FG X a~lP. 5299 GGAAL'IGT C CCAZC7GAC
.~1C~JC~C
867 5003 UGCUOGUC CUGAUC~ X CC~1F. 5300 Tv~C..CCAT C
AL~3:~. GA~OCA
896 5004 GGO~G ~G X ~1P. AL7UC3GCFC 5301 GIGCJCAAT A CIC3CQ3CC
906 5005 CALZJUC.T7IJ CLK~G X CGAA 5302 TGC'~~CT C AFGAFGIG
P~OCA
918 5006 CC.rPLUUU CLfi~G X CGAA 5303 AAGIGCxT C AAA
pD3CALW
945 5007 CCUC<'3CUG CLOG X CGAA p0."l'3CWC5304 GAPL30~,T T C~DO~
946 5008 C~CU CZJC~G X QUA AFC03~7U 5305 AAG~3GIT C PL3CGFL1VA
964 5009 CL7GD~IJG CLOG X OGAF. P03CAUUC5306 CAAZGCCT C CAACC7CPG
979 5010 CL7C3C~'c3JG CTJGAIJCPG 5307 pD~AT C CPLL~3~G
X D;AA AL~CU
989 5011 UGACZ70C~ CX ~ PQJOOOCU 5308 P~OCCAGT A ~CAL'IC~1
996 5012 C~J0~.1 CT~AI~G X 0.~AFa 5309 'I~CFGT C pGCAP~
PL~~.
1014 5013 UGOCC~JU CL~,G X CC~A P~33~7C5310 G~CCCr C APCmCt'A
1028 5014 COGAC~G CLOG X OC~A PGCFL~JOG5311 ~'T A C
1034 5015 UC~~DCrG CZ~G X ~F. AC~f~G 5312 CI'pGL~C~T C
~GC~C'A
1040 5016 GO~AIJG CL7GAUGpG X ~F. 5313 G'P~OCT A CA'I~I03C
PL3~C
1044 5017 P~OGA CT~AL~G X Ct;pA AL~OOC5314 G3C'~CAT C 'I~C'IC3C:I'
1046 5018 GCFDCAGC CL~1L~G X CGAA 5315 CT~Cr C GCIC3CIC7C
pC~l:~
1070 5019 AC~JOC~ CMG X CAA P~3GCUCG 5316 CGAOC0.T A C0.7CAOGT
1079 5020 CC~T~IOQ~C CX ~F. P~33 5317 OC~T C G03C~
1085 5021 GOCUOCT~ QJGpTJGpG X ~ PL~30~C5318 GT~CT A 030CP~CC
1116 5022 ALJOCCCALT CMG X OC~A At~J(IQIU5319 AACAACP.T T A'Ir~OC~IT
1117 5023 C,AUOCOf~1 CLJ~TJC~G X (JGtIF.5320 P~PCATr A 'IO~C~C
AAI~JUQT
x,25 5024 AL)C~7C CLOG X QUA AtX3CCCrWJ5321 AT3C~3CAT C GF~FLAT
1134 5025 pl3CU~. Q~L~G X QGAA PTJOtX~7C5322 ~ C 'n30GFL~.T
1158 5026 OO~A ~ X ~A pl~~ 5323 CDOCInCI' C T'I~OD3C
ll60 5027 CO3Q3COG QJGpIJGpG X QUA 5324 CC'ICICTrT T
PGAGC~ CG~~G
1161 5028 pL~:100CU ~ X AAA AAG9GC~G 5325 CZt3CZC'IT C
PL~3Lt~T
1170 5029 aCOCACx7C CUC~Tfi~G X CGAA 5326 pfl~GT C C~03C
PLD3C3CU
1188 5030 AAGAA03G ~JGAG X CAA. AI~(JODs5327 COCAACAT C ~C'IT
1193 5031 ~3GAFG CC~L~G X 4~A pL333C~IJG5328 CAZOCOLT T CTILOOGG
1194 5032 LJOO~F, Q~iJC~G X ~1A AFC~OGAIJ5329 ATNCCTT C TIC~C~
1196 5033 GAL~733G CUGAL~AG X 0.'A 5330 CCCCfiTG'T T
pGAA~ C~OGP~TC
1197 5034 F~L~3G Q~L7GF~ X CGAA AF~F~335331 CCCI~CIT C C~Cr
1204 5035 GAL7C~3CA CC~L~G X SFr ADO 5332 'ICOOGGAT C 2L3CAGA~C
1212 5036 L7C3C~703C,ZJ Q~G X ~ AIJQJOCFG5333 C'Z~T C P~OC~OCA
1226 5037 C~.3CAGG Cite X ~F. PG40C~ 5334 aC2?OGIt;T C
CL'n3CTAC
1233 5038 ~3CG ~G X CC'~9F, pL3~00CA 5335 'ICC~IC~GT A
C~C~AC
1239 5039 CU~O~J CtJGAI:JC'~G X Q~F. 5336 C'~;.T C POCIO~G
pGO~
1256 5040 UGFL3CF~ QX~I7GpG X QUA 5337 CGAOCIGT T CV'IdC~C"A
PC2~~
1257 5041 L7~GC~G CLOG X CAA AAC~OCOC5338 GAO'~C~'IT C
GIL'3
1263 5042 GC0~1 Q~TJC~G X Q~1A pOCF~F.5339 TI'CGIC3CT C
AACOm3C
CA 02364577 2001-10-03
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'Table V. Hammerhe~.. ,tibozymes to EAR3/COUP-TF-1
115
1280 5043 C~CAIF~. CL~TJGFG X Q~1A 5340 CCFGIGCT C 'IATG~
PGC~
1282 5044 CpC300~ CUC'~L1C~G X CCAA 5341 p~C~ A ~~
PGFC3CALTJ
1304 5045 ~~C3C CTJC~G X ~1A A033Q~ 5342 ppppC~ T ~C~
1331 5046 AC~~C C(JGAI7G~G X CC~F. 5343 (~(~CCT C pC~
PD3CAL70C
1340 5047 CC~JOp3~, X ~ p~pC 5344 (3C
1353 5048 A~~C CZ7GAI~G X Q~P, P~~C~7C5345 G~CpT C p~~
1361 5049 (~WCAC7G G X CGAp, PL30CCAL1J5346 CGInpCCr T CATL9~C
1362 5050 L~CACT C<JC~IJGFG X CIA 5347 G~CTT C ATL3C,ACCA
APD3~C
L374 5051 AAGAL70;~ C1~I7G~G X Q~p, 5348 c~C~T C ~C~
A<JC~~C~JC
1380 5052 L~W~;A CL~ X CX;AA AUC303C~IJ5349 A~GCp,T C TIC,CF~OC~
1382 5053 C~ CLX~L1CFG X Cl.'~F. 5350 C~A~T T Cl~DGFDC
AGAI~310C~
1383 5054 UOCUC'~ CUGAISJC;AG X Q~P,5351 Cl3CATCZT C CPC~Oi~.
AFGAi~3~
1404 5055 PGOL'3CCCJU CLGAL~FG X 5352 GAC~Ap;,T C AFDOCt3CT
CAA PL1CUUCUC
1413 5056 UCC~7G C~7C~L~G X CC~A 5353 AApCCI~.T A CA~~,
F1C~OOOLW
1419 5057 Q~ ~ X ~, ~~ 5354 CTI~C~10~T C
GACIC~pC
1424 5058 AL~OCU CLI~Lfi~G X 0~1A 5355 CGIt7UAC'T C
FGL~O;~ paC~Gi'
1433 5059 Q~DCZ7G CCX~L~FG X Q~1A 5356 FD~~GT A CFOCIC3CC
PL~OQT
1443 5060 ALJt33CUUU Gt~ILJGAG X 5357 P~CC.T C AAFL~X~1T
QUA P~O~J
1452 5061 AAC~3CF1C C<7C~T7GAG X 5358 AAAC3CCAT C GIC3CItiIT
C~1P. AL~3CUUIJ
1460 5062 CLOG GAG X CAF, pL~3CppU 5358 C~C~ T ~p
1461 5063 t7CTJC~1 CUGAC~G X ~A AACAOCAC5360 G'n3~IT C App
1466 5064 PL~O~J CCJ~1L~AG X ~1A 5361 GI~O;,T C AGA~LLT
pp~AC
1484 5065 NOCAWC C<7C~G X 0~1F. p1,~000C~5362 ~C~T C p~C~
1500 5066 P,C30~T3r.L7C CL7CAIfi~G 5363 C~CQ~T C C~OLZT
X AAA AI7C~7033C
1520 5067 03CAC<Z3C QJ~G X 0.~1A 5364 0~~Gr C p~CG
PQRJC~JOC
1541 5068 W~ ~ X ~, p,CL7CCOCC 5365 p;,~ A ~p~,
1556 5069 C~3~ CUGAL~AG X aJAA .~JOC3GTJC5366 C~pOC~T A ~'p,AL>r
1576 5070 WUCCCAP. C~ALJ~G X Q~1A 536'7 CCFL~CC~T T TIL70CAAA
A003COC~
1577 5071 (~7C7p~, ~ X ~ p,~,mpC~ 5368 CACOOC'IT T 'IO3CAAAC
1578 5072 .~C~UC~JOC~ CU~L7GFG X 5369 pDCt~'~IT T C30CAAACT
QUA AAAf~CU
1604 5073 UOOOC~ CL1~I7C~G X CT~A 5370 ACn~C~.T C C3CIC~CT3CA
Ap~C~1
1619 5074 ~C~,OC,~G CUGAUC~G X CC~A 5371 CAO~GT C CI0.~OG
pC3~p3C~7G
1622 5075 L1~03Q~G ~G X CC~, p~ ; 5372 ~TOCT C CTL~r
1625 5076 a~ X CGAA PC~~C 5373 G117C7~~T C CGI~G
1629 50'T7 UOLZ70~YJ CUC~1UC~G X CAA 5374 'ICCZCCGT C ATt~~.
P~~
1632 5078 M3CTJpCx7C Cl3pAL7hAG X 5375 'I~~I~.T C G~C~CT
p~A AI~C~1
1641 5079 P~Q~AC,AA Q~G X CC;AA PO~70QJC5376 C~OC~OGT C TIC.TI17GP
1643 5080 MFG Q~T~G X GSA PL~IOf~C 5377 pC~IOC'ICT T
CTInGItCC
1644 5081 ~DC~1F, C~T7~G X CG~,F, 5378 CAOCIC.Tr C '1'IC~'IbCG
p~,OQ)G
1646 5082 AA03,~ CL~,G X ~A p~C 5379 pT CGILC~IT
1647 5083 AHAOC3~C CU~G X C~1A AAC~G5380 CICTI~'1T C GIC~GITr
1650 5084 P,OC~AAOG C~L7C~G X Q3AA 5381 TI~'I~GT C CGTIZD~T
pIJC~AC~A
1654 5085 PL~10C4 CI7pALJ~G X CAF, 5382 ~OGT T TC~TP~3T
P~,~~F,
1655 5086 t~.t~90C GTR X CWp, AApp~ 5383 ~~IT T p ~'TAO~i
1659 5087 C~7CA~ CU~T~G X CGAF, ,ao~5384 (~ITIC3;,T A
C~~AAAAC
1663 5088 C3D~ICftJ CC~G X AAA AO~A 5385 TC3GI~T A AAAC~
1674 5089 PG~7C CL~ X QUA P,t~0333C~J5386 AOC~CAT C GAAAL'ICT
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Table V. Hammerhea~ _,~bozymes to EAR3/COUP-TF-1
116
1681 5090 G~:~P,L~, Ci~4(JC~G X CL~A 5387 ~C ~CCCC
- PL~~7C~;~_
1683 5091 LK~ ;ALT CUGAL7GFG X CGAA 5388 GFIAACrCr C AT'~3CuF,
P~JUfJC
1686 5092 ALLAtR70~ CZ~G X O~IA AL~FC~15389 ACI~ICAT C p3~A~T
1693 5093 CAC~ACA CUGAL1GFG X CGAA 5390 'ICmCGAT A 'IGTrPCiG
ALmC23GA
1697 5094 CAG~1 C1~G X CC~A PC~LJO~ 5391 CGATA'IGT T PCIGTL'!G
1698 5095 CCFGAC?G ~G X CGAA AFG~LTAt7C5392 C~'ATuIT A CT'TC.'IC3G
1703 5096 UOCUCC~'A CLTGAL~AG X CGAA 5393 GTTAGZGT C ~C3~AOCA
PC~AC
1715 5097 GCCFI~JG CTJGAIJGFG X O~A 5394 C'~p~,pCr T C~ACIT33C
PaCL~3CUC
1716 5098 GOOC~C~JU CC7GA1~ X QUA AAC3CUOCU5395 PG~DCTT C A~OC
1726 5099 OCACAL1~T CUGAUC~G X CT~~A 5396 PL~CCr T r~.'PGILC
FQ0.C~J
1727 5100 U0~ CUGALJGpG X QUA APO3C~?G5397 C'IC3C~CTT A CA2T~'I~CA
1733 5101 AL~AI7G CUC~G X Ct;~IA ACAL~A5398 TrPCA~C~T C c~CPGr
1737 5102 GAOCACL7G CUGAI~G X O~P. 5399 A2~I~CAT C ~CIC
AL7C7~~tJ
1745 5103 PL3C~G CL~L1GFG X Q~1A PL~1TJGG5400 CC~Cr C C'IPGAOCT
1748 5104 CC~POC~TJC CZ~G X O~A Pa~OCAC5401 GTC~.'IC'Cr A
GPLCI'IGG
1754 5105 AAG~ CT~AIJGFG X CC~A PDC~7t7C~G5402 C~CT T Q30COCIT
1762 5106 CAG~ CUGAL7t~G X CGAA AOCC'~OCC'A5403 'IC300~Cr T C~LCIG
1763 5107 GCAO~ CUGALJ~G X CAA AFQCC300C5404 GCX~CTT C ~CICaC
1777 5108 LJC.~L303G CIX~LIGFG X CGAA 5405 'IL3~T C C~CrAGA
ACX~30CA
1783 5109 LJGAC~R'UC CLJGALJGpG X O~F.5906 GTC3=CCCP A C~GACIC~.
PO300C~G
1790 5110 GC~7CCUC'LJ C~ALJGFG X Q~1A 5407 C PL~Lt
P~T~.
1816 5111 ~c~CTIUtJG CZJC~G X CGAA 5408 CA~C~LT C C~AA00~
PLT~C~7UG
1910 5112 UCC3~LftJG CTJC~1UC~G X Q.~A5409 GCP~AAAT A CAA2~OC~r
AL)tJtJC.LpC
1915 5113 C~G~ C~JGAI~AG X Cr~A AL~LR15410 AATAC3;AT C 0.'~C'FAC
1922 5114 AI7GCLlUfJG CTJGAL7GAG X 5411 'I'UOGAOCT A CAAAOC~T
CC~1F. PDQJ00~~
1945 5115 LJCCtTAAAA CMG X CGAA PC~.L~TJIJ5412 AAGAGACI' C
1947 5116 C~IJOCC~F. C<JGF~L~G X CGAA 5413 GAGACIC.T T TI~'IC
PL~JC
1948 5117 LJGAL~~ CUGAIJC~G X D~A AAC~J5414 P~L~'IT T TPD.~AZC~
1949 5118 CC7GAIJC7CU CtJ~IL~AG X QUA 5415 Q~G~TIT T PC~'I~~G
A~1FGACTJC
1950 5119 UCL~A(7t7C C1~LJG~G X CGAA 5416 AC7~C.T1'iT A
AAAAG~1QJ G~
1955 5120 P~L~J QJ~L~G X CC'~1A ALx7CC1~1A5417 TI~iO~IT C PL~2C'IGT
1960 5121 U0~ Ct~IJGAG X CAA AIJC1JC~JC5418 GATT C T~C~C~CA
7972 5122 tJOCUOC~CC ~G X CAA AO~JOCUC5419 GAOC~Gr T O3t~?G~.
2009 51?3 ~C C<7G~G X Q~F. PaC~IUC~J 5420 AAGAAO~ T GIGTC~'r
2014 5124 POCAGAC~ QJC~TJGpG X ~A 1~CAF~3G5421 OCIZG~GT C TG~3~T
2018 5125 L7IJI7~~OC'A ~G X CGAA PL~C~C5422 G'IGI~'IG'r C
ZGGIGAAFs
2042 5126 UCT7CVU0C CT~AiIG~G X CGAF. 5423 P.AAC~AF~T T Q~PL~F.
AWUC~~IIT
2064 5127 LEA C~L~G X CGAA ALJfJC13~9TJ5424 ATL~F.T T T~AFihAAF~
2065 5128 L70U~ CLOG X Q~F. AAL1C1C~JC~r5425 2~.ATt T TAATAAAA
2066 5129 CTJC~T CTJGAIJGpG X Cr~IF. 5426 G~fATIT T AATAAAAC
AAAI~JC
2067 5130 L7C~tAlt~IJ ~ X CGAA AAAAL1UQJ5427 PGAATTt'T A ATAAAFCP.
2070 5L31 UUCL~3W C<JGAIJGAG X ChAA 5428 A'ITITAAT A AAACAC~A
ALJ~AAFdT
2086 5132 P~CAIJ Ci7GAIJGAG X CX~A 5429 POGAA~GT A A~GAL~.T
AL~~LV
2095 5L33 AAI7CIrTJOG CUt~G X CGAA 5430 AT~LCT T CCF0~1TT
PL~JC~ALJ
2096 5134 AAAIJCCUG CZJGAIJGAG X CGAA 5431 'InGAGCTT C Q~;~ATI'T
AAC~JC7CA
2103 5135 CC.ACAAVA CTJC~G X OC~A ALJOCC~5432 T'C~O~.T T TA'I~G
2104 5136 L7CCAChAIJ CUGAI~AG X ~A 5433 CCPL3:~ATT T A2~
AAL~''CiJOG
CA 02364577 2001-10-03
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Table V. Hammerhe:. .~bozymes to EAR3/COUP-TF-1
117
2105 5137 ~,p, ~ X ~ ~ ~4 ~~ A
2107 5138 CCGUCCAC C<JC.~TJGpG X 0.P.5435 OGAT~'~AT T GIC~Af~G
ALIAAPZJpC
2124 5139 AC?GAAL1A CL~'~JGFG X CAA 5436 ATGn3GAT A TATPCIGT
AIJCCACAU
2126 5140 ~A CLK'~IJGFG X Cl'~1A ALTALTC.~1C5437 GI~,T A
2128 5141 CLOG CZ7C~L7C~G X Q;AA AL~L~CC5438 C3GATATAI' T
GAG
2129 5142 CCiJC~Cp. X QUA AAI~It~IJC 5439 GA~ATATr C '103
2L33 5143 UGC~JG CUGAL~AG X CGAA AC~Ai~r5440 TATIC.'ItiT A
CAOC~ACA
2148 5144 CACUC~CF, C<7GALJGFG X CGAA5441 C~AC~T A 'I~3~PGIG
AL~JG
2168 5145 UUUCt~. CL~(IGAG X QUA P03CUUCA5442 TC,AFGCCT A TG~AAA
2172 5146 C~1UUC CLOG X ~A ACAL~03C 5443 GCCTAZGT A C~1A~
2195 5147 LJGAAIIAAC CZ7Gi~lG X CGAA 5444 CTL~ACAT T GITATmA
ALKT7tJC'~G
2198 5148 AAAUGAACT CUC'~G X CG4A 5445 AACATn,T T ATIrATTr
PL~AUC4)C1
2199 5149 AAAAL1GAA C<JGAL~G X aC~F. 5446 ACAIZGZT A T~ATITI'
AFG9AL7a1
2201 5150 PL~,AAAL1G CLJC~LJGAG X 5447 AT~TAT T ~TI~'
CC~A AI~~ALT
2202 5151 UPCAAAAIJ CZx~I7C,AG X O~A 5448 TI~ATr C ATrI'IGTP.
AAI;AAC~P~
2205 5152 LAP, CTJG~G X CC~A AI~AALTAA5449 TI'ATIC7~T T
TI~AAAF.
2206 5153 ALA, CL~C~G X CGAP. AAL~AAt~.5450 '~ATlC~T T T~AAAAT
2207 5154 L~LJUUt~C CMG X OGAA AAAZJGAAIJ5451 ATIC~.TIT T G~AAAATA
2210 5155 LZ~JC1 ~G X CGAA PI~AAAUG 5452 CA'ITIZGT A AAATACI~.
