Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 02221826 1998-O1-28
PEPTIDE T AND RELATED PEPTIDEB IN THE TREATMENT
OF HTLV-1 MYELOPATHY AND MULTIPLE SCLEROSIS
FIELD OF THE INVENTION
This invention relates to compositions useful
in and methods of treating HTLV-1 myelopathy and Multiple
Sclerosis as well as processes for formulating such
compositions.
BACKGROUND OF THE INVENTION
~ Both multiple sclerosis (MS) and HTLV-1
associated myelopathy (HAM) affect the central and the
peripheral nervous systems and both may be present as a
myelopathy affecting both the spinal nerves and the
spinal myelinated nerve fibres.
Multiple sclerosis (MS) is a chronic
demyelinating disease of the central nervous system and
is the commonest chronic neurological disease of young
adults. The incidence of MS and its pattern of
distribution have been unchanged for decades. The
disease remains essentially untreatable.
MS has always been regarded as a disease of the
temperate zones and has a prevalence in the northern
United States, Canada and Europe of 1:1000. The disease
has a gender predilection of 1.5:1 (female: male).
MS usually affects multiple areas of white
matter in the central nervous system (CNS), most
frequently, the periventricular white matter, brainstem,
spinal cord and the optic nerves. The primary process
destroys myelin sheaths and eventually kills
oligodendrocytes creating the characteristic plaque of
MS.
The early development of the plaque is
characterized by the development of perivascular
inflammation followed by the migration of lymphocytes,
plasma cells and macrophages into the lesions. This is
followed by astrocyte gliosis and the attempts of
remyelination by oligodendrocytes. The plaque is
surrounded by lymphocytes.
CA 02221826 1998-O1-28
2
Although the etiology of MS is still unknown,
the focus of research efforts that have led to plausible
hypotheses have been those of immune dysregulation
including autoimmunity and genetic predisposition, both
of which may play a role in the actual development of
disease.
Multiple immunological abnormalities are
reproducibly found in patients in the acute stage of the
disease. The synthesis of immunoglobulins, although
to normal in the periphery, is increased in the central
nervous system and the antibodies produced have a
characteristic banding pattern. The antigenic
specificity of these antibodies is not known and it is
unclear whether they have a role to play in the
progression of disease.
Various stressors known to activate the immune
system such as viral infection or surgery can also
produce an exacerbation of disease. Other activators
such as gamma interferon produce similar effects when
administered. In addition, immunosuppressive therapy
with corticosteroids for example, can produce modest
remission or at least palliation for short periods of
time although this therapy is controversial.
Lymphocyte reactivity against two neuronal
antigens, myelin basic protein and proteolipid has been
demonstrated. Although not proven, this activity would
form the basis for an autoimmune response against
neuronal tissue.
The discovery of the neurotropic capacity of
HTLV-1 in patients from Martinique with tropical spastic
paraparesis (TSP) and in Japan with chronic myelopathy,
has demonstrated HTLV-1 as the common etiologic agent of
these diseases. It has subsequently been shown that the
neurologic manifestations of HTLV-1 infection are the
same despite the varied geographic regions in which they
are described.
CA 02221826 1998-O1-28
3
The neurological signs of this chronic
retroviral infection include involvement of the pyramidal
tracts in a bilateral and symmetrical fashion
predominately at the thoracic level in the spinal cord
and manifested by a slowly progressive spastic
paraparesis with spastic bladder and minimal sensory
deficits .
The peripheral nervous system has been shown to
be involved in patients from Colombia and in the
l0 Seychelles and slowing of nerve conduction velocities in
the lower limbs has been demonstrated. Systemic
manifestations of HTLV-1 in patients with HTLV-1
myelopathy have been described and include inflammatory
involvement of the lungs, skin, eyes and striated muscle
producing a myositis. In addition, the patients
experience profound fatigue similar to MS.
There are at least four possible pathogenetic
mechanisms whereby HTLV-I can involve the CNS to produce
HAM. These may include a slow virus infection, a
cell-mediated lesion or by a predominately humoral immune
mediated mechanism and the development of an autoimmune
phenomenon. The slowly progressive course supports the
hypothesis of a slow virus infection. The finding of
peri-vascular cuffing in post-mortem specimens as well as
transiently favourable response to steroids supports the
possibility of an immune reaction responsible for the
development of HAM.
