U.S. patent application number 10/813661 was filed with the patent office on 2004-12-30 for methods for alleviating symptoms associated with neuropathic conditions comprising administration of low levels of antibodies.
Invention is credited to McMichael, John.
Application Number | 20040265312 10/813661 |
Document ID | / |
Family ID | 32041671 |
Filed Date | 2004-12-30 |
United States Patent
Application |
20040265312 |
Kind Code |
A1 |
McMichael, John |
December 30, 2004 |
Methods for alleviating symptoms associated with neuropathic
conditions comprising administration of low levels of
antibodies
Abstract
The invention provides methods and compositions for alleviating
the symptoms of neuropathic conditions with a pharmaceutical
composition including an effective amount of anti-glutamic acid
decarboxylase (anti-GAD) antibodies.
Inventors: |
McMichael, John; (Delanson,
NY) |
Correspondence
Address: |
MARSHALL, GERSTEIN & BORUN LLP
6300 SEARS TOWER
233 S. WACKER DRIVE
CHICAGO
IL
60606
US
|
Family ID: |
32041671 |
Appl. No.: |
10/813661 |
Filed: |
March 30, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10813661 |
Mar 30, 2004 |
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10223498 |
Aug 19, 2002 |
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6713058 |
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10223498 |
Aug 19, 2002 |
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09918343 |
Jul 30, 2001 |
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6436401 |
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09918343 |
Jul 30, 2001 |
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09774770 |
Jan 31, 2001 |
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6294171 |
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09774770 |
Jan 31, 2001 |
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09514993 |
Feb 29, 2000 |
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6187309 |
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60153838 |
Sep 14, 1999 |
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Current U.S.
Class: |
424/146.1 |
Current CPC
Class: |
A61K 2039/505 20130101;
A61P 25/00 20180101; C07K 16/26 20130101; C07K 16/40 20130101; C07K
16/1027 20130101; A61P 25/16 20180101; A61P 25/02 20180101 |
Class at
Publication: |
424/146.1 |
International
Class: |
A61K 039/395 |
Claims
What is claimed is:
1. A method of alleviating symptoms of neuropathic conditions
comprising the step of administering anti-glutamic acid
decarboxylase (anti-GAD) antibody in an amount effective to
alleviate symptoms of said neuropathic condition.
2. The method of claim 1, wherein the neuropathic conditions are
selected from the group consisting of autism, multiple sclerosis,
Parkinson's disease, attention deficit disorder, diabetic
neuropathy and pain neuropathy associated with chemotherapy
treatment.
3. The method of claim 1 wherein the anti-GAD antibodies are
monoclonal antibodies.
4. The method of claim 1 wherein the administration step is
oral.
5. The method of claim 4 wherein the administration step is
sublingual.
6. The method of claim 4 wherein the anti-GAD antibodies are
administered in an enterically protected form.
7. The method of claim 1 wherein the administration step is by
injection.
8. The method of claim 7 wherein the administration step is by
subcutaneous injection.
9. The method of claim 1 comprising less than 1.0 mg of anti-GAD
antibodies.
10. The method of claim 9 comprising less than 1.0 .mu.g of
anti-GAD antibodies.
11. The method of claim 9 comprising from 1.times.10.sup.-6 to
1.times.10.sup.-2 .mu.g of anti-GAD antibodies.
12. The method of claim 9 comprising from 1.times.10.sup.-5 to
1.times.10.sup.-2 .mu.g of anti-GAD antibodies.
13. The method of claim 1, wherein the anti-GAD antibody is
specific for GAD-65.
14. The method of claim 1, wherein the anti-GAD antibody is
specific for GAD-67.
15. A pharmaceutical composition for administration to a subject
for alleviating symptoms of neuropathic conditions comprising less
than 1.0 mg of anti-GAD antibodies.
16. The pharmaceutical composition of claim 15 comprising less than
0.1 .mu.g of anti-GAD antibodies.
17. The pharmaceutical composition of claim 15 comprising from
1.times.10.sup.6 to 1.times.10.sup.-2 .mu.g of anti-GAD
antibodies.