2215 5156 AFL~G C<7C~G X C1;AA AI~CA 5453 '1GLAAAAT A CrAGIC~iT
2218 5157 AImAAGaG C~L7C~G X CGAA 5454 AAAATACP A GICZ'IT~T
AC~JIJ
2221 5158 AAAAI~1AA CiJGAUGFG X CGAF.5455 ATPCrAGr C TTTATTIT
PL~C~IT
2223 5159 UGAAAALB1 CL~T~G X CGAA 5456 P~C~I' T 'IA2'~
PG~J
2224 5160 AUGAAk~AIJ CTJGAIJGPG X 5457 CTP~i~=IT T AT~AT
O~A AF~LL~G
2225 5161 AAUGAAAA CTJGAZ~G X CGAA 5458 TAGICITr A TI~.Tr
AAFGACtm
2227 5162 AAAAL~.A C~ X CGAA AL~AAGPC5459 GTCTTIAT T TmATiTr
2228 5163 AAAAAI~P, CL~T7GAG X QUA 5460 2C'ITIATT T TrATiTIT
AAI~1AFGA
2229 5164 AAAAAAL~ ~G X CC~A AAALZ~ 5461 CTITATIT T CATITITT
2230 5165 CAAAAAALT CC~1IJC~1G X 0.'A5462 TITAT~IT C A'hITI'ITIG
AAAALTAAA
2233 5166 L~AAF, ~G X CF. AL1~AAAIJ 5463 A'IZTIC~T T TITIGTAA
2234 5167 I~F,A CUC~T~G X CAA AAL~AAA5464 T'rIZrAZT T TTIGTAAA
2235 5168 L~F, CUGAi7GAG X CGAA AAAL7GAAA5465 T TIC~TAAAA
2236 5169 AI~CA CUGAL~G X CGAA AAAAtX~A5466 TIC~TI'IT T 'IGIAAAAT
2237 5170 AAL~C . ~,L7C'~G X aC~A 5467 'ICATITIT T G~AAAF~T
AAAAAi~
2240 5171 UI~AAI7W CU~IJC~G X O~A 5468 TTITIZGT A
PC~AAAAA
2245 5172 C~7U~. Q7GAL~G X CGAA AL7UUf~A5469 ZvTAAAAT T 'L~AAC~.ZC
2246 5173 aGAt~T CI~UGAG X CGAA AAVI7~C5470 GTAAAATT T AAACATaG
2247 5174 PaGALIC~3U CUGAL7C~G X CGAA5471 TAAAATI'T A AACATCGT
AAALIt~7~1
2253 5175 C~OC~C CUC~G X OC~A ALJC~UC~A5472 T~AAACAT C G~P.TOOGC
2256 5176 L~CA CLOG X CGAA P~JI1 5473 AA(~TO:~T A 'I~3CATA
2264 5177 tA)U~AJCW Ci~G X CGAA AI~300CAiJ5474 A'II~CAT A AFC~P~AAA
2285 5178 WCX>1QU CT~iX~G X ~.A AZxJCU(7QT5475 PCAAC~AT T PQOC~GAAA
2286 5179 UUWC~ CUGATJGpG X CC~A AAiIU~IJG5476 CAAGA~7.T A C~AAA
2296 5180 GAAAF~IUGU CLOG X CC~A ALAJUUOLC5477 ~AAAT A AC~TrIZC
2301 5181 AtJ~GtIA CLOG X CC~A AUC~~JCT5478 AFiCAACAT T TI~AAT
2302 5182 L~TRA~ CUGAIx~IG X ~A AA1:~IJ5479 ATAFmIT T 2C7CAAATP.
2303 5183 LA~JtJC~ X ~A AAALJC~ 5480 'LAPCATI'I' T
CCAAATAF.
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
Table V. Hammerhe~ ~bozymes to EAR3/COUP-TF-1
11R
I 2304 5184 AZ7t~,Ut~7G ~ X ~ ~ 5481 AACATITT C C~AA~Al'
2310 5185 IJIJL.L~LTAA~T CL~L7C~G 5482 TIrCAFAT A ATTA~pp,
X pip, AZ~JU(3~,~1F,
2313 5186 UUC,~LT CUGALJGpG X QUA 5483 CAAATAAT T A7~AP~AAA
AUUALnJUG
I 2314 5187 AL1(7~T7U(Ip, X CAA AAUC~IJW5484 AAATAATr A TAAAAAAT
2316 5188 CAAUVUW C~7~ X ~, ~ 5485 ATAATITAT A AAAAATIG
2323 5189 CACPGGAC CUGAIJGAG X Q~P. 5486 'I~1AAAF,AT T
ALA GI'~''CIt;IG
2326 5190 AC~G ~G X ~A ~AUVUJ 5487 AAAATIGT C CIGIG'~.T
2333 5191 G~L~CAVA CUGATJC~G X QG~A 5488 'I~CIG'IGT C
PG~OG~ TA2G~C
2335 5192 L~L~, CZ~AL~ X ~9p, pG~G 5489 CI~IGTCT A ~~~A2C.~IP,
2339 5193 C~1L~GA CT~G X pip, p~ 5490 ~pp~ A
2341 5194 CAC~LTA CUGAUGAG X QUA AI~CAL~G5491 CrAZG'I<P.T C
~T~
2343 5195 AAC~K'~ CUGA1;JGFG X Q:~AP.5492 ATG~tP.TCT A
PL~I~ALJ 'IAZCIGIT
2345 5~6 ~ X ~ 5493 GTAnTAT A 'I~G~IT
2347 5197 PCAAAi~C'A CUGAL7C~G X ~A 5494 AnTATAT C T~TITIGT
AL1AL~C~IJ
2351 5198 AAAL~A CL~T~G X 431A AC~C~AL~TJ5495 A~T~IC~T T
2352 5199 AAe>AL~, CT~UG~G X Q~1F. 5496 TA1C.'IGiT T
AFCAC~AI~ ~TrIT
2353 5200 AAAAAL~,C CMG X CC~1A AAAC~IT5497 ATCIGZ'IT T GrATrITr
2356 5201 C~AAAAF, CUGAUC~G X Q~F, 5498 '~'~IGT A
pL~F,AAC~,
2358 5202 CAC~AAAH CT~J~ X Cu~A AL~AAA5499 TI'I~TAT T TITITCI~
2359 5203 CC~AAAP. CT~AIJC~G X Q~AA 5500 TI'IGTA'IT T
AALZ~AF. TZ'ITCtOG
2360 5204 PLC~AAA COGA1;JC~G X OGBA 5501 TIGTATIT T T~~T
AAAI~AA
2361 5205 AALCAGAF. ~G X Q.~1A AAAAI~45502 T~ATI~T T TI~TC3GIT
2362 5206 C~ACC~ Ct~TJGAG X SAP. AAAHAL~C5503 GI!ATITI'T T
'IC.'InGI'IC
2363 5207 C~F,AG~~sG C~J~G x Q~F, 5504 TATITTIT T CIC~GI'ln2
pAA~,AA~,
2364 5208 UOGAA0~1 CT~i~AG X QUA AAAAAAAL15505 ATTT'ITIT C TC~I'ILCA
2369 5209 UG~G Ct~G X Ct~A PGC~AA 5506 'i'1~C3;~T T
OC~AAOCA
2370 5210 CL~JC1~7G GL~G X Cue, AAp,;pGAF,5507 TTCTC3GTT C CAAAL~CaG
2381 5211 tX~O~~ C~,G X OG~A AUCUOGW 5508 AAOCAGAT T T0~
2382 5212 AUCACpDG CUGAi7C~G X CC~A 5509 PLCFGATr T CST
AAIJCTJO~J
2383 5213 AAI~G CLJGAUGAG X CGAA AAAL1C~J035510 O~ C CTG~'I'
2391 5214 L~L~G C~rG X O~A AI~DG 5511 CCIG'IGAT T C~ATPC~P.
2392 5215 UI~,C~L~ CUC~I1C~G X C~9A 5512 CIGIC,ATr C TATACTAA
AAL~G
2394 5216 L~L7(~. ~G X O~A PmAIJC~C 5513 GIC~.TiCT A 'TACTAATP.
2396 5217 ADL~ ~ X QUA AL~AAI1C 5514 Q~TIC~AT A CTAATAAT
2399 5218 AAAAIA~TJ Q.~L7C~G X 0.~P. 5515 TtTATAGT A ATAATIZT
P~
2402 5219 L~AAAAAL1 Q~G X Q~F, p~,u 5516 ATACTAAT A ATITTIt~
2405 . 5220 AI~Ap. CUC~LJC~G X QUA AL~G5517 CI~ATAAT T TrI~.'AT
2406 5221 UAI~LJCAA Q~UGpG X CC~A 5518 TAA2AATT T T~TA
AAIJtmtJCg1
2407 5222 UI~t~'A CUGALJGpG X CGAA 5519 AATAATrr T TEA
AAAL~7~T
2408 5223 ~t~7c C~JG~G x a~A AAAALIVAU5520 ATAATTTT T GATATAAC
2412 5224 AP~OQGL7t~. ~ X ~A AI~AAAF.5521 Tl~'IC~T A TAACOC'IT
2414 5225 CAAA00~1 CZJGAL~FG X ~''~F.5522 Thl~.TAT A FLC~ITI~
AL~1L1CAAF~
2420 5226 AAC~AO~. C1JG~IJGAG X CGAA 5523 A~C2T T 'IL3C.'IZr.'IT
PL30~IT
2421 5227 t~pp~AC~C CT~G X OGaA p.~3p~,5524 'I~.FL~~.'IT
T C~.TI'L'ITA
2425 5228 AI)C~I~1FG ~,G X OGAA Pc3C~AA0G5525 ~2'ITIC3;.'T
T C'ITATAAT
2426 5229 CALUA~TAA CUGATJG~G X QUA 5526 CTI'IC3CIT C
AFaC~AF~ TIAZAF~G
2428 5230 CZ~LT CUGAL7C~G X CQ~A PGAAOCAA5527 TIC3~'ICT T ATAATt~G
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
Table V. Hammerhe .bozymes to EAR3~rpUp_~_1
119
2429 5231 PLC C~ X ~, A~p~ 5528 ~~ A
2431 5232 OCPL~,LT CT~G X CAA ALA 5529 CrlC~ITAT A
A1GAGInC
2443 5233 ACAACA~, G~7~L~G X OGAA 5530 p~C~ A
AI70pCF~LTJ
2445 5234 ~ X p~ A~~ 5531 TL'~~,TP.T A
~
2449 5235 C~OCi7~C CUC~IJGAG X 4~A 5532 ATATP,TGT T
P~(7 GID~pC
2452 5236 PL~DCCUC Ct~AI~G X Q~AA 5533 T~,2GTItsT C
ACAA~ G4ppC~T
2461 5237 LLT~FG ~ X ~ p~~ 5534 GPL3pCIGT T
CLI~4e~
2462 5238 LRJ~7~,p, C~ X ~ A~~ 5535 ppp~ C ~,p,
2464 5239 AAI~~T~7G CX ~, p~pC 5536 Q~ T
2465 5240 T~AL~W C~,G X ~, A 5537 C A~,~A
2472 5241 UCAAL7Ut7U CT~L~G X C~~F, 5538 T AA~.~
AI~U~,
2473 5242 L~AL)IxT ~G X ~, AAj7~ 5539 A AAATIGAA
2478 5243 (~7C CU~t~G X aC~A ALIT 5540 ATI~AAAT T ~'~A
2490 5244 UtA7CTJtRm, Q~I~G X 03AA 5541 GI~AAA~.T T
AWt~C TAAACAAA
2491 5245 tJI~JC~7UU CU~,UC~G X pC~F,5542 'IGAAAAZT T
AAUt7C~ AAFG~AAA
2492 5246 L7 ~,~ X per, p 5~ A A~AAA
2502 5247 AAI~T ~ X p~ AWt7UUC~l 5544 ACAAAAAT A Ar
Where X' represents stem II region of a HH ribozyme (Hertel et al., 1992
Nucleic Acids
Res. 20: 3252). The length of stem II may be >_ 2 base-pairs.
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
Table VI. Hammerh. .ibozymes to IRF-2
120
Saq.
~I substrate
LD. ND. LD. No.
13 5545 C~AALJGa, CT~L~G X Q3AA 5967 c~CLT U Lx~Uf~C
p~p~UC
14 5546 UGGAAALG CTJC~LJGAG X 5968 ?,~~ U
pC~p, APL3CWCU
15 5547 ALXI~F,ALT CL~ X ~ A~pCC~~5969 CG03CLJW C AWWCAU
5548 G~AAU~A CL~L~G X CUB, 5970 OCUUU~I1 U UCCAUUUC
AL~A~C
19 5549 UGAAAVOG CTS X CC~A AALGAAFG5971 CWUCAUC1 U OCA1JUUCA
20 5550 GI~4AAI7G ~G X ~A A~AI~,AF,5972 LI7 C CAUUW~C
24 5551 Q~7Q7Ga, QJG~G X QUA ALI3GAAAIJ5973 ALAJWCAIJ U t7~Cl~C
25 5552 a~7G ~ X ~ ~7p~ 5974 L7U(70CAU(J U
CP~C~pC
26 5553 O3Q~T CL~L~ X ~ ~p~ 5975 LET C PCPI~~CC
36 5554 ACt7C~I~C CMG X CAF, pp3~5976 Cue'-~,U A O~FC.AC<1
45 5555 CAP~CI~IJ CLJ~(~G X ~A 5977 O~LZJ U AUAOCWG
ABC
46 5556 OC~AOC~ C~U~G X p~A AA~J~7C~5978 CT A UP~CWOC
48 5557 COOCAPLIi CL~L~G X ~A 5979 P~L1 A C~700GG
ALIT
52 5558 AP1RJ0.~C Q~G X OG~A P~AA5980 UC~I~ApQT U 0~3
5559 F~CAAL~C C~L~G X CCAA 5981 UG~AALT U ~~1
p~C~,
63 5560 OC(~A ~ X QUA AG9AL7UOC 5982 OGaAUthiJ A UUChf~
65 5561 A03Q~ C~7G~7~G X C~'~p, 5983 Ar~Li~LT U CK~CGTI
AI~AIIT
69 5562 WUC~C C~7C~G X CGAA ACX'AAUpC5984 CI~t~I~1 A DD~AF~
146 5563 WGG~vU X ~, ~CW 5985 ~u A A~a~7o~
151 5564 W37WIJG CT~~G X pC~p, 5986
pL~JUtiAL7C
161 5565 Pp~ CU~(7~ X ~, pt7p~ 59g7 A~pC~IJ C ~OOpCxT
170 5566 AOOCAQJCT CT~7GAL~G X 5988 ~p~ C A~7pp~
Ct~A pl~OpppCh
179 5567 Ut7QAJC~J(T Q~~G X ~, 5989 AF~OQJ U AACAAOGP,
pad
180 5568 W0~1 Q~7G~G X Q.;Ap. ,A~3pC~J5990 pC~p~ A
197 5569 ALJCL~IAPr QJGALX~G X 5991 A~4'~AL1 U LJC~LT
~A p4~JC1
198 5570 C~LJCL7G~A Ci~IJG~G X 5992 PC~TJCt U Ut~
QUA AAL~T7U~T
199 5571 OGAI7CTx;p, Q~G X ~F, 5993 U ~pC
AAAI~C
200 5572 C30GAL7CL7G Q~G X QUA 5994 AAGpIWT U ACC
AAAAI7CUtT
201 5573 C~O~I7aT C~L~G X CC~ A~,~5995 PGAUU<Rx1 C AC~1JOOOC
206 5574 AU0.~AOGs Q~,G X ~A PTI~AA5996 U(7I7CAG~i1 C
CCa7C~TJ
225 5575 ~7C ~G X ~F, p~ppmqQ 5897 pT~3GG~TJ A ~G
2~ 5~6 ~~I1GAG X QUA P~C~C 5998 aC~,1 C L~,AA
2~ 55~ aCUGAI~G X AAA ~1C~G~1 5999 PDC~T U LZ~,AF,CC
263 5578 Q7c~J CL~7pqG ~ X ~, 6000 Q~7CZAJ U PGAAAL~
264 5579 NOC~1UC Q~ X OGAA A~A~ 6001 C~C~7(1T A GAAA003G
278 5580 O~t7G ~G X CG9A p~CC~ 6002 CC33CAHt1 C C~L~G
282 5581 CWCIt7CW C~tfi9G X aGAA 6003 c~At~L1 A CPflc~AAAG
pig
294 5582 UCCTJOC4IT CW~1;7GF,G 6004 CAAFDCAIT C AAOCpDC~r
X OG~1A AL~3~7C
305 5583 Q~7C ~ X ~, p~pC~ 6005 ~D~1 A CAL~AAOC
309 5584 AL~OCT7U QJGAIJGi~G X 6006 ALT A AAOCLGAU
Ct~A AIX~,C~C
318 5585 UC~JIJU~703 CTJ~L7GF~ 6007 AA~i1 C (~AAACA
X Q~, AL~pC~7(7
339 5586 af~L7C17C~, CTJG~G X ~F, 6008 PD3~AIT U L7C~C,AtIOC
AWQ30CU
340 5587 COCp~ ~ X gyp, ACC 6009 O3~ALRJ U CLOG
341 5588 C~OC.~IJCLT QJC~1I1GAG 6010 0."L;p3lUU<J
X QUA AAALRJU3C C P~47C
357 ~ 5589 pp3C~ApG Q~G X Q~F, A~I~ 6011 ~II~AIT U 0~100C.T1
I
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
Table VI. Hammerhea" ttibozymes to IRF-2
1 21
358 5590 CA~C~,pG CUC~3X~G X QUA 6012 CAL~L)U C CL~7G
AAL~IJG
361 5591 LC CUGAL~GpG X Ct'~A PL3 6013 GAAUC1CCU U GCL~I~
~AAUCJC
369 5592 UUCLTX~?, CTJGAUC~G X O~p 6014 UGOCTJCAU A LJ~,pI~,
p~ppCp,
371 5593 ALL~JC CC~7GAG X CX~A ALLALTCPL~6015 OCC~C~IJ U GA~1AQ1
380 5594 UC1AIJCaJU CL~,L~FG X C(~A 6016 GAPC,AFCAT C AApGAL~A
pL~7C
387 5595 L~C.ZJUCT ~ X Q;L1P, p,UpCi~,6017 UCAAOGAIJ A A.~G~
395 5596 CCT~~UU CUGAL7GFG X Q~p, 6018 AAAAGCAU A APGAAFaG
AUuCL7C7(7IT
408 5597 GAPa~CAL1 CIJGAUC~FG X SAP,6019 AA~AAAU A AU30LZJUC
AUNT
415 5598 AGACtCUu CUGAIJGpG X QUA 6020 UP~P~L~LL.T,T
ppG~ U CFDO~L1
416 5599 UPG~CZTT CU~11C1GpG X Q~1F,6021 AAL7~CW C Ap3C~~.
AAOGCAUU
422 5600 AUUCT3~ C(7G~IJC',F~G X 6022 UUC1~J C LIc~G~AU
~A p~Ci~AF~
424 5601 GCALJU~ CL~LJGAG X pGAp, 6023 Q~GQ~JC..U A O~C
p~AGpL~
440 5602 ~7GA C~I)G~G X Via, ppp3~ 6024 CLX~~'!C~TT A
LJC~GAFOG
442 5603 G00~1 CUGAIJGFG X ~ A~~ 6025 C~CC~L~LJ C pL~1A00C~
453 5604 L~JC~G C~L7C~ X C~ Ap~~ 6026 AAO~CCU U Ct~IAGAAA
454 5605 CUU7CU~. CLOG X per, A~~7 6027 A~CUU C f~GAAAG
456 5606 UC~LAn7aT CL7GAUGFG X CAA 6028 G~0.~JUCU A PC~AP,pC~
~C~
497 5607 AUC~JOCL7U CUGAUGP,G X C~'~AF.6029 GACAAPQJ U APCdC~U
P~7C~
498 5608 GAL7C~.ZT CMG X AAA p,ACUt~J6030 AC1~AAC~Jt1 A
POC~1LJC
506 5609 UC~CW CL~AI7Gp,G X AAA AUCC~Q7CT6031 AAC~CAC~AIT C
AFL~Q~,
521 5610 GAUG~7C C~L~G X ~, ACC7p~ 6032 GA~J U G~JC
526 5611 a~L1 C~t~G X Q~,p, p~,CU 6033 AGLIt7GAC~1 C
AUCL~3
529 5612 G~ CL~(7C~G X ~A p~ 6034 UGA~IT C UC~C
531 5613 AP~C~CCA CtX~IIJGAG X ~A 6035 PGI7CAI7QT C t~3C~0~JCT
pC~I~l
539 5614 CCA~LLT CU~L~G X ~ pp~pps~ 6036 CU0030CU U PI~AUDG
540 5615 L7CCALIf~C CL~,UGAG X ~A 6037 Ut3C~3~.L7IJ A
AFDOCCCp. C~4ALJGQ3
543 5616 L~c~IJ C~,G X AAA P~AOpC 6038 GO~J A AUO~.