These diseases have many similarities and
dissimilarities, both clinical and neurological. Both
diseases are a form of demyelinating disease whereby the
myelin sheath of the nervous system is destroyed by one
of many mechanisms common to both diseases and also
peculiar to either of the diseases. MS is a multi-
faceted disease in that it can be both a central nervous
system disease as well as a form of myelopathy.
Conversely, HTLV-1-associated myelopathy is both a form
of myelopathy and can occasionally demonstrate central
CA 02221826 1998-O1-28
4
nervous system effects. Furthermore, MS can affect the
peripheral nervous system in ways that are common in
HTLV-1. Myelopathy, as already mentioned in being a
disorder of the spinal cord, can be caused by many
potential causes and not just MS or HTLV-1 Associated
Myelopathy. These include:
neurosyphillis,
B 12 or folate deficiency,
sarcoidosis,
l0 transverse myelitis,
arachnoiditis,
cervical spondylitis,
motor neuron disease,
neurofibromatosis,
spinal cord compression from tumour, disc or
arthritis,
lupus erythematosus of the spinal cord and
viral encephalomyelitis.
We have discovered that a particular peptide
having at least 5 amino acid residues is a very effective
agent useful in the treatment of at least MS and HAM, and
predictably may be useful in treating other myelopathies
of the above list some of which have similar disease
mechanisms.
SUMMARY OF THE INVENTION
According to an aspect of the invention, a
composition useful in treating MS and HAM in humans
comprises:
i) a peptide having as its active portion, an
amino acid sequence of the formula:
-Thr-Thr-Asn-Tyr-Thr-; and
ii) a pharmaceutically acceptable carrier for
said peptide.
According to another aspect of the invention, a
method for medically treating MS and HAM in humans
comprises the administration on a repeated basis of a
composition comprising:
CA 02221826 1998-O1-28
i) a biologically effective amount of a
peptide having as its active portion, an amino acid
sequence of the formula:
-Thr-Thr-Asn-Tyr-Thr-; and
5 ii) a pharmaceutically acceptable carrier for
said peptide.
According to another aspect of the invention, a
process for formulating a composition useful in treating
MS and HAM in humans, said process comprises mixing:
i) a peptide having as its active portion,
an amino acid sequence of the formula:
-Thr-Thr-Asn-Tyr-Thr-; with
ii) a pharmaceutically acceptable carrier for
said peptide.
DETAILED DESCRIPTIONS OF THE PREFERRED EMBODIMENTS
The active agent useful in accordance. with this
invention comprises:
i) a peptide having as its active portion, an
amino acid sequence of the formula:
-Thr-Thr-Asn-Tyr-Thr-
These short peptides were first disclosed by
Pert et al., EPO application 0 249 394 published December
16, 1987.
It is appreciated that the peptide having the
core sequence of Thr-Thr-Asn-Tyr-Thr- may have at both
ends additional amino acid residues, some of which are by
the formula:
X-Ser-Thr-Thr-Thr-Asn-Tyr-Y (I)
wherein X is an amino acid terminal residue
selected from the group consisting of Ala and D-Ala and Y
is a carboxy terminal residue selected from the group
consisting of Thr and Thr-amide.
A particular preferred peptide of the group of
peptides has the aforementioned core sequence of the -
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6
Thr-Thr-Asn-Tyr-Thr-. These peptides of the above
formula (I), and in particular a variant Peptide T of the
formula -Ser-Thr-Thr-Thr-Asn-Tyr-, were found to be very
useful in inhibiting binding of the human
immunodeficiency virus (HIV) to human cells by blocking
receptor sites on the cell surfaces. The term Peptide T
is used throughout the specification to reference
peptides of formula (I) which a11 include the core
peptide sequence. It is therefore intended that Peptide
T encompass a11 of the compounds of formula (I) where it
is understood that a11 such compounds are variants of the
normally understood octapeptide T of the particular
formula D-Ala-Ser-Thr-Thr-Thr-Asn-Tyr-Thr-. Peptide T,
in addition to preventing infectivity as discussed also
may induce antibody production against the envelope
protein of the HIV virus. It is thought that these
peptides could therefore be used as vaccines to prevent
development of Acquired Immune Disease Syndrome (AIDS).
Monoclonal antibodies to these peptides would also be
useful as diagnostic agents to identify HIV since the
original identification of the short peptides by Pert et
al supra. In order to provide a guideline for the
adminstration of and insight into the use of the peptides
and the treatment of MS, HAM and other forms of
myelopathy and the formulation of the compositions, the
following is offered as a guide based on the extensive
work already conducted in the use of peptide T for
treating HIV infections.
Peptide T is an octapeptide homologous to a
region of gp120, an HIV envelope glycoprotein, and to
vasoactive intestinal peptide (VIP). It was originally
developed by Pert et al supra, to block the binding of
gp120 to CD4 and prevent the binding of the virus (HIV)
thereby blocking its internalization into the cell and
subsequent replication. CD4 receptors which will
facilitate viral entry into cells have been demonstrated
on lymphocytes, macrophages, neurons and numerous other
CA 02221826 1998-O1-28
7
cells. Binding of HIV to the CD4 receptor has been
demonstrated to effect viral entry. Binding of free
(non-viral related) gp120 of the HIV envelope has
resulted in neurotoxicity both in in vitro and in vivo
studies.
The efficacy of Peptide T in reversing signs of
HIV-induced dementia has been demonstrated in both the
Peptide T Phase I clinical trial at the University of
Southern California in Los Angeles and in the Phase II
clinical trial at the Fenway Clinic in Boston. Both
studiesa have demonstrated improvement in the HIV-induced
neurocognitive impairment in patients with AIDS.
To date, the Peptide T/gp120/VIP homology has
been used to explain at least two possible mechanisms of
action of Peptide T. Firstly, that it competitively
binds to CD4 (the known receptor for HIV) on human cell
surfaces and competes with both HIV and gp120 for binding
sites.
The binding of Peptide T and its analogues of
formula (I), to CD4 could produce a blocking effect to
prevent the binding of any other molecule capable of
binding to that receptor; alternatively, or in addition,
the binding of Peptide T to CD4 could induce a reaction
similar to that caused by the endogenous ligand.
CD4 is the differentiation antigen that defines
the T lymphocyte subgroup of helper/inducer cells, but it
is also present on a wide variety of cells including
neurons, activated macrophages and B cells. CD4 is the
predominant receptor for HIV and was originally thought
to be necessary for cellular infection. Using the
monoclonal antibody OKT4, Pert et al. (1 & 2)
demonstrated the presence of this antigen throughout the
human CNS and showed that it is present in highest
concentration in the dentate gyrus, hippocampus, amygdala
and deep cortex. This distribution was found to be
similar in other higher mammals. Peptide T and similar
analogues were found to inhibit the binding of
CA 02221826 1998-O1-28
8
radiolabelled gp120 to rat hippocampal membranes and to
do so in 0.1 nM concentrations.
Using Peptide T and the same analogues, Pert et
al. (1 & 2) were able to demonstrate a reduction in the
detectable levels of HIV reverse transcriptase when these
peptides were present in an assay of HIV infectivity. A
ninefold reduction of reverse transcriptase took place at
100 nM concentrations of Peptide T.
Since gp120 is not identical in a11 isolated
strains of HIV, a comparison was made with nine different
HIV isolates Pert et al. (2). Significant homology was
found between the isolates examined and Peptide T when
comparison was made with the core pentapeptide, peptide
T(4-8). This comparison has now been extended to over
twenty isolates.
The inhibition of gp120 and HIV binding to CD4,
as well as the demonstration of reduced infectivity of
HIV in the presence of Peptide T and its analogues,
provides one possible mechanism of action to explain the
clinical effects of Peptide T. In this regard, Peptide T
in sufficient concentration may prevent new cellular
infection with HIV. Initial research in this area was
focused on the CNS for two reasons: a high concentration
of CD4 molecules was found on neurons and one of the
major effects of HIV infection is the development of
neurocognitive dysfunction. These facts are particularly
important given that Peptide T is transported from the
blood to the brain by an active, saturable transport
system, while its exit is by diffusion only, [Barrera et
al. (3)].
Although it is well accepted that HIV can
infect not only lymphocytes but also neurons, it is
difficult to ascribe the neurologic dysfunction seen in
HIV patients to active CNS HIV infection, since only a
small number of neurons are actively infected. It has
been suggested that the neural deficits seen in HIV
infection may occur not only as a result of infection but
CA 02221826 1998-O1-28
9
also as a result of a viral "toxin,' such as gp120.