551 5617 P,C~T C~ X ~ ~,C~ 6039 AAUOGF~C~J A AC~~t7CU
558 5618 PLaQ~AF. Q~7~G X ~ Ate, 6pejp C UUUC(7CQ1
560 5619 tX~G~, ~ X ~, p~ 6pru, U tX~JCCUGa.
561 5620 CL7C~1GGPG CUGAL~G X ~, 6042 QJG~AT U QJOCTJC~
A~
562 5621 ALTJCApC~. C(~1UC~G X UG~A 6043 L7GAL1CtIU(1 C
AAFG~, UO~T
564 5622 AL~1C23G Q~tIG~G X ~A Ac~AAGAiT6044 AL~1 C QJG~T1
571 5623 GGA00.~A Q~L~G X ~ Ate, 6045 UO~JG~T A U~13C~J~
578 . 5624 GAAQ7C~G ~G X ~, p~~ 6046 L~UC~03J C C;JC'~JUC
585 5625 L~1L~7UG CLOG X Q~, p~ 6047 UC~I1 U Q~K~L~
586 5626 L7~t~1 ~G X ~ A~7~pG 6048 a'TJG~7U C AFL~Ln9A
591 5627 ~~ X ~ 6049 Q~ALU A CA~AAAAL1
593 5628 L~I1IJ~JI1 C~I~G X C(~ A~7U~,6050 t~FLT~IJ A AAAAAUGA
609 5629 C~ ~ X gyp, ,~qt7p~U 6051 AAC~OC~ItJ A c.~OCZJG
612 5630 Q~,OOG CL7~G X 03AFi , 6052 UOGAL~1 A ~1C~AC
623 5631 AC.~FG~9LT CTJ~7~G X pG9F, 6053 Q7GAAL~U C AL~~JUQT
p~I7C~7C~C
626 5632 ~.AC CLOG X 0.;AA AL~L~J 6054 AACAZJCAIT A C~J(7C~OG
629 5633 UC~7~.L~C CTS X Q,~1F, p 6055 AL~IJ~T U c~3~A
632 5634 GACUQJCC Q~ X CG~1 pC2~A~ 6056 AL~7QT A Q~7C
640 5635 C~ C~AL7GFG X ~'~F. A~J 6057 AOGAI~T C CC21IJCZJOG
645 5636 GC~~. CT~UGAG X QUA AL133GACC16058 PC~~C~IT C LJ~C
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
Table VI. Hammerhe_ .~ibozymes to IRF-2
177
659 5637 C~AWCUC Cf~I~ X ~,. p~~1 6059
PDC~ U
666 5638 AAI~L~L7U ; X ~ ~~
6060 ~ C
674 5639
C~ X C~ p~ 6061 U ~~
5640 p~~t7t7ac~1 X Cue, p 6062
C p~,~
684 5641 ~Cti CZ7C~G X CLAP
AC~tX~~JGA
, 6063 ~p~ C q
695 5642
ACwoO~ c~7~t~G X ~, 6064. CCPGACp,U U UoCCAA~1
696 5643 AACtJC703C CX C~ ~ 6065
C~C~Cp,W U p~CT
704 5644
AOCUCi~C CU~L~ X pp~ p~pCA 6066 ~~ U
707 5645 G~,CCiJC CMG X . ~A 6067 A
740 5646 CUC~IJC3CL1 CtJ~I:JC~G X 6068 (~ppCp~ C pQ~
O~A AC~JGGCtJG
755 5647 AGAQ~. ~ X OGAA P~C~CU 6069 pOQ~p~7 C ~~
757 5648 aC~ ~ X Cue, p,~CUCti 6070 OGApCUCZT A COQ~C
762 5649 G~CA ~ X ~ pQ~ 6071 T~~ C Up~7C
770 5650 A03C~A ~ X ~ A~~ 6072
772 5651 PG~3~ X C~ p~py 6073
781 5652 CAL~pC~,A GL~G X CC~A AC~~ 6074 ~~ C
783 5653 LJOC
A~,pG CI~G X CC~A pC~3 6075 O~L1 U C~JC7Cp
,
784 5654 CUOCAL~1G CUB X QUA App 6076 OG~U C Q~UpCAG
787 5655 t~~ ~ X C~,p~ p~ 6077 ICJ A ~p~
810 5656 03pC~C C(~I~G X ~,p, ~3 6078 OA ~7~
,pe
867 5657 (3CC(~A C~ X CQ~A AL~''COC'iT6079 ,
~ A Wpb
869 5658 UUC~CCTft7C CTJ~T7C~ X Q3~p,6080 ApG~ U p~ppC~
ALI9tJUpCLT
883 5659 UOCUG~3G CMG X aC~A p 6081 (~,~ A C~p~,
887 5660 AL~1 CT~LJGAG X OC~AA pO~JG6082 C~p'V C ppCAAC~i1
903 5661 aC~(~ ~ X p~ p~CA 6083 U033GKLT C C~3pCUC~
910 5662 C~30~G CX Q~F, pldOL~ 6084 L>L~p~7 C C~pC
913 5663 GCApC~ CUGAL~AG X QUA p,~CU6085 1~30CU0.1T A
CQJOCt~C
934 5664 (~p~,~ ~ X Oc3~A Pc~3CCALJG6086 C~ll7ppp~ C C~~,
.
937 5665 AAC~~ CX ~, p~CC 6087 p30C~7 U C~J~,CW
938 5666 GAA~C ~ X ~ A~p~p3C 6088 pp(~~ C
941 5667 L7u3~AC~J QJr~L~G X ~F, 6089 UOCC~J C AC~3(~A
~,F,p~
945 5668 UI~7C~ ~ X p~ p~ 6090 Up3~1 U ~,AF,
946 5669 ~ X Qp~ p, 6091 O~ C
962 5670 Q~ q~ X ~ p~~ 6092 OCOGAOC<T C GEC
968 5671 L~GZT CI~AL~FG X SFr ACCI~,G6093 QJ0~3J C P~IJOAP,
974 5672 L7CCi7r3x7~T OUC~G X ~A 6094 Qx,~OCAiT C AAAC~,
AU03~C
990 5673 AOOCAppG CtiC~J~G X Q~F, 6095 P1.~!OCA~1LT
AUC~CiJCxT C COCA
999 5674 p~7 C~~ X ~, ~~ 6096 OC~OLTT U ACAACApC
1000 5675 AOCL1C~TJUG C~L~G X QUA 6097 QA CA~C~OCV
A~(~pC
1009 5676 OOpOCC~G CT~G X p~A P~OCZJC~6098 CApCA0CL1 C CJO3COCC
1020 5677 ~A X ~ pp~~ 6099 0301 U t~~AAt~C
1021 5678 Q~CT~, CT~I~G X ~A AFO3pC~pC6100 t3COC~CIJU U
L7C~Pl~,OC
1022 5679 PL3C~TJUG C~IX~G X QUA p,F,AppppG6101 Op~(A7 U CAp~
1023 5680 C~O~TJC1 ~G X Cue, p.AAAp3~6102 CL~JUt1 C AF~~TJC
1031 5681 c~A~ppU cX ~, ~p~ 6103
1037 5682 C~pC~, CT~G X C1~A pL3p~G 6104 C'L~p~TT U LX,T~C
1038 5683 C~L3~1FG CUC~I~AG X QUA 6105 U~pp~7 U ~~
( ~ p,~p~,
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
Table VI. Hammerhe. ~bozymes to IRF-2
1 2 'i
1039 5684 U~G~ ~~ X ~, p,~pG03G 6106 ~~ C U~C~
1041 5685 CAL7C33:~pG CLJGAL7C~ X 6107 ~~ U ~C~G
QUA p~,Ap(~
1042 5686 LJC~I~G ~ X ~ p,~pG 6108 0.~JC1 C ~,,C~,
1045 5687 03C~L7CAUG C<7~G X ~ p~p~ 6109 ~CLt C ACC
1060 5688 IX~CUOLTJG C~7~7~ X ~ ALJOCIJ~6110
1071 5689 ~~ X ~ ~C~ 6111
1100 5690 (~TCLTJGAU CMG X ~, pp3Ci7GOC6112 ~CC~1 C AC~.FC~A
ll03 5691 C~JWCJCUCT X O:~A AL~'~3CU 6113 p,G03<X~U C APGAAApG
1114 5692 L~AL~C Ci~IL~AG X CC~1A 611.4 GAAAACAU C a~LlAt~"A
AL~JIJC
1119 5693 CtJ030~. X ~ ACJm~ 6115 CALR~~3~IJ A UI~L~G
1121 5694 C~CCt~t1 ~ X C~,p, p,~C~, 6ll6 Cxx~~tmu C Ar~c~C
1136 5695 CAOCZJCW Ct)GAL~AG X Ct.~A 6117 CaCCOC~(T C APGAC3~7G
AL~pp3pC
1146 5696 FC~ppCW C~7~~ X ~ ~pC~ 6118 p~~ U p~pCC~
1147 5697 C:AG~GCU X gyp, AAC~OCtJC 6ll9 GAGCi7C~JCT A
PL3~
1153 5698 Cue, X ~ pDGCI~A 6120 UtDIF~C~T C L7G~7CUC
1159 5699 PCLOO~Gp, Ci~t7~ X per, 6121 C U~ppGU
p~,G
1161 5700 CC~3~ C~JG~G X CG~A AG~,G 6122 ~ C CG
1171 5701 C~COC~AC CC~7~G X CGAA pl>~,~pC6123 00~~1 U Ci7CZ3003C
1174 5702 GAAOCCCC CL~ X ~A pL~Apf~ 6124 C~~7(JC~1 U C130C3CWC
1181 5703 AAGCCAFG C1~AL~G X Q~F, 6125 Uf~300CU U CTJtJC~3~IJ
P~CX~F,
1182 5704 AAAC~CAA Q~Lx~G X CC'~A 6126 L7C~3CW C W03QJW
AFL~C0.'C'A
1184 5705 PC3~AAOC~ CT.~G X QUA PGAAC~C6127 030~.TJ U C~OLIr7~JIJC,iJ
1189 5706 ACAAAACA C~7~ X ~ pp~ 6128 L~pCU U L~7~
1190 5707 AACAAAAC ~ X ~, AF~OC~,F1G 6129 CvUOGCW U QJUUUC~It1
1193 5708 AACAA(~,A CCJ~,L7G9G X CZ~F.6130 03CW~T U L7~~7UC~JIJ
ACAAF,OCIr
1194 5709 AA1~L~,AC~, CTS X ~ ApC 6131 OQJU(~AT U t~AAT
1195 5710 CAAAC~C C~7~ X ~, AAAC~AF~ 6132 U
1198 5711 AAFCAAAC CT~G X gyp, ACAAAACA6133 t~UUUUf~1 U CTJtIt~fT
1201 5712 L~AACA Q~(~ X O~A ACAACAAF,6134 LAJUGUC7QT U ~7~,
1202 5713 AL1~AA,C CLOG X QUA AACp,A~p,6135 I~JUC~t1 U QJ
1205 5714 AAAALl~, X OGAA ACAAAC~, 6136 L1 U LET
1206 5715 L~AF~C ~ X ~, ~p,~ 6137 L~C~Ax7C4AT U
Q~A~
1209 5716 AAAIm,AAA CC~~G X ~ ~~ 6138 UC7CTJUt~T A UUU(~
1211 5717 AAAAALmFr Q~G X CGAA AL~,F~6139 QAJ~:Ai1 U t.R~LJ~)I7CT
1212 5718 AAAAp,Ai>A CC~7~G X ~A AA(~6140 U U tT
1213 5719 AAAAAAAiT Q~i~,G X QUA AAAUAG4F,6141 LET U AIJ<RJWW
1214 .5720 GAAAAAAA Q~7G~ X CAA AAAALA6142 C~tRAT A I~7U~7C
1216 5721 GAC~AF,AA C~7~,G X ~ ~, 6143 LTALAAA>AiT U
L~T7C
1217 5722 AGAC~p,AA Ct~t~C~G X CG~A 6144 AC~7UC~W U UWUCi7CU
AAt~,p,A~T
1218 5723 GAF, ~,G X p~ per, 6145 CAJUC~JCT U WtJCTJQJC
1219 5724 AC~,A CL~ X ~, ~g~, 6146 L7~I~t7IT U LA~C.U
1220 5725 ~, ~ X Cue, p,~, 6147 L~A~A1 U U~7CtiG
1221 5726 L~!C~G CL~G X CL,AA AAAAF,AL~6148 LmIIUUWC1 U Cite
1222 5727 QJC~ ~ X ~ AAAAAAAIJ 6149 AWCItJWII C I7CTJC~C
1224 5728 Cue, ~ X Cue, p~,~,A 6150 t~WI7UQ1 C t~7C~l~C
1226 5729 1~~ ~p~,G X ~, 6151 C1IJ~7CT~1 C L7C~CU
1235 5730 Q~,AAA Ci~L~G X 0.A A0~ 6152 L7GFL~O:.tT A
UWI1PC~C
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
Table VI. Hammerh .tibozymes to IRF-2
17d
X37 5731 (W7Ct~p, C~J~ X Q~, A~p(~ 6153 ACAC~W U L't~C,FCAF,
1238 5732 CWT X p~A 6154 U
1239 5733 AI~t CU~G X p~A QJ 6155 ACCCmWU U PC~CAAALT
1240 5734 G~LLW7C CL~L~G X OGAA AAAAL~p~6156 CPU ,~
1248 5735 LW~, ~ X ~ AWE 6~ pC UP~PaC3~A
1250 5736 UUWCCCU CUGALJ~G X Q~, A 6158 ACAS A y3p~
1264 5737 CL~I,~ ~ X ~,A papa 6159 AAAAGCLU U C~AL~G
1271 5738 CA~LW7C ~ X p~,A 6160 UA
1278 5739 C~ X ~ p~ 6161 U ~~
1282 5740 C~,pC ~ X p~ 6162 ACAUUGAU U 0~7C
1290 5741 UOC~JUG CWAL~G X Q~Fr p~~ 6163 UC~CUC~JGCT C
1296 5742 PD~G ~G~G X ~ p~ 6164 CnpLi~,
1301 5743 p~
X ~ p~p~ 6165 ALTJCCPGU A ~~GC
1311 5744 L~AG~G ~ X ~, p~~ 6166 ~p~ U
X12 5745 ~ X p~ p,~C~ 6167 LJOG~3CW C L7CL7t7~AC
1314 5746 AAA CT~G X CC~A AC~pCUC 6168 C~p~ C
1316 5747 CL~
, X ~A p~C 6169 p~ U
1317 5748 C~UCT CL~ X q~ 6170 U ~~
1318 5749 UCCJJGFi~T CTJG~G X ~, ~ 6171 U~7C~7U A
X22 5750 c~
L~T1 X p~ p~~ 6172 CU(7C~,F~T.1
1329 5751 ALX~CL7G CL)GALJ~G X QUA 6173 C ?DEC
1338 5752 pl~~ 6174 W~,;,~ C C~,~
1342 5753 ~,CC CL~J~ X aC~F, AL030CUu6175 (~p~,U U Q
1352 5754 CAC~,p~ X ~ p~C~ 6176 ~p~ A ~~
1353 5755 OL~1AC~, Cf~G X QUA pL~p~ ACS U ~,~pC
O3C
W~G GL7r~7~G X (~A per,; 6177 C7~ U ~pC
1354 5756 AC30
~, ~ X q~, p 6178 Q7C~7U C UAC~OOCZJ
1356 5757 ~,ppC(,7U ~ X ~ 6179 GC~AW1 A CADCCUOC
1370 5758 ~7pp(~ ~ X ~ ACA 6180 Ups C W,~
1372 5759 PDOCCL~ C~7~ X ~ 6181 CC7C3~IJC<T C
L381 ~00~
5760 tJGF~,G X ~, ppppCiJOG 6182 C~p~ A ~
1384 5761 ACZ7I~T CMG X O~A pL~GCL.~ 6183 C3ppC~J C
1388 5762 t~AC~T ~ X ~ p~ 6184 t~lCf~1 C AFL~7t~A
1393 5763 ~ X ~ 6185 ACt~.AQ7 U C~AGGF,CC
1394 5764 UOQ~7CT ~~G X a~A AA~G 6186 CC AApGApC~,
1427 5765 ~pC QJC~G X SFr At~pCA 6187 UOCC~C~IJ U ~7pOC~
1437 5766 CC~3pQ7U ~G X QUA ApCT3CA0G6188 0.~OOC~7 C AAC~OOC~1G
1465 .
5767 L~C~W1 CL7C~7~G X per, pDp~6189 pG~C~ C p~
1480 5768 c~W~ ~ X ~ C 6lgp ~ A AL~AC
1490 5769 AIA~pC Q~G X QUA p~ 6191 LA OCUO~AU
1499 5770 GAAL~AAA COC~~ X ~, ~pC 6192 aWp~ U ~
1500 5771 PC~AI~p
A CT
, 6193 CIJOGAAW U t.AJUpTJUQT
1501 5772 ~G X Q~, AAIJt7~G 6194 Up~7U U
1502 5773 AAGF,A(~,A C~7~G X CC~F, 6195 C~AAtWJ U UAWCCJW
1503 5774 AAAUUpCA 6196 ~~7U U ~7~
1504 5775 CApL~,~, ~7~ X ~ p,~,~pC 619'7 W A
1506 5776 A~A~C~AI1 ~ X ~ ~ 6198 L1UIW7AU U Q~F,
1507 5777 ~ X ~ AAAAAATJtI 6199 WUC1UA1J~T C
LW~,FG Ct~UC~G X OC~F, P,LmAAAAA UUGUC~AL1
AUL~, ~G X ~, ~
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
Table VI. Hammerhe .ibozymes to IRF-2
125
1509 5778 AL1AUCICp,C C~I~G X Q~p, 6200 UUUAIJUCL1 U Q~,~;J
p
1516 5779 L~1L7GL~C~, CRAG X CCAA AWCACpA6201 U~~7 A
1520 5780 LX.3CCC1ALJG CUB X O~A ACAL~AU<7C6202 GAp~L~U A CAI~3CA
1524 5781 GUOCUC~ ~X~UG~G X C~A ALIT 6203 AI~U A ppC~pC~
1534 5782 AAL7CUOGC CL~L~G X O~p, pL~JGCU~6204 G~ A ap~U
1542 5783 CAGACUOC CMG X QUA ALJGZJOG1.'TJ6205 AG~Cpu U Q~
1548 5784 CAGAAC~C'A CTJC,AL7GFG X 6206 AL7IJOC~C1 C UpCUCJC~7G
CGAA ACSJGCAAU
1553 5785 Pac~7pCPG C~1C~G X Q~AA ppC~T6207 p~7(~U U COpC~
1554 5786 AA~CA ~G X CGAA AAOCPC,AC 6208 C~JCL70C~1(T C
UOCACQJU
1562 5787 UUCmPGAIJ CT~JG~ X CGAF, 6209 CCIGCACCU U AUC~Ap,
p~C~JpCF~
1563 5788 GAGA CUG~G X OG~p, AF~D~Cp, 6210 C~CUU A iKUC~AF~
1565 5789 U3LTJfJUAA CT~AIJGAG X CC~A 6211 C~CUC~IT C Ut~iAFY3C~.