Brenneman et al. Nature, 1988 (5) found that purified
gp120 from two isolates as well a recombinant gp120
produced significant neuronal cell death in cultures of
mouse fetal hippocampal neurons. Neurotoxicity could be
reduced by pretreatment with antibody to CD4 and was
completely eliminated by VIP. Since mouse neurons are
not infected with HIV, it is evident that neurotoxicity
is gp120-induced and is not a result of viral entry or
replication.
VIP (8-12: TDNYT) and the core peptide (4-8:
TTNYT) share the homologous sequence that binds CD4, and
that is also found in isolates of the much larger gp120.
Peptide T, when used in the same mouse hippocampal
neuronal culture system, completely,antagonized the
gp120-induced neurotoxicity, Brenneman, Drug' Development
Research (6). In addition, CSF from a patient with AIDS
dementia produced substantial neurotoxicity in this
system (44-49% killing at 1:100,000 dilution). This
effect was inhibited by Peptide T, Buzy et al., Amer JJ
Med, (8). Normally gp120 is produced in vast excess of
amounts required for viral replication; this excess gp120
may exert a neurotoxic effect far out of proportion to
the number of neurons actively infected with HIV.
Peptide T may also act as an agonist in
addition to or even without its protective effects
against viral infection and neurotoxicity. In addition,
direct agonist activity has been demonstrated in two
ways. Ruff et al. FEBS Letters, (4) showed that Peptide
T and two analogues were potent agonists of human
monocyte chemotaxis. Their rank order potency as
chemotactic agents corresponded to their relative ability
to inhibit both gp120 binding and HIV T cell infectivity.
As a further demonstration of the agonist
activity of Peptide T, both Peptide T and VIP exert their
cellular effects via the regulation of protein kinase C.
Zorn et al., (11). Agonist activity of Peptide T is thus
CA 02221826 1998-O1-28
implied by the production of a transmembrane signal that
can influence the regulation of protein kinase C.
Further evidence of Peptide T's potential
VIP-like agonist activity is provided by results from
5 experimental testing of the hypothesis of Komisaruk et
al. (7) that VIP released from pelvic nerve terminals
into the spinal cord can produce analgesia. Knowing that
naloxone-independent analgesia produced by administration
of VIP to the periaqueductal grey matter in rats had been
10 shown they attempted VIP administration directly to rat
spinal cord and measured the pain threshold to distal
noxious stimuli to test the hypothesis. Spinal
administration of VIP produced analgesia as measured by
the fail-flick latency test and the tail-shock induced
vocalization test by action on both opiate and non-opiate
modulated pain pathways, Komisaruk et al., 1988 (7).
The existence of clinical benefits from the
administration of Peptide T to humans has been suggested
in a11 studies to date: in HIV disease, by the pilot
Swedish data, the USC Phase I and Fenway/CRI studies, and
the Toronto Western Hospital compassionate administration
to 41 patients; in psoriasis and other medical
conditions, in case reports from Sweden (Marcusson,
Lazega, et al., 1989-9, and Marcusson and Wetterberg,
1989-10) and in 8 patients with psoriasis or other
medical conditions in Toronto.
Neurocognitive improvement found in HIV
positive patients and improvement in constitutional
symptoms in both HIV positive and HIV negative patients
may well depend primarily on Peptide T's VIP-like
neurotropic and agonist effects.
Not wishing to be bound by any particular
theory, with respect to the use of these peptides with
treatment of MS and HAM, and in view of the above
guidelines and discussions in relation to the use of
various peptides of formula (I) and their analogues in
the treatment of HIV, it is hypothesized that there are
CA 02221826 1998-O1-28
11
numerous similarities of disease expression and potential
similarities of disease etiology. Peptide T appears to
act as an agonist and as a blocker of CD4-mediated immune
function rather than as an antiviral drug. In our
investigations, patients with non-HIV disease such as
psoriasis, multiple sclerosis, HTLV-1 associated
myelopathy and chronic fatigue syndrome have a11 been
treated with Peptide T.
Now that we have discovered the effectiveness
of these peptides of formula (I), we suggest the
following as hypothesis as to why the compounds do work:
1) both HAM and MS are chronic CNS diseases
as is HIV disease
2) both diseases have possible viral
etiologies; it is now generally accepted that HAM is
caused by the retrovirus, HTLV-1, a virus in the same
family as HIV; MS has also been suggested as a
manifestation of HTLV-1 infection and the chronic fatigue
syndrome has recently been linked to a number of possible
viral infections both of DNA and retroviral etiologies,
3) the two diseases share a number of common
symptoms, for example, fatigue, lack of balance and signs
of autoimmune phenomena; it is worth while noting that
HTLV-1 disease exhibits numerous signs of autoimmunity
such that it maybe expected that some retroviral diseases
have a concommitant expression in autoimmune phenomena.
One common theme among these diseases may be peripheral
neuropathy which is based on the process of
demyelination.
4) the basis appears to be the common
denominator of both demyelination whether it be in the
central or peripheral nervous system and the common
autoimmune manifestations in HAM, MS and HIV disease.
In accordance with various embodiments of this
invention and in view of the above guidelines gained from
the use of peptides of formula (I) in the treatment of
HIV, similar doses of peptide T and its analogues can be
CA 02221826 1998-O1-28
12
administered to humans for purposes of treating MS, HAM
and other forms of myelopathy. The peptides, according
to this invention as used in the compositions, may be
formulated for injection or other routes of
administration which include intranasal, oral, buccal,
topical, rectal and various injection approaches.
Compositions as adapted to these various routes of
administration will be in solution, suspension or
emulsion combined with the use of various formulating
agents which include suspending agents, stabilizing
agents and dispensing agents. It is understood that in
the administration of the compounds they may be in
lyophilized form which are then put into solution for the
purpose of administrated. It is understood that the
compositions of this invention may contain from 0.001 to
99.9% of the active peptide. For administration by
injection or infusion of the composition the daily
dosage, as employed for treatment of adults of
approximately 70 kg of body weight, will range from 0.2
mg to 20 mg of active material which may be administered
in the form of 1 to 4 doses over each day. Such dosage
ranges depending upon the route of administration and the
condition of the patient.
The selected peptide of formula (I) for use in
this composition may be synthesized in accordance with
any normal manufacturing techniques. For example,
peptide synthesis may be routinely used to produce such
short peptides by either solid phase or liquid phase
methods. The solid phase method may be the usual
Merrifield technique. It is appreciated however that the
peptide could be synthesized using recombinant techniques
and optionally treated with enzymes for providing peptide
length. In accordance with a preferred aspect of this
invention, the preferred peptide T is made by peptide
synthesis and is readily obtained from Carlbiotech S/A
Copenhagen, Denmark. The peptide is usually formulated
and packaged in a sterile manner in 5% dextrose solution
CA 02221826 1998-O1-28
13
in multi-dose vials. It is appreciated that the peptide
may be packaged in other carriers which may include
saline. Preferably the concentration of peptide in each
dose is in the range of 8.5 mg/ml for subcutaneous
injection.
In order to demonstrate the significant effects
that the peptides of formula (I) have on MS and HAM, the
following examples are provided which are in no way
intended to be limiting with respect of the scope of the
accompanying claims. The peptide used in each of the
following examples is a variant Peptide T of formula (I)
having the sequence D-Ala-Ser-Thr-Thr-Thr-Asn-Tyr-Thr-
Amide.
EXAMPLES
Example i - HTLV-1 Myelopathp
A 45 year old female was diagnosed as HTLV-1
seropositive after experiencing dysesthesia of the feet,
pain in the feet and legs, weakness of the legs and
urinary frequency. Her neurolo~~~~ examination confinaed
increased reflexes, spasticity of the lower limbs and
pyramidal weakness of the legs. The diagnosis was
confirmed by somatosensory and auditory evoked potentials
and HTLV-1 seropositivity. Therapy consisting of 10
milligrams of Peptide T was given subcutaneously each
morning. In two months time, the patient reporters
feeling improved. She could lift both feet off the
ground instead of dragging them and could walk without a
cane. She could stand without support and experienced
decreased burning in her feet and knees, could climb
stairs for the first time in 2 years, and had decreased
urinary frequency.
After another 2 months of therapy, the patient
was still experiencing decreased symptoms and improved
walking. Her neurological examination remained
unchanged.
CA 02221826 1998-O1-28
14
Having run out of Peptide T during a holiday,
the patient was without therapy for 5 days and noted
progressive fatigue and became bed-bound. Within two
weeks of stopping the Peptide T treatment, a11 of her
symptoms had recurred and on restarting Peptide T, her
symptoms again resolved. At various times she stopped
therapy and her symptoms worsened but when restarted, she
improved.
Example 2 - Multiple Sclerosis
A 40 year old female was diagnosed as having MS
after presenting with weakness, loss of balance, double
vision, and paraesthesia in her right arm at age 23. She
was treated with prednisone and later with physiotherapy.