AI~AC~~7G
1567 5790 Pi~CL~l1 CLOG X QGn,A P~L~FpG6212 CCL~tJC~T U AAFl3C~LLT
1568 5791 AAC~LTnJ QJGAUGpG X CJ~F. 6213 ~(7 A ppOCp~
AP~,I~FG
1576 5792 CT~7 CUGs,L7GFG X CQ~p, pC~CUW6214 AAAOCAGV U AC~C~AI~G
1577 5793 CCT~IJCZ7G CZ7GAI~FG X Cue, 6215 AAOCALTJU A CPC~p;,
AAC~LI:IIJ
1583 5794 PGAAOC~ C1~G X CC~A AL7C~7C~9F,6216 L~GF,U A p3CC(R~J
1589 5795 PTR~CAAG CLOG X Q;~A pp~~J 6217 AUAOGCCU U C~7~LT
1590 5796 GAUC~A CZJGA1;7GFG X CG~p, 6218 UAC~3CCW C UU~JC
AAppCQ~
1592 5797 AAGAI~C ~Z~FG X ~A pL~AppCC 6219 pG~ U
1598 5798 UAC~C3CAA CLJG~UGpG X CC~A 6220 CL~X~7GFU C VUC3CU'~1
ALJt~~C~G
1600 5799 GAL~AOC Ct7GAUGaG X CC~A 6221 ~ U G
pC~
1604 5800 ~ ~ X ~, paC~p~U 6222 AU'T)UGCU C
1606 5801 CC~AGA CT~G X O~A PC~hC~G 6223 CUUOOT,7C..TJ
A i7~JC~1C~G
1608 5802 UC~GL7G~JGA Q~G X O~A AL~G~ 6224 UGQ~T~i1 C L7C~C~1
1610 5803 UC~0~1 Cz7~G X Q~, pGF,L~G 6225 C~LJ~T C AC~CF,C~
1621 5804 ~CL1 CT~G X QUA PQ7C~JOQT 6226 AG~C~L.V C PL~CAL~L.T
1632 5805 O3GC~G Ci~,G X Q.~A At~303C~7G6227 CACOCC~U U C~CCC
1633 5806 IJOQ3~ C~7G~G X pG~A AAppp3~T6228 AC~CW C L7C~700~,
1635 5807 AALJOOOQ~ Q~L~G X CAA pC~AppC~6229 0.''OQ7t7CTJ C
U00.'~C.~L~T
1643 5808 03~30G CTJG~L7GnG X OG~p, 6230 CUC~'~C'~IJ U
AIJpppCnG C~OC
1644 5809 PO3C~ CLOG X CG~, AAL~~1 6231 UC~~'AIn1 C CCQ~00~T
1653 5810 t~pG~ C1~L~FG X CAA AOpL~G 6232 ~CCU C t~7A
1655 5811 C,AL~!OGp,A Q7GAI~G X a~F. 6233 CFDCCL~1 C L~I7C
F~OCt7G
1657 5812 O3C~HL~G Q~L~G X ~F, pl~ppC 6234 C~CCUCi~J U ~1UC1'~C
1658 5813 U0~ X CAA AF~C~,C~G 6235 aCLJCUCUtJ C CCF~L7C0~.
1661 5814 ~3~, Q~G X AAA ApGAPI~G 6236 C:~.U A UC~AUtx
1663 5815 U0~ COGA1;JGAG X Q~F, AL1F13GAFG6237 CUUOLT~IJ C CX'~IJpOI~,
1668 5816 L~OC~I~G CUG~L~G X ~F, Ai~3GAL~,6238 UAUCCCAIJ C O~C~1
1673 5817 UOC;u~Ai~ QJ~i7C~G X CGAA 6239 CAtx7CC'1~1IJ
AI~33GAI1G C C~1I7C70C~.
1678 5818 U03~3 CLOG X AAA AL~3~~L~ 6240 CAUC~C~.L1 C OC~LJOGL~A
1683 5819 UC~OC,AUOG Q~1I~G X AAA AIJOOC~It~6241 CAIJOOC~IJ C
CC~L1170~1
1688 5820 UO~AL~G CTJGAUGAG X CC~F, 6242 CAIJOOC~LT C ACA
AI70~,L~
1693 5821 CGOG~G CUGAI7Gi~G X AAA ALJOOGALJG6243 CALx.7LC~1IT C
CC~OCG
1698 5822 AAC~O~ G X O~p, pTJG~ 6244 C~L~CCAIJ C CJ
1704 5823 LmpGAAAA Ci~JGp,G X CAF, 6245 ALR~OOCV C UUtA7CCUpr
,~GD~~TJ
1706 5824 A~.~r~.lp, Q~,G X O~p, pC~~ 6246 C1;!~C~LT U UUOLT1
CA 02364577 2001-10-03
WO 00/61729 PCT/LTS00/09721
Table VI. Hammerhe_ _ .cibozymes to IRF-2
126
1707 5825 AAC~~ X pip pp,~ 6247 ~~ U W,~U
1708 5826 AAPQpaG ~ X ~,A p,Ap~pG j 6248 CGCL~L~J U CQ~(T
1709 5827 ~ AAA CtJGF,LX~G X O~A Ap,AFC~pC6249 OLT~WT C CC~CWW
1712 5828 PaC,A~r~r~ CL~L~G X Cue, 6250 C~W~~7 A CWUUCCU
pQ
1715 5829 C~,F,F~F, CL~J~ X Q~,A pL~~,p;~A6251 UUCCLmLZT U UUCCWCC
1716 5830 a~ X gyp, Ap~p~ 6252 WCt~LIU U UCCU~
1717 5831 PG~~ ~ X ~ p~G 6253 CC~CiICn1 U C~TJU~J
1718 5832 G'~C~OGAFG CL7GAUC~G X CLEF,6254 ~U C
AAAApL~G
1721 5833 LW~ X gyp, pQ 6255 CWCWCU U CCCUC~AA
1722 5834 CW7G~3G CUGALX~G X CVAA AFaGAAAA6256 WUUCC<JU C CLWjAPG
1726 5835 GAFL3CWU CLJ~LJGFG X QUA 6257 ~0.'Z7 C AAAGCUUC
PLUG
1733 5836 UGG~AL~3G CW~L7C~G X Q~F, 6258 UC~AAOLT1 U CCAUtJCCA
pad,
1734 5837 Q70C~,A1JG CUGALJGFG X Ct;AA6259 CAAFL3CUU C CAWCCAC
A~UG
1738 5838 O;~IJCT70G CZ~FG X CVAA ALpGFIAOC6260 C~CIJUC~C~1I1
U p~CP~C
1739 5839 COC~L7CZJG C<J~J~G X QG~A 6261 CUUOCAW C CACAZJCOG
AAUOGAAG
1745 5840 CIJOCU0.I,i CLOG X C.~AA 6262 UUOCAC~TJ C 03;~G
AL~~~,A
1769 5841 LCX ~ pp~ 6263 AAAL7C',AAtJ U
t~C~,
1770 5842 CTJ~G CLJGAL~G X CAF, AAUUCAL7CT6264 AALJGAAtnT U CT~G
1771 5843 TJCi7~, CX ~ ~ 6265 AUGAAUW C U~
1773 5844 1 CX ~, p 6266 C~AUUUC<J C
1775 5845 G~A~,LKi7G CL7C~G X ~A pG~C~p~6267 AL~1 A ~I7~7C
1783 5846 GAAAAIJOG CTJ~C~G X gyp, 6268 AC~,(~U C ~7UW
AC~I~T~J
1788 5847 AAA C~AUGP~ X AAA AUOGGACA 6269 UC~LCF1L1 U UU~1
1789 5848 ~, X ~, A~LJOOC~C 6270 C~OC~ItJt1 U UC~C~T7G
1790 5849 aCpGT7CW CC~,ifi~ X pGAF, 6271 tJ04~t7~J U C~GALT~3C
p~AAIJpC~,
1791 5850 PDCA~7Q1 CIJGAI~G X 0.;AA 6272 C~CAUUUtI C PGALTJOW
p~AAAI~3G
1800 5851 UUWUC~, CZ~7~G X CVAp, ppC~JC~J6273 PC,~70CU U vAAAAAAA
1801 5852 TJUWUfJIJU CLOG X p~lF, AFIp~6274 GACUGCUCJ U AAAAAAAA
1802 5853 AI~JUIJUtT CT~G X CAF, AA~CAC~16275 PLUOCT7C7~1 A
AAAAAAAU
1811 5854 AIn~F,G C~ X ~ ~ 6276 AAAAAAAIJ C CC7UC~AI7
1814 5855 CAC~;~9G COCFJ;JGFG X ~A 6277 AAAAI70CU U CC~,AZJC<JG
POGNJOUU
1815 5856 0~ C~L~,G X OG~A AFaGAUUU 6278 AAAI~CW C L~AL~OC
1817 5857 L~1~Q4G~LJ Q.1;AUGAG X Q~4A 6279 AWCUUQJ A AIx~OCg1
pt~ApC~iJ
1820 5858 Of~i~OCp, Q~TJ~G X QUA ALA~AAG6280 Ci~AI1 C UC3CC~3C
1825 5859 LJ~,FDCP, Q~L~G X ~A p~CAC~L~U6281 AALJC~.~CU A UGCC~AA
1830 5860 LJGOCAUUC C'~tIGFG X Q;AA 6282 aC~CU U GAAL70CLA
AC3CAL~L~C
1845 5861 UtJ~JC7C~ Ci~L~G X AAA PLX~Q~JG6283 CRCDO~LT A CAAAC~G'4A
1859 5862 WOCAU<.~ CT~G X OC~A AGL~JC 6284 GAAp.AAQJ A L~L~;~A
1861 5863 AUt~J CUG~G X CAA AUPLt7UW 6285 AAA~IJ C AUOGAAAI1
1870 5864 UUOCAL~A C~AI7GpG X QUA AWUOCAIJ6286 AL1~AAIJ A WAUOCAA
1872 5865 A(I~C~I1 CT~G X CL,~p, p~(JWCZ6287 a~~AAAL~J U pI~,AAL1
1873 5866 P,AIJtAJOCA CMG X CAA AAL~JI7C6288 C9AF~7(J A UGCAAAW
1881 5867 AALJCUC33G CL~L~G X ~A AUUCx3CAIJ6289 ATJC~CAAAL1 U
NCAC~1LAT
1882 5868 AAAL~7C'~ CUGAUGpG X QUA 6290 (~AAAW C OC~GAL1UU
p,A~~,
1889 5869 L, CLOG X Q~F, AtJC~JppGp, 6291 UC~OC~IJ U Lfi,~~A~C'A
1890 5870 LR7C~~JC C~I~G X Q.~1A AWJC1~3GG6292 CLCAGALHJ U GAAC~A
1903 5871 AAt~G CLOG X CT~. AIJUIJ~7I~16293 Af~AAAAtT A Ci~AIUU
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
Table VI. Hammerhe. .ibozymes to IRF-2
127
1906 5872 L~AAiJt~, CI~Ai)GF~ X aGAA 6294 AApp~ C
~WU
1908 5873 QJI~,GAAL1 CRAG X Q~p, FC~U 6295 AAL~U A pC7t~"~C
1911 5874 CL70~G C(JC,AL7GFG X Q~1A 6296 ACU~~ U ~p~
AUC~C~L1
1912 5875 iJCTJC3~JC~ CUGAIJ~G X CC~A 6297 (7 C ~~,
AAUt~GF~G
1914 5876 OCCJCLJC3QT C'UGALJGAG X 6298 CUAAUUC.U A ALCAC~10C
Q~F. PC~AC)f~G
1928 5877 AAAL~AAA CT~G X Q;AF. pC~~JpCV6299 PGCAAGC<J U LJf1
1929 5878 AAAALTAAA CTJGAL~FG X CC~A 6300 C3CAAOCW U DUCT
AF~C3CUC~3C
1930 5879 AAAAAL~A CUGAIJGAG X 4;AA 6301 CAAGCUW U t1
AAFDCWG
1931 5880 AAAAAALTp, C~L~FG X q~F, 6302 AAGCTJIJW U L~1L~J
AAAAOCLR1
1932 5881 L~1AAAAAL1 G X QUA AAAAApaT 6303 PGCWCTW U ALTUC7IJWp.
1933 5882 ALB~AAAAA CUGD,LJ~,G X Q2~A 6304 C~TJt7UU<7tT A
AAAAABGC TJU(xTUt~TT
1935 5883 C~LmAAA CC~P,L7G~ X CJ3AA 6305 UtlU<JUC~1 U LIUClUAL~C
AvAApAF,A
1936 5884 C7~ALL4AA Cite X ~A AAL~ApAA~,6306 C1W~7U U U~;~,
1937 5885 CLX~I~F, ~7G~7~ X Q~F, AAAI~,F,A6307 U G
1938 5886 CCT~,L~, CT~I~G X pGAF, AF,AAL~,AA6308 t?UVAUtA7IT U
L~.~
1939 5887 0.'~~,L1 CLJGALJGFG X pC~A 6309 LTVAIJWIAJ U AT.~OC~
AAPAAL~F,
1940 5888 CLCCUC~L~1 CWALJGAG X CGAA 6310 L~,UC~J A vAC~p3~
AAAAAAi~,
1942 5889 UCTCLCCZJG CT~G X ~A AL~AAAAF,6311 UUWUtiALJ A CAOW.7AF.
1952 5890 GAAIi~AAA CLOG X CLEF, ATJUOCCCU6312 Appp~ A
1954 5891 UUC~ALLAA CMG X O~A ALmUIX,7CC6313 QO~AL~U U U(~1LAJC~A
1955 5892 CC1~F1AL~~ CT~IIC~G X QUA 6314 C3Gp,ALIFIi)U
AALp~I7UpC U L~,I7~AG
1956 5893 ~il~AAiT CUGALJGAG X SAP. 6315 C~AI~JUCT U AUUCAAOG
AAAL~1C
1957 5894 ACCUUGAA CU~G X CGAA AAAAI~W6316 A~~ A U~,p~
1959 5895 UI~XTR~ CC1CAI~~G X ~~A ALTAAAF~6317 L1AIJUI1UAIJ U
CAAGC~A
1960 5896 UCI~CUtJ CLOG X ~ AAL~AAALT 6318 ALTUCIUAW C AFaC~~AA
1966 5897 L~AAWU Q~G X Q~F. PLZUU~A 6319 Ll~AAOCU A AAALJUCOA
1971 5898 UCmIJUi~?G CtJGAL~G X QUA 6320 C~I:AAAHIT U ~A
ALJ~.~OC
1972 5899 LJUUAL1CH>p. CUGAiIC~,G X 6321 C~AApinT C L~F,ALmAA
Cc~F. AAIJUtliJAC
1974 5900 AI7C1UC1AIAT CUC'~IJ~G X 6322 p,~7CU A A~,pp,~
QUA AGAAI7UUCT
1978 5901 UUAUAWU Qf~G X p~A p23 ~ A ~
1983 5902 AACAAUI~, ~J~G X CAF, AC7~7C16324 AW~AAAI7 A t~A~JWCT
1985 5903 AAAFL3~A1J C~LT~G X C~1A 6325 L~AAHL1AL1 A ALA~J
AL~LAJ~
1988 5904 L~AAp,AAC ~G X CG9A AWp,L~J 6326 AAIl9t>AALT U
~JC~
1991 5905 AGAImAF,A Q~G X pc~A ~ ' 6327 AI~AtA~1 U UUUC~L7C~1
1992 5906 APGAI~,AF, Q7~,G X ~F, AAC9AIJUA6328 L~AI1UG~T U LAR)AtJC<JCT
1993 5907 AAFC~LB~F, Q~G X Cue, AAACAAUIJ6329 AALIUQJI7U U UC1ALJUU
1994 5908 Ap,AAC~i~, Q~G X CAF, AAAF~ALT6330 AL1UC~JUUI1 U
UALTCTJWU
1995 5909 GAAAA~ C~,UG~,G X C~ ~ 6331 LlU~UtJtT U ALJC1'JUUUC
1996 5910 AC,AAA~C~S C1G X ~A AAp,F~AAC~,6332 UC~J~JUUCT A L7CUtitJC~J
1998 5911 Q~,AAp, ~G X C73AA AIIAAAAAA6333 LAJUU<JC~IT C
LC
2000 5912 ~,A Q~G X C~1A AC~L~1AA 6334 LT~.tT U WCt~G
2001 5913 O~T~. CLOG X 0.3AP. AFC~I~AA6335 i)UCL41;JC~JfT
U I~4GC
2002 5914 UC~CC~ CMG X ~1A AAFGAI~F. 6336 W~TTCTJUU U CL~C~10C'A
2003 5915 (A~ C1~G X C~A AAAAC~L1A 6337 UALJG~JLAxJ C
UPCpLaC~IF.
2005 5916 AL7~CUG CUGA1C~AG X CGAA 6338 LJC~Al<JUC~T A
pI~.AA~ C~~AAiJ
2014 5917 AAAUCt~ ~ X QUA AC1(Jti'3Q~ 6339 CAGCAAAIJ U Lmt~AtJ~7IJ
2015 5918 AAAAUt~IiT ~G X Q~, pA~.T 6340 AOCAAAW U AI)1
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'Table VI. HammerhE Ibozymes to IRF-2
128
2016 5919 L1AAAHL7C~, CC1C~L7G~G X 6341 C~AAAUUU A UAAUUC7CL4
~A AAAIJUUOC
2018 5920 CUI~AAALT ~ X ~A AtiAA~L~JU 6342 AAALnJCLAU A AIJUfJUAPG
2021 5921 aAL~JC~A CL7GALlC',l.~G X 6343 UUCL~L~,ALT U
fir. ACn.TAI~AA (7f~AGALRJ
2022 5922 GHALICL)f~ C~L~AG X O~p, 6344 L~p~U U L~)UC
AAUC~L~p;
2023 5923 Q:~AL1C<7C1 C<7GAIJC~G X 6345 C~L~AWU U pp~7pC
~A AAAUUAUA
2024 5924 PL3C~PTJC1T CTS X CAA A 6346 AL~~AUWU A pG~JCCU
2029 5925 PC~AAPL3G C(7GAUGFG X CC~A 6347 UUfl9P~AIJ U CC~lUt7UCT1
AL~Ap,
2030 5926 AAGAAAPG CLOG X CAP, AALJ~7(~,A6348 UC~F~C~W C QJUlJUCW
2033 5927 AACAPC~F. CL~U~G X ~, pa7 6349 AC,AUWCT1 U LJ
2034 5928 AklrY3~AC,F. Cf~9LJGAG X 6350 G~WCCT.1U U L~T~JtJ
Q~P. ApC3C,AAIJC
2035 5929 LIAAACAFG C~JGFG X CGtIA 6351 AUUOCUUU U CI~JfJC~.
AAF~~AIT
2036 5930 ALmAAC~IA C1~,G X D~F. AAAFD2AA6352 UC1CCLJUI~7 C
UUGUUf~IJ
2038 5931 LJC~L~AFG CLfi~L7GAG X O~A 6353 C~.LA~J~JC.U U
PC~AAFY~ .
2041 5932 UOCLJCAI~ CiJGAI7C~ X GSA 635,4 LET U L~IJC~3Cp.
AC~AGAAA
2042 5933 CT~CT~LT C~JC~G X CC~A A~a~p,~,~,p,6355 L~7U U ALX~O~G
2043 5934 PLTx3~ Ct7C~G X QUA AAACA~. 6356 L7CLn7GUUCT A
LJC.~DC~T
2045 5935 CAPLL7C3CU CT~AUC~G X CGAF. 6357 UU~LT C PDC~TJ~JG
AL~AFI~F.
2052 5936 C~AL~AC CvC~G X C1~A PLZJGCpGA6358 UCAOCPL~~J U GUI~C
2055 5937 GAI7C~PS1 CL~C~G X ~A p~P~JpC6359 OCPL~C7C~J U AI~I7C
2056 5938 aGAIUC~.~F. CUGAi~G X CCAP. 6360 C~1I7~T A tuP,CAL7U~
AAC~1PQJG
2058 5939 AAO~I~J C~LJGF~ X OC~1A PAC 6361 C~JC~7C1ALT U
P~~UCCZ7f7
2059 5940 ~,p~ ~ X ~ ~~ ~~ A ~~
2063 5941 aCC~FG CU~AL~G X O~A AL~1AL~6363 L~L~IT C CUU~3C
2066 5942 tx~x~C~C c~G X Cc~,A ~OC~t~.6364 U~CU U az~cl~CA
2076 5943 L~AAAAAF. CTX~tIC~G X 4;~A 6365 UOC~7~IJ U UUWUUC~.
AZ~~.
2077 5944 UUAAAAAA CMG X OG4A AAI~JOOC6366 03C~U U L~A~F.