She remained unable to walk without a cane or a walker,
was depressed, showed horizontal nystagmus, and weakness
of hip flexors bilaterally, weakness of knee flexors and
of dorsilflexors of the feet. Tone was increased in both
lower limbs and she had bilateral ankle clonus. Deep
tendon reflexes were 2+ in the arms, 3+ in both knees and
ankles and the plantar responses were extensor. She was
treated with Lioresal (Baclofen) with some improvement;
however, she experienced progressive worsening until she
became wheelchair dependent and complained of weakness,
spasticity, clonus, urinary incontinence and recurrent
urinary tract infections. When she was evaluated her MRI
scan of the brain showed findings consistent with
multiple sclerosis.
She was started on 1o milligram subcutaneous
injections of Peptide T daily. After i 1/2 weeKS, her
symptoms had improved. She was assessed again after
about 5 weeks and reported functional improvement. After
6 months she was showing maintained improvement in her
symptoms. Her frequency of nocturia was reduced, fine
motor control improved, stuttering decreased, her legs
were less spastic and she could stand with minimal
support. She showed marked symptomatic improvement in
CA 02221826 1998-O1-28
intellectual and motor functioning within a few weeks
after starting treatment with Peptide T, such improvement
being sustained over a 6 month period. Worsening of
symptoms occurred when the patient stopped Peptide T for
5 3 weeks, but improved when she restarted the drug.
Example 3 - Multiple Sclerosis
A 28 year old female was diagnosed with optic
neuritis secondary to multiple sclerosis after presenting
10 with numbness, impaired motor function, and blurred
vision (20/300 bilaterally). Her somatic neurological
examination was within normal limits. Minor episodes of
numbness and impaired speech, balance and co-ordination
had occurred over 6 months, as well as headache and loss
15 of vision.
Peptide T therapy was started. Six (6) days
later a reassessment showed remarxably improved visual
acuity (21/30 bilaterally). The patient noted functional
improvement over the next week. A prior episode of optic
neuritis took six months to recover (compatible with the
natural history of MS) compared to this episode which
recovered much more quickly than would be expected for an
episode of MS-induced optic neuritis.
Example 4 - Multiple 8clarosis
A 34 year old woman with her first multiple
sclerosis episode had optic neuritis and complete
blindness in the right eye for 2 weeks, numbness in her
right leg and then both legs. Her symptoms worsened.
She was give prednisone and experienced some improvement.
She had worsening of her ataxia and blurred vision. She
was given prednisone 80 milligrams per day. An MRI scan
showed multiple high intensity signals periventricularly
as well as in the brain stem, consistent with the
diagnosis of MS. The patient complained of oscillopsia.
The ataxia and some visual problems seemed to improve on
steroids. Another MRI scan about 16 months later showed
CA 02221826 1998-O1-28
16
extensive periventricular white matter disease with
involvement of the corpus collosum. Findings were
typical of demyelination consistent with MS. At that
time the patient showed resting oscillatory lateral
beating nystagmus and lateral nystagmus with bilateral
gaze, an ataxic gait, a slight impairment on her heel
shin test but good finger nose testing. The tone was
increased in her lower limbs and she had non-sustained
ankle clonus bilaterally. Her knee jerk was increased on
the right compared to the left. Plantar responses were
both upgoing. She had decreased position, vibration,
light touch and cold sensation in the feet compared to
the hands.
About 2 months later the patient was started on
Peptide T 1_0 milligrams subcutaneous~y daily. Within 1
to 2 weeks she reported subjective improvement. She
experienced improved feelings in her fingers, fine
movements of her hands and improved cognitive function.
When she stopped Peptide T therapy she noticed an
increased fatigue and ataxia. She obtained minimal
symptomatic improvement from prednisone 150 mg daily.
After restarting Peptide T, she noted a remarkable
improvement of her fatigue, ataxia and fine motor
function.
Egam~le 5 - Hultipl. sclerosis
A 56 year old female with a history of
dizziness, ataxia, episodes of vertigo, impairment of
motor function and generalized weakness of the legs was
treated with dilantin and admitted to hospital.
Subsequent examination showed vertical nystagmus, some
saccadic smooth pursuit and an impaired tandem gait. She
was reassessed about 2 years later for episodes of
dizziness, and complaints of leg spasms. Her physical
examination showed decreased visual fields with a partial
left lateral hemianopsia in the lateral field and a right
constricted field. She showed impaired tandem gait,
CA 02221826 1998-O1-28
17
decreased right hip flexion and strength and decreased
deep tendon reflexes in the right brachioradialis
compared to the left and in the right knee compared to
the left. Plantar response was downgoing and she had
upwards gaze vertical nystagmus as previously noted.
The patient was treated with Peptide T 10
milligrams subcutaneouslv daily and within 10 days
reported increased energy and intellectual function, and
improved vision. When Peptide T therapy was stopped, she
l0 regressed symptomatically to her pre-drug status. Her
physical examination at that time showed no change from
her examination before Peptide T therapy was begun.
Although preferred embodiments of the invention
are described herein in detail, it will be understood by
those skilled in the art that variations may be made
thereto without departing from the spirit of the
invention or the scope of the appended claims.
CA 02221826 1998-O1-28
18
REFERENCES
1. Pert, C.B., Hill, J.M., Ruff, M.R., Berman, R.M.,
Robey, W.G., Arthur, L.O., Ruscetti, F.W. and
Farrar, W.L. Octapeptidies Deduced from the
Neuropeptide Receptor-Like Pattern of Antigen T4 in
Brain Potently Inhibit Human Immunodeficiency Virus
Receptor Binding and T-Cell Infectivity. Proc.
Natl. Sci. U.S.A. 83:9254-9258, 1986.
2. Pert, C.B. and Ruff, M.R. Peptide T~e: A
Pentapeptide Sequence in the AIDS Virus Envelope
which Blocks Infectivity is Essentially Conserved
Across Nine Isolates. Clin. Neuropharmacol.,
9(4):S198, 1986.
3. Barrera, C.M., Kastin, A.J. and Banks, W.A.
D-(Alas) - Peptide T - Amide is Transported from
Blood to Brain by a Saturable Systems. Brain Res.
Bull. 19:629-633, 1987.
4. Ruff, M.R., Martin, M.B., Ginns, E..I., Farrar, W.L.,
Wahl, S.M. and Pert, C.B. CD4 Receptor Binding
Peptides that Block HIV Infectivity Cause Human
Monocyte Chemotaxis: Relationship to Vasoactive
Intestinal Polypeptide. FEBS Lett. 211:17-22, 1987.
5. Brenneman, D.E., Westbrook, G.L., Fitzgerald, S.P.,
Ennist, D.L., Elkins, K.L., Ruff, M.R. and Pert,
C.B. Neuronal Cell Killing by the Envelope Protein
of HIV and its prevention by Vasointestinal peptide.
Nature. 335:639-642, 1988.
6. Brenneman, D.E., Buzy, J.M., Ruff, M.R. and Pert,
C.B. Peptide T Sequences Prevent Neuronal Cell
Death Produced by the Envelope Protein (gp120) of
the Human Immunodeficiency virus. Drug' Dev. Res.
l5:361-369, 1988.
7. Komisaruk, B.R., Banas, C., Heller, S.B., Whipple,
B., Barbat, G. and Jordan, F. Analgesia Produced by
Vasoactive Intestinal Peptide Administered Directly
to the Spinal Cord in Rats. In Vasoactive
Intestinal Peptide and Related Peptides. Ed. Said,
S.I. and Mutt, V. Annals of the NY Acad. Sci.
527:650-654, 1988.
8. Buzy, T.P., Haseltine, P.N.R., Parker, E.S., Eaton,
E., Ingraham, L.J., Gill, M., Ruff, M.R., Pert, C.B.
and Goodwin, F.K. Improvements in AIDS Patients on
Peptide T. The Lancet, July 22, pp.226-227, 1989.
9. Marcusson, J.A., Lazega, D., Pert, C.B., Ruff, M.R.,
Sundquist, K.G. and Wetterberg, L. Peptide T and
Psoriasis. Acta. Derm. Venereol. (Stockh.l Suppl.
146:117-12l, 1989.
CA 02221826 1998-O1-28
19
10. Marcusson, J.A., and Wetterberg, L. Peptide-T in
the Treatment of Psoriasis and Psoriatic Arthritis:
A Case Report. Acta. Dean. Venereol. (Stockh.)
Suppl. 69:86-88, 1989.
11. Zorn, N.E., Buckley, A.R. and Russell, D.H.
Vasoactive Intestinal Peptide and Peptide T Activate
Protein Kinase C in Purified Rat Spenocyte Nuclei.