2078 5945 AvUAAAAA CUGAIJGFG X ~A AAAL~6367 ~I7U11 U LJ~JI)(1C~1AIJ
2079 5946 AAL)CmP~AA CI~IJC~G X CAP. 6368 1 U UtnAB~AtiU
AAAAT~JG
2080 5947 AAAU(~AA CUGALJG~G X O~A 6369 PL~WWU U UUU9AiJUfJ
AAA1~J
2081 5948 AAAAUC~A CT~G X CC~1A AAAAAAiJG6370 CAUWUUU U UUAAIR7W
2082 5949 CAAAALJUA GZ7C~G X ~ A1~AAAAAiJ6371 AUC~tJUUU U L~AUIJ~A7G
2083 5950 PCAAAALJU C<J~G X 0.A AAAAAAAA6372 L~JC~JU U AAUUUIXTJ
2084 5951 L~AAALT COL~t7C~G X ~A AHA~AAAAA6373 L7IAl(~T A AWUU~
2087 5952 CU~CAA CUC~I7C~G X CAA AI7UAAAAA6374 LA7UIJUp,AtT U
UC~AAG
2088 5953 a~ ~G X ~. AALJUAAAA 6375 UUtJUAAW U L7CUAAA~G
2089 5954 PIJQAJU~1C ~G X O~A AAFT~AFr6376 t~Ai7UtJ U C~AP~3J
2092 5955 L1UI~1LCW ~ X ~A PCAAAAL~J 6377 AAI~T A AACd0UCi9A
2108 5956 dLZ7C~L~F, CZ7C~J~G X OQ~A 6378 AAAAA(~CL1 U tJI~C
AOCLTUUUCT
2109 5957 POC~I~. CC7GALfi~G X QUA 6379 AAAAGCW U LQJ
AFL3CJtT
2110 5958 C~OQJCAIJ Q~IJC~ X CL'~F. 6380 AAAC~CT~JIJ U
AAAL~7W ACX~10~7C
2111 5959 LJGAO~ ~IICAG X ~'~,P. AAAAQW6381 A~O~J A I7C~OCL~A
2118 5960 UOCU~I1 CL~L~G X CC~A AOC~Lm6382 UAI~O~J C AL~.T~C'A
2121 5961 C-A~C~. CT~G X Cc~A AL~~JC 6383 GADC~.iT C UFC~AAUC
2123 5962 CLJCAWOC QJ~L7C-AG X 0..A 6384 ~L~J A OCAALJC~G
PC~OC
2129 5963 C~,AAAt7CTT CL7C~TJGFG X 6385 CCZ~ALT C P~7C
C1~F. ALA70Q~G
2134 5964 CAC1~0~1A CUCAIJ(~G X QUA 6386 AAI7C~t1 U UUC7
AI7C17G~1
2135 5965 C~~1 CZJ~G X QUA AAtJC~IJ 6387 AUCPGAU(J U UO~JOG
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Table VI. Hammers. .tibozymes to IRF-2
129
2736 ~ 5966 ~ t~c~ X a~,A AAAUC~, 6388 L~U~7U U acu~c~.
Where "X" represents stem II region of a HH ribozyme (Hertel et al., 1992
Nucleic Acids
Res. 20: 3252). The length of stem II may be >_ 2 base-pairs.
CA 02364577 2001-10-03
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Table V1I. Hammerr, .tibozymes to CDP
130
Seq. S~betzate
LD.
LD. Pb.
33 6389 PG2L7C~3Cp, Ci~AIJGF;G 6929 CC~33.~ACr C 2C3CC~
X QUA ~CpG
48 6390 CPC CZJC~AG X CC~A ACALTOCAC6930 GPp:~ T GICI~C
55 6391 ~C~ CtX;AL7GpG X O~A ACJ3C~F.6931 TIGI~CD'I' A 030.~GF~
69 6392 CT~JC CL7CAIJC~G X OGAA 6932 PL3CCACITT T GApGAGpG
ACCi703CtT
82 6393 C~30~L7C Ci7C-ALA X OC~A 6933 AC~AACr C GA~GOCAC
ALT
100 6394 UC71700CAA CUC~UC~G X 6934 O~,p~T A Z~pC~
CGPA ACC~C
102 6395 ~Ox CLOG X CuAA AL~1COCTnJ6935 AA~GTAT T C30CGAACC
132 6396 CI;L~7G CL~JC~G X Ct;AA 6936 ~ C C71C~AAOC
pLUp~,
145 6397 L~7CIJ~LT CiJC~L7C~G X 6937 AAG0.30CT T A'ICJGAACp,
O;~F, PL3000C<JCT
146 6398 CUC~JIR~ CL7C~G X OC~F. 6938 P,GOfh~-1T A ~ACpG
AFL3COpCLI
148 6399 CL~C~UC CZ~G X CuAA ALglpppCV6939 ~C~'~AT C GAG
165 6400 ~,G X ~ p~~ 6940 N30GAGT T CApGAI~A
166 6401 L~UU Q~AZ~G X C73AA A~('~6941 mO~GIT C AAA
179 6402 AL~JC<JG Q7C~GAG X aGPA 6942 PGAACACr C CF~~.T
pGI~7CU
188 6403 CWOCOCp. CLOG X ~P. AI~JG6943 CAG~AT T 'I~30C~CAAG
189 6404 aCUJOQ3C Q7~IJC~G X CGAA 6944 AGA0~2T T 00.~AAOC
AAIJCCUCU
202 6405 POCZ33C3C CL~~G X O~A 6945 AAGCFL~T A QOOC0.L'T
AOQJOCtJU
221 6406 UOCC1U0~. QJG~AL1C~G X 6946 'It;AFGpGT T 'It7CAA0~1
CC~A PLI~JCA
222 6407 CUCCUI~ Ct7G~ X Q.~ AACiJCtAJC6947 C~,p~T T ~pp~
223 6408 UCLJC7CZnJG ~G X gyp, 6948 AAG~GTIT C Cp,ApC~,
AAACOLUU
235 6409 ~CAL7C C1~LJC~G X ~ AIJC~JOC6949 a~FGAG4T T GA'I~L'r
248 6410 CIT~Jt? CMG X O~A PG~OUG 6950 ~ A AAAGAAOC
~5 ~ A~I~FL~1 CLJ~1UC,~G X 6951 AFOC~GCT T 'Ir'1'IC'~AT
0.A POCUOC1JU
6 ~2 ~L1U~FG Ci~IJGAG X ~F. 6952 FOCFLL'iT T CI~AA1G
AA~.T~LTJ
277 6413 ACAL7~F, CLOG X QUA AAAOCII3C6953 OCAOCTIT C TI~AZGT
279 6414 PC~WC CCI~1UGAG X O~A 6954 PL3CI~I~T T GAAZGIC.T
pL~AAO~J
286 6415 CL7UI~, ~G X Q~F, A~ 6955 TIG'AATGT C ~AAFG
288 6416 AIJC'IAJIJ(h Q~G X Q~, 6956 C~1AZG~C,T A CAAAAGAT
p~
297 6417 a~,p,I7C ~ X ~ ~ 6957 CAAAAGAT T GAT~03
301 6418 dO~CC~JC aJ~G X O~A PI~AL~T6958 pC~T T GAOGi~
3~ ~9 aG~ QI~G X Q,~A PU3JC~Ai16959 ATI~O;,T C OC~ATL~
314 6420 t7C~3~3G C~I7GFG X O~A 6960 TCOC~AT C C~'A
AL1C~7~
319 6421 AAF~G Q~G X ~'~Fa ppp3C~iJC6961 GA'~,T A CCAOCTIT
326 6422 c~c~t7o~. ~G x a~ poi 6962 ~OCT T ~32~CZC
327 6423 O~AI7CC Q~LX~~G X CK~A 6963 AO~OCTT T ~~T~'Il7G
AF~TJ031
332 6424 Q~7p0~. Q~L~G X CAA AIJOCAAAG6964 CTI~T C 'IL7C~~G
334 6425 tpC~C QX~G X tTz9A P~LJC7C~A6965 Ti~C.T C OC~OCA
346 6426 IJUC.~3CUG CfJ~C~AG X 6966 CAO~PC~ C CAOCIrAF.
C1;AA P1~7~
352 6427 UOCAC(7C~1 ~G X 03~F, 6967 C'lCx~OCT C AAHGI~C~.
.~C~~J~G
374 6428 tJ~P. C<J~L7G~G X ~?A 6968 'It3CA0GAT A '1'iGAAACA
ALI~JOC~
376 6429 UCT~JWC ~G X QUA AI~t7mUG6969 C~OC~TAT T (~AACFL~r
397 6430 ~CCI1 CT~G X O~A PGUC1C~ 6970 C~AAACr T AC30~~AAC
398 6431 P1~7UUl7pC Q~T~G X ~A 6971 ~1GAAACIT A C~0~1AAGT
APL~7(JCU
407 6432 UUCUUC1C~ Q~J~G X ~A pC~TJUU~C6972 a3GAAPL'r C TO~A
417 6433 0CUC~TJC~1G X OC~F. .'9IJII~6973 O~FL~AAT A C~FflG
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Table VII. Hammerh~...._ ~tibozymes to CDP
131
429 6434 CUIX~, C~7~ X QUA AUUUCWG 6974 T ~~
430 6435 ACC~C CUGAI7GpG X 0~1F. 6975 AA~A~ T Q
AAUC10GW
446 6436 AACCUCUU CZ~L~AG X O~A AUUUUC7C,A6976 ~ C p,~GAp~
454 6437 L~JC~IR~T Ct~,t~ X gyp, 6977 CAFC~3;,T T A~A~,F,p,
p,C~
455 6438 L~LJC~ CT~7~G X ~A p~ApCC~JU6978 A~~ A CAA
460 6439 PGUOCUW ~G X CQ~A AL~C 6979 ~~ A p,~C~
469 6440 L~L~,TJU~T CLJGALIGpG X 6980 AAHOCACT T ~G~A
~ p(~7pq~
470 6441 L~U CUGAUGPG X ~'~P. AFL~7GQJIJ6981 AF(3CACIT A AAG~AA
481 6442 LCi7GPT7GAG X C'G~A pT~ 6982 G~,pp,T C CGpGAA'I~.
489 6443 t~JUC~ CL~,G X CC~F, AI~G 6983 C~FC~.AT A T:~P~.
523 6444 UC~F~,GC CX SAP. AI~C~1C 6984 GAA~T A Q
527 6445 CTJUCLTCAA CLOG X Q;rIF. 6985 ~pCr C
ppCCmL70G
529 6446 UCCUUCiJC CMG X Q~F. PC~~IJ6986 A'IAOC'IrT T C~C,
546 6447 CAL~T CLOG X ~ 6987 P,C~Cz~FGT T ACpGAATG
547 6448 (~AUC~L)G X CGAA AAC~7G 6988 CFL~1FGZT A
558 6449 UUUC~CA CLJGA~G X CVAA PQ7~7C6989 ~ T ~~,
559 6450 (~T~3C CC7CAL~G X Q~F. AF~LRI6990 PA'Ir~.-TT T aC~AAA
597 6451 PDC~T~C~JG CZ~AL~ X CAA 6991 p~ C CrpC~
PL~,I~T
606 6452 ~OCCnJU CC~,UG~G X ~ P~JG 6992 CAOCACCT C AAFL~C'IT3G
629 6453 CUGAAOCU C~I7I~G X O~A AL1C~CLJC~G6993 CIC~.T A p~GI~G
~4 ~~ AG3~JG CLOG X CGAA PIJC~ 6994 CA'1'P,AL3sT T
CAG~OCT
635 6455 UPL33CUCZJ C~IJC3~,G X CAA 6995 A~3IT C PL~DOL'TP.
AAOCUUALT
643 6456 aCL~IUOG C~JG~G X QUA .~DC~CUCxIG6996 CAC~L30Ci~ A CAAAC~OC
~
665 6457 UCl~n7C C~L~ X CAA ACJ 6997 AAAAAPLT C C~AL~A
675 6458 O~AAt1 Q~G X O~A ADUC~JI1 6998 AAC~AT T ATr2C~
676 6459 PL~~,A CMG X CGAA AA~J 6999 AC~A1T A TI~IGFLGT
678 6460 t~D~ CL~L~G X Q~, AL~AIJC~J7000 pC~T T ~,~
679 6461 UUCAOQJC CUGAL~FG X CX~F. 7001 (~ATIATT T C~CTGAA
AAI~AIJtIC
696 6462 C<JUC~ ~G X ~, p,~~ 7002 AAOCAAAT A O~G
710 6463 CT7WOCAG C<J~IJG~G X O~A 7003 API~,ApLT A CT3C~AFG
PC~7~JlJ
730 6464 ALA Q~L~G X ~A ALA 7004 C~F,T T Q~AA1GAT
739 6465 UC~L1 Q7GAL~G X ~A At~LJUUC7005 C~AA~AT C ATG~GA
751 6466 QOOQJtJI7C Ct~L~G X N~~A 7006 A03~7GT T GAAAOQ3C
pl3C~J
782 6467 Q~ ~G X CG~ ~,pCU 7007 P13GIOOGT C PL~GF~AG
801 6468 c~A7NCW Q~G X CC~A PC~7CTJOC7008 ~.T T AFCaa~AAC
802 6469 I~CLx1 C1~IJGAG X O~A AFO~)C<JC7009 C~'IT A AO~.
814 6470 D0~ ~ X O~A FC3~ 7010 t~AC~OCT C 'Il~~:I'~3C
.
816 6471 UOO~IJ QJG~I1GAG X CAA P~DCC1C~J7011 PC~DC~C.T C A'I~OC30CA
'
819 6472 c~0' ~AL~ X C~F, AI~,pC 7012 aC~T C 03~AZC
827 6473 G'~33GAGZ1 QJGAL~G X ~ AL1~0037013 0300C~AT C PL~LOCIC
831 6474 C~CUOC~L~ CI~I7GAG X ~A 7014 ~ C C~ICCPOC
p~JG
835 6475 (~~ ~ X ~ ~~ - 70~ ~~ C CAOCT~30C
846 6476 aGAI~T Q7C~~G X AAA AGGOCPDC7016 C~CI03Q.'T C PLPC~
_
8~ 6477 OCCUt~TJG CZ~IJGAG X ~A 7017 TC~,T C CPC~3C
ALA
883 6478 hOCPaLJC ~G X CUAA AL~30CI~7018 CA03CCAT A C~I~GT
900 6479 C(~1L~3CUG C~L~G X CGAA 7019 C~CT C CAOCCTAG
P0030~7C
[ 907 ~ 6480 ~ LJC~pLUUC CMG X CGAA pp3~,7020 1DC~OOCT A C
~
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WO 00/61729 PCT/US00/09721
Table VII. Hammert. .tibozymes to CDP
1'i~
913 6481 a~ ~ X ~ p~ 7021 CTp~,p~ T ~y
918 6482 L~p~ ~ X C~ ~~ 7022 PGTIGAGr T Q~CP.
940
6483 PAC ~ X ~ ~'~ 7023 ~O~C~T C pC~p~CT
970 6484 CCJG3CCUG CZ7~7~G X CGAA 7024
982 6485 ,~~~ 7025 ~,p~ C ~~.1,
1001 6486 P~GCUI7t~~1 X ~, per' 7026 ap(~~ T ~pC
1002 6487 c3CV0pNG C~ X q~ C 7027 aC p~OC
1015 6488 C3pC~ X ~ ~~ 7028 pG~ C
1017 6489 PC3CU~ CL~C~ X pip, p,~~ 7029 CCA~.T C Ac~DL~I'IG
1024 6490 CAAGCUQT ~ X ~, p 7030 TCAG~OCT T C~C~,
1057 6491 t~t7GC<7C ~ X ~ pp~ 7031 Ap
1078 6492 P~ X ~ p~~ 7032
1095 6493 UOO~T~tT ~ X ~, p 7033 app A ~q~
6494 0.'~7C7CA ~ X ~ p~~ 7034 T
1.124 6495 C~7tICAG CUGAL7C~ X QUA 7035
1131 6496 AL7~UC~G 7036 CAn3;,pGT T T~GT
1140 6497 O~C~, C~7~ X ~ 7037
1141 6498 PLTJp~G X ~ p 7038 p~~~ T ~p~
1149 6499 ACA X ~ ~~ 7039 T~LCC~T C 0~33c3p3
1197 6500 C~UpC X ~ ~C~ 7040 c~~C,.~GT T aC2Ca~GA
1215 6501 03~ CUGAL'~G X C1~P, pL~~,7041 GAAC~C.T C OCIDCFGT
1224 6502 L~C ~ X ~ p~CAOC 7042 C~~ C
1246 6503 ACC~;~pC X CG~, AOCOG(R7C 7043 CTQ~3C,~,T C Tt~ACpG
1248 6504 ~ X ~ p~~ ~ ~,~ C
1269 6505 ~ ~ X ~ ~~ 7044 (~p~ C ppp~
1304 6506 CL1CT Q~G X ~, p~p~C 7045 C appp
1317 6507 c.70CL7pp~T X ~ p~~ 7046 pC~T C TIZC~O~
1319 6508 ACC ~ X ~, G . m3~TCT T 'Ir~CC
1320 6509 ~,A ~ X ~ ~~ 7047 p~ T ~~
1334 6510 C~O~DOC~, CUGALx.~G X CGAA7048 CC~C~T C CI~'~G
1337 6511 Pl~t7CJ0~ 7~ CC~ T
1338 6512 appC~C ~ X ~ p 7050 ~CIT C TC~C
1340 6513 QJGAGAFG Q~ X ~, pp3ppppG 7051 C'IdCI'iCT C AGIZC~
1344 6514 ~ X ~ ~~u 7052 T appCp~p,
1370 6515 ~~, ~ X ~ p~ 7053 .~GCAGOCT T
1371 6516 Ca33G9AQ1 CC~X~,G X ~, ' 7054 ~~ C ~,Tp~,.~,
1376 6517 p~p~ 7055 ~~ A
1379 6518 L~ppC ~ X ~ p~ 7056 C~,e,CT A A~pCA
1385 6519 F~,LA~ CU~,~ X C~ .~GOCt~Q17057 C~;~T A CMG
1395 6520 L~ X ~ p,~pp~pC 7058 p~ T ~
1396 6521 A~ ~ X ~,p, p~~ 7059 C~GTr C ~OC~C3C
1398 6522 (~ X ~ pQ~ 7060 ~ C pp~p~
1410 6523 ~ ~G X ~ pp~ 7061 Ap00C~T T A~,AG
~ ~ X ~ p~~ 7062
a~ (X ~ p 7063
CCOCUO~T Q~G X 4;~, G
CT~~W ~G X ~ p~CU
1411 6524 UCZ7IJG~L.fT C~JC~I7~ X 7064 O~IT A PGICAFG~,
1415 6525 ~, p,~~C 7065 CRAG)' C ACT
AAi~1 Q~L~ X ~ p,~pC
1422 6526 PDCtJGAAA CUG~7~G X ~.~F, 7066 T ~,p~
,
1423 6527 C~OCUGAA CUC~I~G X ~,p, 7067 T ~
A~7G
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
Table VII. Hammerh, .Zibozymes to CDP
133
1424 6528 TJGFDCIJC~ C~L1G~G X Q~AA 7068 Ap~~ T ,
AAFQ7CW
1425 6529 AL7C~L3CCJG CUG~JGFG X 7069 PCB T CFDCIC~.T
CC~A AAAAGUCTT
1426 6530 GAIJGAO:L1 ~ X Q~P. ~AAAPQJC7070 T C pp~
1431 6531 C~C~JJ CUB X O:~A r'~L3C.ZJC~AA7071 TI~p~T C t~CT~',
1434 6532 UC1C3CCF~ CI7GAL~F~ X CAA 7072 CAOCIC:AT C C~IC~3C~A
AL7~G~7G
1453 6533 aCC~:OQ3G CLJGAt7GF~ X 7073 CCCAGCCT A CCOCILOC
QUA PL~CUC~3G
1463 6534 LTC~TJC.~G CL)C~(~GAG X 7074 C~CIC3CGT T C~GA
~A pI~CFD3G
1464 6535 UIJCCCJ~P. C~ALJC~G X Q~1A7075 CC'I~'3C3CIT C
AF~DCCFC~G '~,A
T466 6536 WUUCCUG CtTG~LIGFG X aC~IA7076 'IC33C3CTIC.T A
PGAAC~!C~ C~AAF,
1476 6537 UC~ALL~JOC~ CCJG~G X Q2~A 7077 pp~~T T ~C~,.~,
AWUIJCX.TJ
1477 6538 WC~C~ CUr~JGFG X Q~p, A~UUI7pC7078 aT C~
1483 6539 pGpG~ICT C~L~G X AAA p~,AA7079 2T~,CT A AAC~T
1488 6540 oGF~F~. CUGAIJGaG X ~A 7080 ACTAApLT C ~'I~C
PQJUUPQJ
1490 6541 CUC3~A CiJGAIJGF~ X CAA 7081 C T~C~G
PC~tJUUA
1492 6542 CpCi7C~ C<JGAUGFG X CAF. - - AAG~'I~T T CIC7CP1~
PC~?C,A~J 7082
1493 6543 C~CC7C~A CL7C~G X AAA AFG~J7083 p~
1495 6544 L7C30.~JG CLOG X Q~AF. 7084 'I~~ C CF~C~3CA
PC~AC~AC~.