The Endoc. Society. (Abstract), 1989.
CA 02221826 1998-04-O1
SEQUENCE LISTING
1. GENERAL INFORMATION
(i) APPLICANT:
(A) NAME: MacFadden, Douglas K.
(B) ADDRESS: 288 Chatham Avenue
(C) CITY: Toronto
(D) STATE/PROVINCE: Ontario
(E) COUNTRY: Canada
(F) POSTAL CODE/ZIP: M4J 1K9
(G) TELEPHONE:
(H) TELEFAX:
(I) TELEX:
(A) NAME: Carlen, Peter L.
(B) ADDRESS: 529 St. Clements Avenue
(C) CITY: Toronto
(D) STATE/PROVINCE: Ontario
(E) COUNTRY: Canada
(F) POSTAL CODE/ZIP: M5N 1M3
(G) TELEPHONE:
(H) TELEFAX:
(I) TELEX:
(A) NAME: Reed-Doob, Penelope
(B) ADDRESS: 1 Fenwick Avenue
(C) CITY: Toronto
(D) STATE/PROVINCE: Ontario
(E) COUNTRY: Canada
CA 02221826 1998-04-O1
21
(F) POSTAL CODE/ZIP: M4J 3H2
(G) TELEPHONE:
(H) TELEFAX:
(I) TELEX:
(ii) TITLE OF INVENTION: Peptide T and Related Peptides in
the Treatment of HTLV-1 Myelopathy and Multiple
Sclerosis
(iii) NUMBER OF SEQUENCES: 1
(iv) CORRESPONDENCE ADDRESS:
(A) NAME: SMITH LYONS
(B) STREET ADDRESS: 40 King St. West, Suite 5800
(C) CITY: Toronto
(D) STATE/PROVINCE: Ontario
(E) POSTAL CODE/ZIP: M5H 3Z7
(F) TELEPHONE: (416) 369-7200
(G) TELEFAX: (416) 369-7250
(v) COMP UTER-READABLE FORM
(A) COMPUTER: IBM PC Compatible
(B) OPERATING SYSTEM: MS. DOS Version 6.21
(C) SOFTWARE: ASCII Text
(vi) CURRENT
APPLICATION
DATA
(A) APPLICATION NUMBER: 2,221,826
(B) FILING DATE: 28 January 1998
(C) CLASSIFICATION:
(vii) PRIOR
APPLICATION
DATA
(A) APPLICATION NUMBER: US 08/554,758
CA 02221826 1998-04-O1
22
(B) FILING DATE: 08 November 1995
(C) CLASSIFICATION: A 61K 38/08
(viii) PATENT AGENT INFORMATION
(A) NAME: SMITH LYONS
(B) REFERENCE NUMBER: CBB582-Can
2. INFORMATION FOR SEQ ID NO.: 1
(i} SEQUENCE CHARACTERISTICS
(A) LENGTH: 8
(B) TYPE: Amino Acid
(C) STRANDEDNESS:
(D) TYPOLOGY:
(ii) MOLECULE TYPE:
(iii) HYPOTHETICAL:
(iv) ANTI-SENSE:
(v) FRAGMENT TYPE:
(vi) ORIGINAL SOURCE:
(vii) IMMEDIATE SOURCE:
(viii) POSITION IN GENOME
(A) CHROMOSOME/SEGMENT:
(B) MAP POSITION:
(C) UNITS:
(ix) FEATURE
(A) NAME/KEY:
(B) LOCATION:
(C) IDENTIFICATION METHOD:
(D) OTHER INFORMATION: The amino acid terminal
CA 02221826 1998-04-O1
23
residue Xaa is selected from the group
consisting of Ala and D-Ala and the carboxy
terminal residue Xaa is selected from the
group consisting of Thr and Thr-amide.
(x) PUBLICATION
INFORMATION
(A) AUTHORS:
(B) TITLE:
(C) JOURNAL:
(D) VOLUME:
(E) ISSUE:
(F) PAGES:
(G) DATE:
(H) DOCUMENT NUMBER: US 5,686,417
(I) FILING DATE: 08 November 1995
(J) PUBLICATION DATE: 11 November 1997
(xi) RELEVANT
RESIDUES
IN SEQ
ID NO.:
3. SEQUENCE DESCRIPTION: SEQ ID NO.: 1
Xaa Ser Thr Thr Thr Asn Tyr Xaa
1 5