1507 6545 C~C.TZ3CAC1 CC~1I~FG X 7085 ~pCT A A~~
0.~AA PL~~OOG
1515 6546 P~L~C,AAG C~C~G X ~A ALL~U~J7086 AA~C~GI' C CrI~.'l~Cf
1518 6547 U~?C~~G G X ~A AO~LLTX3C 7087 ACT T COCA .
1519 6548 UC~AGLTr: ~G X Q~P. APD~~lCt~7088 CAGZCC,''IT C TPL'ICCAA
1521 6549 CCUUC'~GpG CUG~LJGFG X 7089 GICCTItT A CIC~CAAL~
QUA PC~1F~C
1524 6550 L~GCCLnJG CX CC~A P~AG 7090 CTICTPLT C CAFOOCTA
1532 6551 UUOCUOCA CLOG X CC~A PL~2tAJOG7091 ACT A 'n3~
1561 6552 X ~ p~~ - -70~ ~~AT T
1562 6553 C~C7GAAP. CL~,(~G X OGAA 7093 a~GA2'r T TITCAACA
AAL~JpC
1563 6554 CCLOG X CC~Ip, p.F,AL~t~ 7094 CATL~TIT T TIC~P~G
1564 6555 p~7~, ~,G X ~ ~ 7095 A~TIZT T 'IC~PL~3G
1565 6556 ACCi~,UUG C<JC~G X p~F, 7096 '~.TITTT T CAPpDGI'.
P,AAAPTJ~.
1566 6557 GAOCUC1JIJ CLOG X QUA AAAAAAUC7097 C~TiTITT C A~1~
1574 6558 aC~I7G ~G X CAA P~JG 7098 CAACAGGT C CA~GC
1578 6559 WC~70CUG Ct7GAIUC~G X O~A 7099 pO~PCrAT A C~A
AUC3GAOQJ
1590 6560 AAGAL'~L7G ~,G X aGAA p1~7~7100 CP~,ApLT C
1594 6561 UOC~~A CUGp,L~G X O~A ADOGF~J~T7101 AACIt~CAT A n'ITCOCA
1596 6562 UUUCOC~. Q~G X CL~a AL~IJ0~1G7102 CTfX'ATAT C TI~AF,
L598 6563 ~G CLOG X O~A PC~I~Lx3G 7103 CCA~TCT T COCAAF1,T
1599 6564 X ~ p,~,~ 7104 C~TATCIT C CC~AFG'~C
1607 6565 UIJ~PTJG CLOG X ~A PGVW03G7105 0.~CAAAGr C CF~T~F,
1611 6566 UUUC~7t7C~J G17GA~G X O~p,7106 AAG~C~T T ACAACAAF~
p,Up~W
1612 6567 CL~1C)G Q~UG~ X ~A AAIJOC~C,U- 7107 AG'I~CATT A CAPG9APG
~
1630 6568 AtJOCC~fJ CLX~IJC~G X QUA 7108 ~Gr C AAZC~OCAT
AC~UC~O~
1647 6569 03CU00~ CMG X AAA AL~3CC 7109 ~OCCAT C C~CC
1659 6570 C~GL1W~1 CLOG X O~A ALT~3pCUG7110 CAOCCFGT C PGAAFGIG
1678 6571 CC~.TJ00~1 CT~7~ X O~A 7111 O~~T C TOCC~3G
PmCL100C
1680 6572 CUCCCUC~ ~G X a:~A PGAOOCUC7112 GAGOGICT C ~D3~G
1711 6573 U00.~C C<JC~PG X QUA AL)IA7CTJOC7113 O~AAAT C 000.mCA
1738 6574 UUC~JOCZ7U CMG X ~A AL7CAOCUG7114 CAGCIC~T T AFDCFL~F.
I
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
Table VII. Hammerh tibozymes to CDP
134
1739 6575 AU(X~CU CL~AIJG~G X ~A ~ALJC~pL~7115 pp~ A e~L3CAr~AT
1748 6576 UUC~JC~~, ~A~ X ~ ALnJGUC~CU7116 pGC~T A ~~p,
1750 6577 ~C ~ X p~ z~~ 7 ll7 Cp,C~,TAT C G~pC
1760 6578 WCu'4AAA C~AI~G X CAA ap~JUC~7C7118 GACAAp3r A T~I~3
;A
1762 6579 LK~JCCC~ CL~~JGFG X CGAA 71] C~~, T T~
AL~CC~C~ 9
1763 6580 ALK~COC~. CUGAIJGpG X ~, 7120 AAOGTATT T 'I~p:~L~IT
AAI~IpC~
1764 6581 Ar~IJC~'C~ C<JC~ X Q~1A 7121 PLGrATIT T CO~C'ATr
AAAL7A03J
1765 6582 U1~AUC~C CUGALJC,AG X Cx~,A7122 CGI~TTr C GC~C'AZTA
AAAAL~p;,
1772 6583 C~,ACACAil CLOG X Q~p, AL~pC~,7123 TCOGACAT T AT~IGhIG
1773 6584 C~~,ACA~, CX ~ A~~ 7124 Cz.3GACAZT A G
1779 6585 PCAL~KCC CLR~L7GpG X QUA 7125 TTA2~I~T T GpC~ICIC~T
AC~,C~L~A
1788 6586 ALCCL7IJGA CL~ X O~A AC~OC 7126 Q3GACIGT C 'I~,AOOGr
1790 6587 C~AL~CW ~G X ~Ap, pG~7C 7127 GAC~I~T C Ap~~GI~C
1797 6588 COCLJCFLG CL~LJ~G X QUA 7128
p,C~JGA
1810 6589 0~3CCFG CUGALJC~G X Q31A 7129 pp~~ T ~~
AL7CTJrz3CiJ
1811 6590 ~30pC~, ~ X per, A~3C 7130 GCGACATr C W3CCL~~
1835 6591 A~1C1 CvGAUGpG X O~ Al7t~.,C~7131 c~,2~AT A AACm~CT
1846 6592 UUC~~ Q7~ X C~A AGE 7132 C~I~ T C~~
1847 6593 CL~CAC CZ7GAL7GpG X C~~1F, 7L33 ~ C G~C~,G
AAC~
1863 6594 LTGTJIJGtJGA CL~JGFG X AAA 7134 ~pCCp,T T .
AIJC30CC7C~
1864 6595 ALK~JG C~~G X pG~ AA~C~ 7135 GAC~CCATT T C~PGAT
1865 6596 CAL7CTJUGU CZ7r~G X QUA 7136 PpC~TIT C ACAAGAZG
AAAUr33LTJ
1881 6597 OOC~ X ~, ACL~7C 7137 T ~~
1882 6598 UC~OG~G Q7G~,G X ~F, AACUOUW7138 AAA~C~Tr C CIC'I'CCGA
1885 6599 i7~pGp, CTJGAtJ~G X ~A F~APQ7G7139 (~1GPICCT C 'I~p;,A~,A
1887 6600 GCUC.7~I~7G QJ~LJC~G X ~1P.7140 GTIbC'ICT C 03AZC~OC
AC~OGAPC
1903 6601 P~C~3CCAG CLOG X Q~1A AI~JUC<7G7141 C~,~,T C C~CpCT
1912 6602 AUC3CCTAOG CTJC~U~G X QUA 7142 C~3C~CCL.T C (~'mOCAT
P~OC~~G
1916 6603 L~C C~7GALJ~G X QUA AC~3C~p~7143 ~CCzT A GCATCCAA
1921 6604 CL~T1C7G CZJC-Al:7C~G X 7144 aGTAGt~IT C C~OpC~G
CC~A AUp~
1943 6605 CZX~CxJG C'U~L7C~G X Q~1A 7145 GAC~Gp,AT C C~Y30CX'PG
AI~JC
1966 6606 UCCU~,AA ~.L1~G X AAA P~J 7146 AACpGAC~ A T~pp(~
1968 6607 C1JUCCUC~ Q~G X CGAA AI~Q~ 7147 c~,T T ~G~p,G
1969 6608 PLT7UOCUG Q~L~,G X 2~, ACT 7148 AC~'~T~ T C~G~~FGr
1970 6609 Z~~ X ~, A 7149 C~~TATIT C AOGAAGTA
1978 6610 ~ OCR;, C17C~G X ~A AC1JJUOQJG7150 C~G~pGT A C~AACG
1998 6611 UAOCiIfx~ CMG X 4~~AA ANCPT~17151 AAA~3C~T C 'IGAAO;~TA
2006 6612 O~JC~I7Q1 CLOG X AAA pL~CUC~G7152 C'~AAp~ A PCA2CPDC
20ll 6613 03~T Q~L~G X C~, A~pC 7153 G~AACAT C A~OC~7G
2023 6614 GAC30CtJC~ CLOG X a~lA At~3GU7151 PLOOp~.T C CT~OCL'~C
2031 6615 C;4QJCUpC Q~,G X ~F, pL~JppG71,55 CCX~G0.T C O~C~Y.'IG
2043 6616 CLn7~ CU~t7C~G X ~A pL~c~C 7156 GAG~p~ C ~
2056 6617 AtJO~CUU C1~IJGAG X CGAA 7157 GAAGCCAT C APGTCCAT
ALIGOCUUC
2061 6618 CL~3C~LJG C~I~ X ~, 7158 Q~P,GT C C~CTAG
2065 6619 UOCUCUPG CT~L~G X Q~p, AI~F,LW7159 AAGICCAT C C1.~C~L3CP.
2068 6620 GCUUpCUC QJC~G X C'~AF. 7160 'IL~CATCCT A GFflCP.FC3C
PDQ~Lp;~,
2089 6621 U3CFLUJG C~LJGp,G X U.~A 7161 P13~'~AOCT C C~PG'IC~CA
PL3CTJOxTT
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
Table VII. Hammerh, ;ibozymes to CDP
1ZS
2123 6622 LL30l7G~C3G CX pip, pmt 7162 CCCAGCCT T COCA
2124 6623 AL7C303G'"-G CL~UC~G X 7163 CC~CCTT C C'~p~T
2127 6624 ~A A~ppCUOG 7164 act C ~.~G
2133 6625 COGHUC~ ~ X gyp, ~~C 7165 ~p~T C ~~G
2148 6626 CGCUC~.'C~ ~ X ~F, Apps 7166 ~3GAACT C ~C
2161 6627 O~U~, CL7~I~ X Q;~, p~~ 71~ ~~T C ~~
2166 6628 pi)p~~ppG ~ X ~ p~~ 7168 CATLLOCT C CATLC~
2170 6629 OCAOGAL7G CC7GAUGaG X CGAA7169 Cp~T
2215 6630 i~ 7170 ~CLT C C~C'~3C
2226 6631 UGCUGC~G CL7C~JG~G X Q~, 7171 CCCIGCCI T AAFC3CFL~G
2227 6632 p~p~ 7172 CC.'IC3CCIT A APL~C
2244 6633 C~CPL3GCT~C C~AI~ X ~ papp~7173 l~LCAC~GT C C~G~G
2257 6634 CCUC~~J C1G X ~ pp3~G 7174 AG7~ACp.T C AC~A'IC~T
2263 6635 OCCt~C1 Ct7GAZ~AG X AAA 7175 A~p,OCAT C ~~
2266 6636 APD3~IpG 7176 AO~ C p,~~
C~L~X~G CL~I7~G X ~,p,
AGGAZ~T CUCX QUA p,U~ACtJ
Q33C~G CL7GAUGAG X O~,p,
AI7pC~~1
U~Gp~T CL~1LGFG X QUA paGAL7C~,tT
2278 6637 C~70~G C~ X QUA ppCCJC~pG 7177 ~~ T ~~
2279 6638 aQJOGAC~. CTJGAIIGFG X 7178 CCApp~-IT C ~GICC~
~A AP13CUUpG
2283 6639 ~~ G X gyp, AC~GAFL~C 7179 OCTIC.'IGT C CALC'ICnC
2289 6640 aCAIJOC~ ~ X pG~p, App 7180 GET C c3CCC~C
2307 6641 Q~CZ7G CL~AIfi~G X AAA 7181 (~pG~T C ~G~
AC~~7G
2313 6642 GAOC~3~ CiJGAUGpG X Q~p, 7182 GI~pCT A CCCALCIC
p~CUOGAC
2321 6643 GAI~OC~. CUCAt7GAG X c~AA 7183 p,C~,T C ~,~
PaC~3pC~J
2323 6644 C~AGAi~C CL~,G X CPA P,GAG(~X3G7184 CCAL~'IC.T C QO~CIC
2329 6645 LlC7t'1~00~, ~G X QUA AImOC~G7185 CICbOCAT C 'IC7~A
2331 6646 L~T~OG CC7G~ X ~A p~OG 7186 Cpp~ C al
2346 6647 C~ApCUC3pG C~U~G X ~,p, 7187 G~~
p~pGL~JC
2354 6648 C3GCC~G ~UGaG X pGAp, AGOG7188 COLT C C~IGA~C
2370 6649 aCAGAOCA CLOG X p~A P~00G 7189 ~CLT
2375 6650 C~lt~3GC~, C~7~G X AAA 7190 ~,.,T C T~,F,C
pQ~GG
2395 6651 UOCUfJUUCI . CZX~IJr~G 7191 0.t30CC~T C AAAiAAOC~
X OGAA P~3GOOpG
2447 6652 UUC~~3C~C ~,G X QUA AL1~3(Z7G7192 CAGOrT~IT T GroC~C~A
2461 6653 LAG QJC~LIGpG X QUA PmOC~7G7183 C~,pdppGT C
2553 6654 ~C~G QX~L~G X CGAA A~C31 7194 T3C~OCT C CIC17~
2556 6655 ~70CTJ~ CL~U~G X ~A p~pG 7195 ~p~T C ~~pG
2633 6656 CUI~OC~ ~I7GpG X ~F. PDOCLD3C7196 ~G'rT C ~,,pGn~
2648 6657 CiJOC~OCU CLOG X OGAA PLTIOppQl7197 pL~~C~GT C AGCIC~G
2653 6658 aC~OQ~ C~L7~ X ~Ap, pp~1 7198 p~T C ~~
2664 6659 Ci~.~C~C CT~TJC~G X CGAF, 7199 D~~T C G~~G
pL~,7pCC
2667 6660 ACUCUC~C CUr~II7C~G X CC~F,7200 p,O~T C
A~ppG7
2670 6661 PC~~,CUCLT C~U~G X pf~A 7201 C'R70TGuT C PC~GLACr
ApC~p~,G
2676 6662 C~CAG CLJGAUC~G X AAA PLC 7202 GIC~GF~T A C'1~;~
2703 6663 PEG X ~qp, ~p~
2709 6664 L~~G CMG X Q~p, At~p~C 7204 G'i~"~CC~1T A CIC.~'~c~,
2712 6665 AGCOC~JC~ CC7C~UC~G X CAA 7205 GLCATACr C CUPC~OLT
P~C~G
2721 6666 LJC~?C~L1 CL~~I7~G X a~F, 7206
ppLT~JpG
2732 6667 0.'~~ CL'~G X AAA PLi~pLU 7207 PGCIGFGT C 'IGA0030G
2781 6668 L7C~3pC~c~G CZ~t~G X p~A 7208 CL~CCAT C Cit700r7GA
AZJCaGCAGG
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
Table VII. Hammerh.. tibozymes to CDP
136
2784 6669 ~03G CCJC~UC~ X CAA pa~C 7209 pCC
2791 6670 AL7C~OGCAC Ct.~AU~,G X Ci3~A7210 ~G~T C ~~T
ACJ~3pGA
2802 6671 LJ090CUpG C~ALJG~G X CC~A 7211 pCCCA~
p~3C
2820 6672 033C~C,AOC X C~ pp~CWG 7212 (~, C pG~~
2824 6673 POOOOQ3G CtJC~G X QUA pppGFL~GG7213 CCC~GT C CC~CpGCT
2847 6674 PGACC(X~ CMG X a.~P, ACT~C<7C7G7214 C~Cp~;T A CG~G~
2854 6675 L~,L~ C(JG,AC~G X al:~lp, 7215
p~~,
2856 6676 ~~ ~ X q~ ~p,~ 7216 C~~3GICT A ~C
2862 6677 CCT~G CS~I~G X QUA p~g~ 7217 C~,~;T A ~G~G
2881 6678 C1~DCUC ~G X CC~A AC7C~GL~LJC7218 GACACCAT C GppC'ICPG
2887 6679 UG~30C~J CLOG X QUA pDQ~L1 7219 AZt7GAGCT C AL~CO3Cp,
2899 6680 UUUUOCUU CUGAL~G X CCAA 7220 CpGC~OGT T AAC3GAAAA
ACC~O~
2900 6681 CUtJWOCU C~AL~G X ~1A AACCL7pc~7221 CaOCAOG!'I' A
AOGAAp,AG
2926 6682 CtJCTJGOCA CTK~IJC~G X ~A 7222 AAC~p(~,T C 'IC3~GFG
AI~OI'~JtT
2938 6683 t~~~,A CU~T~,G X CG4A AL~T7CUG7223 CP~G~,p~T C TIl7G~
2940 6684 LJCi7t702~ CL7r~L7C~G X 7224 GT ~3~
CG4A PGAUUC<JC
2941 6685 U(KTX~C0.~ C1~LJ~G X CGAP. 7225 ~ C Q~G~,p,
APC~1L1UQ1
2964 6686 UOCCC.L~ CL~,G X O~P, AC~C~OCC~7226 aGpC~ C COCA
2977 6687 AI~'~7 ~ X ~ p~ppC 7227 ~,pCCr C papG~AT
2991 6688 C7C~~G CT~I~ X cT~A AC,~pC~;t7G7228 CAZC~IGT C COC~~1
3039 6689 LJC~1I7G CfJ~ILIGpG X Ct;~A7229 AGA~pC.-r T CA2~pp~
pa~C~LT
3040 6690 AL7~GAL1 C~tJC~G X CGAA 7230 GAAL~CTT C A'ICCOGAT
AF03CC1UC
3043 6691 UGCALR~ CT~U~G X CL~A AL~A~G7231 CC~T C C~2OCA
3055 6692 UtJCAOQ~1 CLOG X AAA paCLIC~,U7232 A'~pCr C ,~'1p~~,p,
3073 6693 0.'~Ct~ CLOG X Q~F. ApCUmx 7233 O3CL~OCT A pGCG~3G
3085 6694 P~OC~mG CMG X ~F, pC~pQ~ 7234 CAQ3~GT T CTALCCGT
3086 6695 G~~.1 CUGHHIJGaG X Ct~,A 7235 Pc3~ C T,~C'CpGIC
AACACOC3T
3088 6696 U0CL~AIJC~G X CGAP. pGAAG~ 7236 a~,T A CQ~
3094 6697 I~3CCCtJG CZJGAUGAG X O~A 7237 CTPLCCGT C C~pL~A
~3~
3ll8 6698 C~~G CUC~TJC~G X O~A AC~Op~7238 030~GT C CI~CPL'IC
3121 6699 PLOC.~7G Q7GAIJUFG X CC~F, 7239 C~G1C~T C CAL'IOCuT
p~JpG
3126 6700 AI~AOG Q~G X CC~F. G 7240 CC'IOCF~LLT C
CGIGAC~T
3135 6701 0.~GApC Q7~JC~ X Ct~A p,T~J~;,7241 ~T C C3C.~X~pG
3L39 6702 ~CUG CC~~T~G X Q.;~A pp~J 7242 ACA'I~OCT C CPD~OOC
3171 6703 LOCCA7UQJ Q7C~G X 03AF. 7243 'IGI~GT C AC3~APaC~.
P~
3182 6704 a~7CUCR7G CL~~G X ~A pL~Jp~AT7244 AAFOCAL'r C CAAAC3~C
3192 6705 PGCI~G Q~G X ~A A~7CCJW 7245 AAAGACCT C CD~CT
3219 6706 Ur'AUWOG CT~J~G X QUA PL~C~ppG7246 0.'~CI~GI' C OOCGA~,
3230 6707 CL7C~t7pG ~G X QUA pGUC'AUQ;7247 C7GA'IGFGr T OCAG.'tL'~G
3231 6708 ALTX~t7G ~ X Ct.-~,p, p,~,~7248 c
3240 6709 L~C C~,G X (~ p~ 7249 C~GIC~1GT C GGIGAFC~,
3265 6710 CC~70CtJG QJ~JC~G X ~1P. 7250 GAGCTC~T C CAOC~~OC
PL'CAOCCJC
3278 6711 GALJ0033G CTJGALJGFG X QUA 7251 PL'~OCL~IGT C
AC~~~ ~OCG~
3286 6712 CUOC~QJC ~G X (IAA AL~C~003337252 SCAT C GFL'30CC~G
3336 6713 C33C~ CT~I~G X C1~A p~IJp~GC7253 ~OCAT C CC~L'INC
3342 6714 UC~30CUOG C~I7C~G X CAA 7254 .~fIC7CGAGT C
P~C~~IJ C~O~
3365 6715 LJC~, CLX ~ P~00;, 7255 CGGI~3CCT C 'IC.'IC~OC~A
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
Table V1I. Hammerh. rtibozymes to CDP
137
3367 6716 L~C~A CL~7~ X ~ p~pG 7256 C~C~
3369 6717 PL~7Q,'C~ ~G X ~ p~~ 7257 c3
CCZC;ZCr C C~
3378 6718 C7GAQ
3pCC ~ X ~ p~,CG 7258 ~~ C p~C~
3385 6719 t7C3GAUGLV ~GAL)GfiG X 7259 ~~ C p~~
~A pp~~,
3391 6720 A
AUCJCL1UG GL~G X ~ AOpC~G7260 C~C,n,T C C~,ATr
3399 6721 UC~3CLpLU CL~(~ X gyp, 7261 CCAPGAAT T pG.~~
~
3400 6722 ALJC'~3Ct~~C CL~ X ~, 7262 C~~ A G~,p~T
~
3403 6723 GACAC7O3C CC~AC~G X af~A 7263 GAATTpGT A C3CCP.TCIC
1~~
3411 6724 aCi7C~pG CL~A~G X Cue, 7264 P~.~ C ~~C
~ ~p~
3429 6725 UC~LJGC~ CC7G~L~ X ~ p~~ 7265 p~~ A ~pCp,T,~
3436 6726 CGCtJUOC,~T CUC~,L1~G 7266 '~C3CAT A ACCAPDC~
X ~1P, ALX3C~,
3475 6727 ~CUOOC~ CLJG~G~ X Cep, 7267 C ap
p,G~
3486 6728 0.'~~AALT ~ X ~ pappC~ 7268 CCAO~ T ATTTC~p3G
3487 6729 UCCOC<1AA C~J~,G X ~Ap, ?269 CAC~3CIT A T'1'IG~
,
.
3489 6730 L7C~JOCCCp, C~7G~G X C~ 7270 C~3CITAT T T333~
A~pCpC
3490 6731 C~~ ~G X ~ A~~ 7271 CG~ T Cpl
3502 6732 AC3CLZimA CUGAI7G~G X 7272 SCAT C T~~
CC';Ap. A~7C
3504 6733 U~OC~J CUr~T~ X ~A pL~~ 7273 GAC~.ZC,T T PL~3CIl"~.
3505 6734 QJGApp~ CL)GA~ X QUA AAC~1L~3~T7274 p,Cp~'IT A 030CTCAC
3511 6735 C~pc~1 CL7GALJGa,G X QUA 7275 Tl~A~pCT C p~,p~
p~'!CT~F,
3522 6736 C3~C~p, ~ X ~, ApCCLJ(~ 7276 CC ~I~
3526 6737 PC~Q~, CX ~, HOC 7277 C30CICIGT C 'IC
.'IGApCT
3528 6738 C~C,AOQJC~ C~~G X CGAA 7278 ,
p~G CC 2L;~CCT~C
3535 6739 03ppCAAG CLOG X ~1A pGQX2~,7279 ~pCT
3538 6740 ~Op~~C ~G X ~ p~ 7280 GALCfiCr T a~C
3560 6741 PG'~'~C3L~J CT~4I7C~,G 7281 SCAT A PDCIC~G'I'
X OGAA AZx~L~G .
3565 6742 (7<~GACU CL~L~,G X ~ pQ~ 7282 CA'~.T C PGIC.'I~A
3569 6743 UCCWC~, X ~, p~CC 7283 pGC~ C ~~
3588 6744 UC~C~OG CUG~UC~G X Q~,A 7284 p~~T T ~ppG~
pL~~'~J
3589 6745 AIR7J3C~C ~ X ~ ~p~ 7285 G~Op
CCIT C G~~,~T
3592 6746 UOCAI70C~ CTfi~J~G X ~, 7286
A~P
p~
, ~~ C Cp
3669
6747 G~ ~G X ~ pppCWUC 7287 GAApGCIrT A CATGAFpC
3690 6?48 CPLL~,AC<T Q~G X ~lp, 7288 OQ~GGT C AGI~~GIG
pp~C
3694 6749 CLOT Q~ X per, p~CU ' 7289 P~GCI~L,T C PGI~G
3723 6750 L~O~ ~ X ~, papp~ ngp pC~ C qGDOCC~A
3727 6751 UCD~ CLOG X ~Ap, pC3~C~p~7291 CCCT~'IGT C ~pp~
3738 6752 CCiJ0pC0u CUC~I~ X pQ~ 7292 CACX7~T A C40C~
p~~
3800 6753 CUp~; ~G X ~ p~G~ 7293 TL7CZC3~.T C OO~OC~G
3831 6754 L1UUC~~7C.~, ~G X AAA 7294 AOC~3C~T A T~pC~AA
pp~C~
3833 6755 CLnAJfJC3CU CL7C~I7C~G 7295 C~GOGmT C PL3CAAAPG
X Q~F, A~,pp~
3846 6756 ~pppG ~ X ~, ~~ 7296 AAFC~CC~T A C~7GIL~C
3852 6757 UtJUI7Up~1 C~~ X ~ p~p~ 7297 AT~CCC'~T C ~C~AA~,~,
3865 6758 pOC~J~.ZA7C CUGAUC~1G 7298 AAAAOCAT C GAAG~DCT
X Cu~AP, AL~JUUIJ
3874 6759 LJOpC~JOpC ~,G X ~~Fa 7299 Ga,FC~OGT C pCC'
p~[7C
3886 6760 L~~tT C~7GaG X ~ ~~. 7300 ALQ~OCT C P,AOC~F,A
3907 6761 ~(I ~,G X CC~. AO~T 7301 ~C~T C ATCAACI~
3910 6762 A1 ~ X ~ A~~ 7302 ALCGI~.T C AFGZC3GIT
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
Table VII. Hammerl. c2ibozymes to CDP
138
3918 6'763 PC~Jt~ ~ X Cl,~p, p,~,~ 7303 C~ACTp~' T CC~CAACT
3919 6764 CCt7~ X CGAA ~CpC~IU 7304 AACIC3GTr C C~ACr?.
3927 6765 GAC~CZ7G CL7GALJC~G X QUA 7305 CCACAAGT A CAOG'IC'IC
Pte;
3933 6766 GGAIJCC~A CCIGAIpGF~ X CQ~A7306 CtACApGr C 'IL70:~A1CC
AL,COCT~G
3935 6767 GCQ~L~C CLOG X CAF, pGFCCC~17307 A~pGICr C GGATOppC
3940 6768 (JC<7C~X~C~ CZ7GAIJt~,G 7308 T~ ;AT C CpC~
X Ct~F, ALmQ~,
3954 6769 OCC7r~AUG CL~TJC~G X pulp, 7309 p~-~ T
ACpQ~U
3955 6770 UCCtxAAIJ ~ X CL;nA AACPI~JIJr=7310 C~L'IGTr c ATIGFL~~.
3958 6771 AIJIJUCCtJC CLJGAIJGpG X 7311 CST T C~3~AAT
CGAF. AL~G
3967 6772 CC1'~3CCZ7G ~ X O~A ADI~JC 7312 C~3~,AAT T CAOOC'Q~
3968 6773 C~CCCT CZ7GAL7C~G X Q~1A 7313 pL~C~AATr C PC~3CC~
AFrL~JU~1
3980 6774 CUD3CGCU CUC~L7G~AG X O~,p,7314 CCCC~C,AGT C PL~30~1G
PLL7C0.'t;G
4005 6775 CCG~GOC~J Ct~,G X Q;rIA 7315 CAOOGFCr C ACS
P~C~"~C~CTJG
4011 6776 LZ30L'~30C'~ C<.~AL7C~G 7316 C1~Q~LL~.'r C
X O~p, pp3~G 03CC~'A
4041 6777 m~X..T7C~ CUGAZx'~G X CGaA 7317 GC~OCT C OC~PD~
PL~CCIr~3C
A11 6778 CCRX!Ct7GA CC~AUC~G X CGF1F~7318 GC~PGT C 'IC~GO~G
'3 PLa~303C
4115 6779 CUCC7CCCU CUC,,AUC~G X aC~P.7319 CCAAGIC.T C pl3p;~G
AG~JOG
4176 6780 03~ CT~AI7GF1G X Ct;AF, 7320 GC~CCCT C 030~~C
AG03L170C ~
4263 6781 OOC~JCOL~ C~7~,G X QUA PB'~030C~G7321 0.L~r C p3C~COG
4307 6782 OOCC7GFC~ CLJGALJC.pG X 7322 ACCT A CCIC~CC
CC~A PL3C~OOT1
4311 6783 ~C~CV C(7Gp,L7GFG X ~. P~p~7323 ~C~ C pt~pC~
4353 6784 QJOC~OOOG Ct~I7GpG X CAA 7324 0.'~OC~T C Q~CC~~C
P~pG
4407 6785 LJC.LpCPL3C CUC.~I~AG X 7325 (3C~I' C GC'rOCAGA
a.~A PL~~C
4420 6786 PC~3~A CUGA1;7GFG X CL~F, 7326 CAC~I3CCr T TIC700CCr
A~
4421 6787 GAC3pC0~, CMG X 4~p, AFCdOCUCtT7327 PGFflCCTT T 'ImGOCIC
4422 6788 C~'~OGCI.G Ct~AI7GAG X CGAA7328 GAC3CCTIT T Cp3CL'ICC
AAA~C~Ct7C
4423 6789 GOC~OOCIr CUC~L~G X QUA 7329 pC~~T C Q~~
AAAPa3CU
4429 6790 C3CCUCn3G C1~JGAG X ~A P~C~O~r7330 T'r0030CT C CCnGA00C
4455 6791 L7C~70303C QJGAiJG~G X CIA,7331 C~OGALT C GCGT~9Cp.
pl~~
4494 6792 UOQ~JC CMG X CC~A PL~7f700CG7332 ~~,pLT T ~pCp,~
4504 6793 ~QJ~ALT C<JC~IJG~G X CAA 7333 AACAOCAT C p,'I~C~D~
AL10CL~lJ
4507 6794 pOC300CTJG CTJGAL~C X ~A 7334 ApCF~C~.T C C.~OOOCX.'r
AL~I~3CU
4544 6795 OCAIJU~A Q~J~G X AAA 1~(~JI~T7335 1~Q~ACLT A TCC~ATL~G
4546 6796 UG~Jf7C QJGAL~G X ~ ALT~3C~JUC7336 GAPOCTAT C C~AT3p(;p.
4557 6797 0.'~C~t7CAG Q~,G X a.~A 7337 A'~30~,~GT T CZ~App3G
ACCJLOC~II
4558 6798 GCOQZJCA Ct~G X C~A AFQ.J~'A7338 TOT C 'IGPD030C
4618 6799 CCCL~JCC CC~.~iJC~G X CX~A 7339 (~,OOp~T C ~p~
P~OOOCQJC
4656 6800 0300. Ci~G X QUA PL300Q~OG 7340 CL'IOOC3CT T GOCC~OC~
4713 6801 GGAOO~JG C~JC~ X Qua App33C~1C'7341 GAC~C~r C ~~DC
4720 6802 PaC3~pC~ CL~ X CAA P~~, 7342 ZCCAOOGr C COmOC2T
4750 6803 m00CTJ~JG CUGAIJC~G X CAF, 7343 GCOCAGAT C c~App0.~
ALI~I~OC
4774 6804 GOOCmCA ~G X G;~A pL~G~ 7344 GALOCACr C 'IC300G1~
4801 6805 GC~~ C(~7Ga,G X p~,p, p~~p,7345 'I~3~OCT C CAOCAAOC
4853 6806 PGUp~'~, C~JC~G X 0~1A Pt~~7346 GC~90C~3CT T 'IC~C~GT
4854 6807 AALL~OC~ C(~IJC~G X CAA 7347 GAO~CTr T G03CAL'IT
AA0003JC
4862 6808 ~330pC~1 CL~L~G X Q.7HA 7348 'IC~~~LT T ACL~~.T
pQpCO(,~,
4863 6809 CAOC~30~ CT~ALJr~G X CL~A 7349 003CACZT A 0."t~CCCIG
AF~JOOOC
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
Table VII. Hammert. ~Zibozymes to CDP
139
4889 6810 CCC~ ~ X ~A n,L7~~ 7350 ppC aC
4895 6811 C~ X ~ ~pG~ 7351 A~CAT A p3TAF~
.
4909 68L GL'U t3C~'.~ ~ X ~A ?,LIp~CCiJ7352 ~C~T A
4911 6813 LT~)GZ.T~ CtR;ALJG?G X ~ 7353 GrpCp,Tp,T A ~pC~,
AI~CAC
4928 6814 UI~30~,U CT~GAI7GFG X Q'~p,7354 p~(~T T A~,~
AL'c3CfJCCTJ
4929 6815 AUUC~3LT1 ~ X CAA, AAUGCLJCU7355 C~'~OCATT A SAT
4938 6816 ~G=L'~, C~A(~ X C(~ p~7~U 7356 PGC~1AT C .T~'I~InGT
4940 6817 ACP~-G~, CLOG X CC~, pC~33G7357 CC~p,~ A ~,G~
4944 6818 G'1AAAC'-~ CC~AUC~G X QUA 7358 A2CTA'IGT C GI~ITfi
ACALIFGAtT
4949 6819 UCCU(J~A CTJGAL7C~ X OCAA 7359 ~I~IGT T T~~~,
ACACGAC~.
4950 6820 UUCCU~. CTJ~7~ X CCsA AACAO~~,C7360 ~T T ~
4951 6821 CUUCCLT~ CUCALT~G X CAA 7361 'fiGIGTIT T CMG
AAACAO,:,A
4952 6822 L~,U CZ7GAUr~G X Q;AA AAAACAOG7362 C~ C AACGAFCA
4978 6823 AAAFaCZJC CL7GAt)GpG X CIA 7363 T~;,T
ACCACACA
4984 6824 QG X ~,A paCC~C 7364 GI~ApCT T TITIG~AC
4985 6825 ~?A CL~AL7r~G X QUA APC~CLJ~'~.7365 'I~,OCIT T TI'IGTACC
4986 6826 ~C'-,el CTJGAI~ X ~A AAP~CUOG7366 CGFGCTTT T TIGTACOC
4987 6827 AOCt7C~,L~pG X ~F, p,AApC3CUC7367 GAOCIfiIT T 'IC~'rACCC.T
4988 6828 CAOG~rC CUGAL~FG X O~F. 7368 P~CITl'I'T T GTACCCIG
AAAAAOCU
4991 6829 CtJI~ CC~4UGpG X Q3AA AC~AAAAA7369 ThI'ITIt;T A C~CI~
5003 6830 AL~AA?:~?. L~7GAL7GpG g 7370 2~ T
p~A Ate,
5004 6831 AAL'~r~?r1 CUGAIJC~PG X 7371 CA~G~IT T TI~TTATr
Q~e~. AP~C~LLJ(7C
5005 6832 CAAUA~ CL~p~AG X CGAA AAAC~J7372 AAG~'iT T TITI:~TIG
5006 6833 C~AL~~, CT~G X ~A AAAACALU 7373 p~ T T~Tp,TIpC,
5007 6834 O3CAAI~A CC~WJC~G X Q;AP. 7374 GT T~T~3CC
AAAAACAC
5008 6835 a03C~i~ CT~AL~AG X 0.'A 7375 ~ T ~~
AAAAAACA
5009 6836 A~,r~,iT CL7t~L7C~G X ~~A 7376 GITITITT T ATIO~C'P
AAAAAAAC
5010 6837 UPL~OGC2A Gt~G X ~A AAAAAAAA7377 TAT A T~~p,
5012 6838 CUC'~C~G3C Ct~G X ~1A AL~AAAAA7378 'ITITITAT T aCLL'LAPG
5018 6839 P~AAI~1 CTJGAL~G X pip, 7379 ATIC~CGT A P~F:rIT
pp~C~
5025 6840 CCL~~, CL~,G X ~F. AI~LL~, 7380 TAF~'iGAT T T~3
5026 6841 PLL'~JOG CUGAI~G X CAF. 7381 AAGIGA~T T C~C~1C~T
AAL~7(1
5027 6842 AAfJ~ CI~I7C~G X ~ AAAI7C~17382 P~TTT C CMG
5035 6843 UAL7UCCFG QJ~AG X QUA pp~G 7383 CC~O~T T G'~AATA
5036 6844 WAt~ Q~,G X p~,. 7384 ~GTT C TO~ATAA
5043 6845 J CC~IUG~G X Q~p, pvU~C~ 7385 '~3GAP,T A ACn_ITAC
5047 6846 PDCUC~A CL1C~IJC~G X O~A 7386 GAATAACT C TI~CT
PL~7C
5049 6847 AAPDCCx'3J CT7C~UC~G X 0.AA7387 ATAACIrT T AC90CITI'
AC~C~Ip~IT
5050 6848 CAAAGCUG Ci~~I7GFG X CAA 7388 TAPL'I~'IT A CAOCrIZG
APC~
5056 6849 ACp,PaCaCA CL~J<~G X CQ~ 7389 TACT T 'IC~CCI~GT
pp~F,
5057 6850 CCt~~ X Q;Ap, ppp~,~g, 7390 'IAC'~10CTT T
aCCTI~IG
5062 6851 GAO CUGAL7r~,G X CVAA pp3(~AAG7391 CT'I'iC3CC'I'
T GIG'ICCIC
5067 6852 AACAA~G Clfi~(7G~G X QUA 7392 CCTIG'IGT C CI~'I'PG~T
pG~,ppG
5070 6853 COGAAC~ CIJ~IJGAG X CAP. 7393 ACT C TIG'I~C7C3
PL~~~2C?.
5072 6854 CAOC~AFC CT~G X QUA PC~13~,7394 2t;TOCI~.T T GTI~Du'IG
5075 6855 CC~ CL~IJGAG X CC~A ACAAGPL3G7395 CC'R.'I~T T COGI~33
5076 6856 0.'~CAC~ CLJC~I7C~ X CIA 7396 CIC.TIGIT C ~'IDOG
APCAPC~G
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
Table VII. Hammer. Ribozymes to CDP
140
5087 6857 LX gyp, p~C~ 7397 ACT T ~
5088 5858 UUUCUC~1 CZIC~JGFG X ~A 7398 Gn3C~CIT T AAAAGAAA
AAL~CCC~1C
5089 6859 C~I)CT CUGAIx~G X ~ AAFGC~P,7399 Tr~3CITT A AAPC,AAAA
5103 6860 C~LW CUGRLJC~G X O~A ALJtJUUWtI7400 AAAAAAAT C AAAOCC~C
5114 6861 CCUUUUAA CL~JC~ X ~P, AI~~J7401 ACCCACA'r A TTA,~AFaG
5ll6 6862 CCCCIJWfJ QJGALJC~G X AAA 7402 CC~~,TAT T AAAApp3G
ALB~I~
5ll7 6863 CCCC~.LL'U ~ X O~A AAL~ 7403 C~TATT A Apps
5128 6864 CAC~L~,p, CLJGAL~G X ~A 7404 p~C33p(~.T T TITATC.'IG
~'L~J
5129 6865 aC~C~A C~JG~G X ~~A Ap~C~C 7405 d00ppCIT T T~2~3C
5130 6866 03CaGAL~, CL)GAUC~G X CAA 7406 O3C~C3CI'IT T 'I~1~'IT3CC
AAFC3CCCC
5131 6867 UOC3CAGALJ CZJGAL7C~G X 7407 p;;C~T T AT~p~
CC~A AAAAOCrC
5132 6868 ALJCI'~~GA CUGAL1GPG X ~'~1P.7408 C3GCTTTIT A ~CC~.T
AAAApDCL
5134 6869 PC~~ G X ~A AL~AAA~ 7409 CTZ~TI'AT C 'IC~CCA'I~,T
5141 6870 PDC~ACJUA CU~L1~G X O~A 7410 'IC.'IC~CCAT C
AL~C~A TAA'1~.'r
5143 6871 GAPC~CAL1 CUGAI7~G X ~. 7411 'IG~ A ATCp~
PC~IJC30CA
5150 6872 cxroCt~ cud X ct;AA pr~c~. 7412 ~pcT T C~pa~
5151 6873 ALJOOCL~J CL~L~G X CJ~A -74~ AA2~C~C'IT C ~F1GC1JAT
APaCCAIJU
5160 6874 UAC~~>,AL1 CT~G X ~Ap, AIJOOCUCU7414 AGFL~F.T A ATACFC~A
5163 6875 ClAP~7G C~I7C~G X SAP. AU~C7415 aCG~TAAT A CAC:CATTP.
5168 6876 GAPC~L~Ipi C~L~ X pC~A pLT7C~lAU<J7416 AATACACr A 'I~T~'I'IC
,
5170 6877 AAGAAC~IJ C~JGAG X OGAA 7417 '~C~,CLAT T ATCI~IT
Ate, '
5171 6878 L~1AG~'~F. CC7C~L7GFG X 7418 PC3~L'TA1T A 'IC.'I'TCITA
CQ~A AAL~7Q1
5173 6879 WImAC',AA C~L~G X Q~1F. 7418 C TIrTl'AAF,
AL~1AL~1
5175 6880 ac~JC7~FG CL~L~G X Q~F, 7420 TATI'F1'I~T T CZ'1'AAACC
pC~L~Ai~
5176 6881 L7C~C~JIIC~A CLOG X QUA 7421 ATrP.'ICZT C TIAAACCA
AFL'~LmAL1
5178 6882 CCUCa~JUI1 C~I~,G X CuAA 7422 TAICTItT T AAACG~
PC~AC~L~,
5179 6883 UCCUOC~7U CT7G~G X O~A APL~FC~1U7423 ATCI~'IT A AACCPDGA
5194 6884 CCCCCUUU C~I7GFG X C~4A 7424 GAAAAAAT A AAFfl030G
AI)UUI7IJIJC
5211 6885 UUCU CAAA C<JC~Z~G X CC~P. 7425 ~GAT T Ti~A
AUOCCF~LC
5212 6886 t~7~F, C~L~s,G X pGAp, AAL~p~C7426 G'IC~O ~ATr T TIC~C~AP.
5213 6887 L)<Jt~, CL~,G X CvAA AAAL~'JOCA7427 'I~3C~.TIT T 'IC~GF,AAi:1
5214 6888 UUIJI7fJC<JG CUGA~AG X CC~.A7428 03GAT1'i'T T CFL~APaAA
AAAAIJ~C
52L5 6889 AIJULItJUCTJ CtJC.~I~G X 7429 a~~.TITIT C AC~AAAAT
~ PAAAFdJC~
5224 6890 L~L~A~J ~ X ~A ps7f~J 7430 PGAAAF,AT A AAAAAAGA
5237 6891 CCL~P,AA Q~G X Q~, AL~AJ 7431 APLL~~AAGT T ThIG'B~OC
5238 6892 AGCC>AC9A CZ7GALX~G X CL;AA7432 PGAHAGI'T T TIGI'AOCT
AAGU(JtiCLT
5239 6893 CFL3CUACA C~T7~G X aGAP. 7433 GAAAGIZT T ~CIG
AA~7C
5240 6894 P~,p~ ~ X ~ pp, 7434 AAPGGTTIT T GI~3CIGT
5243 6895 ZJGAPCAOC CZJGAUGAG X QUA 7435 G'I'ITI~GT A 0
ACAAPAAC
5249 6896 O3CAAC<JG C~AL7GAG X Q~1A 7436 GTPDC'It;'T T ACC
AC.~GQ~1C
5250 6897 L130CAFLTJ CZJGAt7~G X CQ~P.7437 TAC~C.'IGTT C AGI~3CC~
AFCAOCUpr
5254 6898 IBC CT~G X CC~P. ACtiGAAC~.7438 ZG'I~Gr T ~~F.
5261 6899 C~AZ~1 Ct~LJ~G X C1;AA pL~Op~,p,7439 TIdC~LT A PGAGATIG
5268 6900 GAG~70C C1~G~G X c7~A At~T7t~.7440 '1'APGAGAT T a~PGrC
5276 6901 C~UI7W CL~I~G X a~A pLl~Cp,7441, 'IC1CACPGT C AAAAACIC
5284 6902 L~Ut~ Ci~L~G X aQ~p, AGUUCAxJG7442 CAAAP.ACr C '~AAC~.
5286 6903 ~ AG~J~1U CL7GALJ~1G X 0.F.7443 ~ AAAPL'ItT A AAC~CT~
~ P~A~J ~
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
Table VII. Hammed. Ribozymes to CDP
1 41
5295 6904 AL1CCAAFC CL7C~,UG~ X O~F, 7444 ARC~C~CT A GMAT
pL~~7U
5298 6905 c~AAWC~ CCJG~LGpG X CGAA 7445 AG~'~ T Zp~C
pL~J
5299 6906 Pt3C~IUC~ CUGAt7C,FG X CuAp,7446 ~~ T pp~mCr
AALT.~G
5304 6907 tIAIJUI7r~p;, C~J~L~G X 7447 G~~,T T ~~.A
CGAA AL7CrAAAC
5305 6908 aL~IIJUUpG Ct~I~G X Cl';AA 7448 TT~3GATr C ChAAATAT
AAUCCAAA
5308 6909 AAAAUAtn1 MFG X Q1AA pD:~AAL7CC7449 ~~T A AATATl'I'I'
5312 6910 CUUGAAaA X CGAA AWUAOGF. 7450 SAT A T
5314 6911 U<JCf~AA CT~AUGF,G X CGAA 7451 CTAAATAT T 2'I~FC~F,
AC1AWLIAG
5315 6912 LAMA CTJGAL7GAG X CGAA ppl~7U~,7452 TAAATATr T '~~,nG~,AF,
5316 6913 UUtiUCUUG CL1GAUGpG X Cry, 7453 AAATATIT T C~,AAA
AAALTAWU
5317 6914 CUUUUClft1 CL~I7G~G. X pQ~A7454 AATA~'IZT C APGAAAr~G
AAAAt~J
5329 6915 AAA CZ7C~JG~G X ~F, AID 7455 AAp,FGAF.T C TILT
5331 6916 CAAFDC~G ~G X OC~A P~CJIJC.W7456 AAGAA2Cr T C~'t'IG
5332 6917 UCAAACJGA CLJ~1~ X CL;AA 7457 p~T C
AAGAIJC7C.U
5334 6918 tJUU~AF,C C~L7C~G X CC~F, 7458 AAn'I'IC..T C G~F,AA
pGApC~u7
5337 6919 AAC~A)UC~ CUGqUC~G X ~ P~OG~PG7459 Ci~'~T T ~,p~T
5338 6920 AAFL~JIR7C X CGAA AAOG~F, 7460 TI~'I~UIT T C~AACI~'I'
5345 6921 UC~At7tJC~1 Q7GAL)GFG X 7461 TIGAAAGT T 'I~Tg,A
C~Fr PL.~JUUCAA
5346 6922 t~AVUC CL~A~ X pC~A AAGUt7UCA7462 ~AACIT T GAATTHAF,
5351 6923 L7U CL~1UGAG X aC~A AL7Ul~AAG7463 CTZTGAAT T AAAATAAF.
,
5352 6924 UU()UAIJCnJ X Chp.A AALAJC~AA7464 Tr~T A AAA~AA
5357 6925 AUQ)~(T CLOG X AAA AIJUUtiAALT7465 AT1~AAAT A AAACACAT
5366 6926 c~C~ CLJGAL7C-AG X ~F, AL7C~t7GUW7466 Ap,AC~CP~T T 'TPLTCCAC
5367 6927 t~GF~T CL~L~G X C~, AAL7C~T7467 AAC~T T ACInCAC'A
5368 6928 CL7~02p,G C~I~G X ~1A ,~AAL7C~JC~J7468 AI~.TlT A G'I~CPG
w nere wx~~ represents stem 11 region of a HH ribozyme (Hertel et al., 1992
Nucleic Acids
Res. 20: 322). The length of stem II may be >_ 2 base-pairs.
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
142
Table VIII. Sequences for controls & Hammerhead and Hammerhead-like R.ibozymes
SEQ. I.D. ~ a
Ice.
196 14240 c c c L cC~GAuGac c~ B
278 14244 gsuscgu5gac cLIGAuGaggccgtn~a99ccGaa
Auuugca B
204 14252 c ugc cLIGAuGa cc ua cGaa g
p~
281 14260 c cca ct7GAuGa c ccGaa Aa B
3581 14336 cL7GAuGa c ccGaa Atn nacuu B
y
3504 14341 cL~GAuGa ~ c~ pc B
4993 14437 c aag ci7GAu c ccGaa Aacuuuu
- B
5090 14452 c c c~ B
c
13196 c c cUGAuGa cc ggccGaa c B
13201 c c cu cUAC~Ga c ccGau Aa c B
6929 c uc~ ct7GAuGa ccGaa IcucuucB
c
6930 c ccc ci7GAuGa ccGaa IccuucuB
c
6931 cc ~ I B
6932 c cu cL7GAuGa cGaa I B
c
6933 a~n~ ctlGAuGa ccGaa Icacaac8
c
6934 c ucc cL7GAuGa ccGaa I B
c ccc
6935 c c c ccGaa I B .
6936 c~ c~7GAu~a c cGaa I c B
6937 c c ccGaa I B
6938 c c ccGaa I B
6939 c c ccGaa Icca B
6940 uua c cGaa I 8
6941 c c cGaa I B
--
6942 c c cGaa I B
6943 c cau cOGAuGa ccCaa I B
c
6944 c c c c~ I 8
6945 ccc cDC~Ga c ccGaa I B
c
6946 coc c~At~Ga c cGaa Icc B
6947 c c cGaa Iacc B
6948 cUGAt~Ga c cGaa I B
-
6949 c~Ga c I 8
6950 c cGaa I B
6951 c c ~ I B
6952 c cGaa I B
6953 c cL7GAuGa cGaa Ia B
cf~AuGa c ceGaa Iuuaaca
B
6955 c c ~ I 8
6956 c c c~GAuGa c cGaa I B
6957 c c cGaa I 8
6958 cca c c cGaa I c 8
6959 c c c ccGaa I B
6960 c c caGAuGa c cc~Gaa I 8
6961 c c c cGaa IacacacB
6962 cU~ c ccGaa I a
6963 c c c ccGaa I B
c
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
143
'Table VIII. Sequences for controls & Hammerhead and Hammerhead-like Ribozymes
6964 asgsaagagct7C~uGacraccguuaggccGaaI cuu B
6965 ct7GauGacc ccGaa Iu aau B
6966 g ctu,gct7GauGa
cuc ~ c~ Iuaacaa B
6967 aac c~GAuGaggccgmaggccGaaIcuu c B
6968 c cuu ct~GAuGac cGaa I ccu B
6969 uai cL7GAuGac cGaa Icuucau B
6970 c aug cL7C,AuC,ac _ ccGaahnniucu B
_
6971 c cCIGAuGac ccGaa I B
aau
6972 _ c~GAuGac c~Gaa I B
caa
6973 cUGAuGac ccGaa Iaumazu B
6974 c c cC7GAuGac ccGaa Iaa uu B
6975 c c c ccGaa I B
6976 c c eGaa I B
6977 tpr c c cGaa I B
6978 c ccu cLIGFuGac ccC,aa Iaaacau B
6979 c c c ccGaa I caa B
6980 cLIGAuGac ccGaa Ica B
6981 cnGAuGaggc ccGaa Igca B
6982 cuc c ccGaa I B
6983 aac c c ccGaa I cu B
6984 c c c ccCaa Iuaaaaa B
6985 c acu c c ccGaa I B
6986 cOGAt~ac cGaa I B
6987 c c ccGaa I 8
6988 aua cDGA~~Gac ceGaa Icc~n.am B
6989 uw cnGAuGac cGaa I uuc B
6990 c c c ccGaa Iacc~n~u B
6991 c caa cnGAuGac ccC,aa I ccu B
6992 cOGAuGa cGaa Icuccau B
6993 c c~ c c ccGaa Iccavau B
6994 c c c cc~aa I B
6995 c c cGaa I B
6996 acu c Iucc B
,.
cGaa
6997 ~ cDGAt~Ga cGaa I B
6998 c c~ cGaa I B
6999 cDGAt~Ga I H
7000 c ccGaa Iaaactni H
7001 uua c cGaa Iuuc B
7002 cU~ c cc~aa I B
7003 c ccGaa Iuaag~ni B
7004 c c ccGaa Ica B
7005 ucc c ccGaa I B
7006 cDGAuGa ccCaa Iu B
_
7007 c c ~ I B
7008 c c eGaa Icacwic H
7009 ct~GAuGa cGaa Icauucu B
7010 c c c cCaa I B
7011 c c cCaa I ca 8
7012 c c cGaa I B
70L3 c ucc cC7GAuGac cGaa I B
CA 02364577 2001-10-03
WO 00/61729 1 4 4 PCT/US00/09721
Table VIII. Sequences for controls & Hammerhead and Hammerhead-like Ribozymes
7014 c cc cGaa Ia B
ua
7015 c cL7GAuGaggccguuaccC~aaI _ _ _ g
7016 c cOGAuGacc ccGaaI B
7017 cL~GAuGac ccGaaIua B
7018 c cDGAuGac ccGaaI B
7079 c c cc ccGaaIa B
7020 g qag
g ggccguua ccGaaIuuucga B
7021 aca cC7GAuGacc ccGaaI c B
7022 cL~At~Gac ccGaaIaca B
7023 c cUGAt~Cac ccGaaI ca B
c
7024 c aaa cL7GAuGac ccGaaI cuc B
7025 c uai cDGAuGa I~c g
c
7026 c ccc ct7GAuGac ccGaaIccuucu B
7027 c c cGaa I B
7028 c c c ceGaaI B
7029 auu cDGAuGac ccGaaIcacaac B
7030 c ucc cc~a c ccGaaI ccc B
c
7031 c uag ct7t~.~Gacc ccGaaI B
7032 C.~1c c ccGaaI c B
7033 c cL7GAuGac cGaa I B
7034 c c ccGaaI B
7035 cLlG~ac cc~aaIcca B
V
7036 c ta~ac c ccGaaI B
7037 c cGaa I B
7038 cLIGAuGa cGaa I B
7039 cau cnGAuGa ccGaaI B
7040 cOGAuGac I B
7041 ccc c cGaa I B
7042 ccc c ccGaaI B
7043 c c c ccGaaIacc B
7044 c c cGaa I B
7045 ct7GAuGac ccGaaI cc B
7046 cUG~a c ccGaaI B
7047 c c ccGaaI B
7048 c I B
7049 cD~a c I B
7050 c ccGaaIut~aaca B
7051 c cd~aaI B
7052 c B
7053 g c I B
7054 cc-ac c cGaa I B
7055 c ccGaaI B
-
7056 c c cGaa I H
7057 cDGAuGa ccGaaIaC3cac B
7058 c I cu B
7059 c c cc~aaI B
7060 cL~a c ceGaaI B
7061 c c ccGaaI B
7062 cuc ctJGAuGac ccGaaIuaacaa B
7063 aac cUGAuGac ccGaaI c B
CA 02364577 2001-10-03
WO 00/61729 PCT/US00/09721
145
Table VIII. Sequences for controls & Hammerhead and Hammerhead-like Ribozymes
7064 cuu cL7Gr~.uGacc
ccGaaI ccu B
7065 ucu cUGAuGacc ccGaaIcuucauB
7066 ct7GAuGac ccGaaIuuuucuB
7067 c c c cc ccGaaI B
a~ ~~
7068 c caa cL7GAuGacc ccGaaI B
7069 cUGAuGacc ccGaaIauuuuuB
7070 c c cC~AuGa
guu c IaagauuB
9g
c9~ggccGaa
7071 c cL~a c cGaa I a B
7072
ctlGAuGac cc~GaaIca B
y
7073 uuc ccl~,uGac ccGaaIuu B
7074 c ccu c c ccGaaIaaacauB
7075 c cnGAuGac ccGaaIu B
7076
c c ccGaaI B
y
7077
c cc ccGaaI ca B
7078 cuc cL~AuGac ccGaaI _ B
7079 aac cOGAuGac cGaa I B
7080 c c cC7~a c cc~aaIuaaaaaB
7081 g acu cLIGAt~Gaccguua_ I B
cGaa
7082 c c c eGaa Ica B
7083
c c ccGaaI cc B
7084 c c c c cGaa Iccuu<niB '
c aua
7085 ucu c ccGaaI uuc B
7086
c c cc~aaIaccmnig
7087 caa c cGaa I ccu B
c
7088
c c ccGaaIcuccauB
7089 c~ c c Iccauau
B
7090 c c c cGaa I 8
7091 cDGAuGac ccGaaI B
7092 c acu c c IuccccgB
7093 atax c ccGaaIc B
cOG~a
7094 c cI c cGaa I B
' ~
7095
c c cGaa Icccu B
7096 cUGA~~Gac ccGaaIaaacuuB
7097 uua c cGaa Iuuc B
7098
c ccGaaI B
- _
7099
cnGAt~a cC,aaI B
-
7100
c I B
-_
-
7101 ~ uoc c~GAuGac ~ I B
_
_ ~
7102
c cC~aaIu_ B
7103
c c ~ I g
7104
c c cGaa Icacuuc8
7105
IcauucuB
7106 cOGAwGa cGaa I B
7107 cc~AuGacc cGaa I B
7108
c ccGaaI 8
7109 c ucc c c ccGaaI B
7110 c~GAt~Gac ccGaaI B
c c ccGaaI B
c c ccGaaI B
c ccGaaI B
CA 02364577 2001-10-03
WO 00/61729 1 4 6 PCT/US00/09721
Table VIII. Sequences for controls & Hammerhead and Hammerhead-like Ribozymes
7114 c ,q mg cL7GAuGaggccauuaag~cc~aIguaNgB
7ll5 c c cc c~ I g
7ll6 cUG~Ga c ccGaa Iuuu B
7117 aca c c cGaa I B
7118 cUGAuGa c c~aa Iaca H
7119 c c ccGaa I B
7120 c aaa c c cGaa IagucucB
7121 c c ccGaa I B
c uua c c cGaa I B
c c ccGaa I B
7124 c c ccGaa I B
7125 c c ~ ~ B
7126 ct~a c ccGaa I B
7127 c c~GAuGa c cGaa I B
7128 c c cC,aa I B
7129 c c ~ B
7130 c c I B
7131 g c c~aa Iamnn~uB
7132 c c ccGaa Ica B
7133 c c aua c c cGaa Iccmu~uB
7134 c~GA~uGa c cGaa Iaaac~aB '
7135 c cDC~a ccGaa I B
7136 c c I 8
7137 cU~uGa I B
7L38 c cGaa I B
7139 cGaa I H
7140 aaa c cGaa I B
cuc
7141 caecuc cC Q1 AO~AL~C~C,,C~pG a
tJ~ B
7142 uGAi1 cuacc
B
7243 t~L1 ca uGcac ava B
lower case = 2'OMe
U = 2'-C-Allyl-U
G,A, U= ribo G,A, U
g = phosphorothioate linkages
52=dithioate~linkages
B = inverted abasic
I=ribo-Inosine