18. The pharmaceutical composition of claim 15 comprising from
1.times.10.sup.-5 to 1.times.10.sup.-2 .mu.g of anti-GAD
antibodies.
19. The pharmaceutical composition of claim 15, wherein the
antibodies are specific for GAD-65.
20. The pharmaceutical composition of claim 15, wherein the
antibodies are specific for GAD-67.
Description
[0001] This application is a continuation-in-part of U.S.
application Ser. No. 09/918,343 filed Jul. 30, 2001 and issued Aug.
20, 2002 as U.S. Pat. No. 6,436,401, which is a
continuation-in-part of U.S. application Ser. No. 09/774,770 filed
on Jan. 31, 2001 and issued Sep. 25, 2001 as U.S. Pat. No.
6,294,171, which is a continuation-in-part of U.S. application Ser.
No. 09/514,993 filed on Feb. 29, 2000 and issued Feb. 13, 2001 as
U.S. Pat. No. 6,187,309, which claims benefit of U.S. Provisional
Application Ser. No. 60/153,838 filed on Sep. 14, 1999; the
disclosures of which are hereby incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] The therapeutic use of antibodies is generally limited to:
(a) immunotherapy, where a specific antibody directed against a
discreet antigen is used to counter the effect of that antigen,
e.g., using an antitoxin administered to neutralize a toxin, or
antibody against an infectious agent to interrupt the
pathophysiological process induced by that target organism; (b) the
administration, often i.v., of high levels of antibody (gamma
globulin therapy) to compensate for transient or permanent immune
deficiency; and (c) monoclonal antibody therapy to combat cancer,
certain autoimmune disorders, metabolic diseases, and symptoms
associated with neuropathic conditions. In all these cases,
antibody is provided in relatively high concentrations for the
purpose of having that antibody combine directly with its target
antigen to render that antigen inoperable, non-infectious or
neutralized. For example, Gamimune.TM. (Bayer Biological) contains
50 mg protein (immunoglobin) per mL and normal dosing can be up to
1000 mg/kg body weight. Gammar--P I.V. (Aventis Behring) is
administered at dosages up to 400 mg/kg body weight. Bayhep B.TM.
(Hepatitis B Immunoglobulin) (Bayer Biological) is 15-18% protein
[immunoglobulin] is administered at dosages of up to 0.6 ml/kg body
weight=0.01 g/kg=100 mg/kg. Further, Imogam Rabies--H.TM. (Aventis
Pasteur) is 10-18% protein and is administered at a dosage of 0.133
ml/kg (240 mg/kg) body weight.
[0003] Diabetes mellitus is a metabolic disease state that is
caused by a deficiency of insulin (Type I diabetes) or by the
body's resistance to diabetes (Type II diabetes). The disease is
characterized by chronic hyperglycemia, glycosuria, water and
electrolyte loss, ketoacidosis, neuropathy, retinopathy,
nephropathy, increased susceptibility to infection, and coma. Type
I diabetes results from the autoimmune destruction of beta cells of
the pancreas. Thus, proteins produced by beta cells have been a
prime target in the study of diabetes as potential autoantigens
that serve as the target for the immune response against the beta
cells. One autoantigen found to correspond to the onset of Type I
diabetes is glutamic acid decarboxylase (GAD) [Tisch, Roland, et
al., Nature 366:72-75 (1993)]. Another example of a beta cell
autoantigen is insulin.
[0004] Much of the research involving the autoimmune response
against beta cells or the autoantigens thought to be involved in
the autoimmune response has included the administration of
autoantigens, immunogenic portions of autoantigens, or molecules
that mimic the autoantigens. Tian, Jide, et al., Nat Med 2(12):
1348-53 (1996) discusses administration of GAD to alter the diverse
immune response that can lead to diabetes. Ramiya, Vijayakumar K.,
et al., Autoimmunity 26:139-151 (1997) discussed administration of
insulin and GAD in non-obese diabetic mouse to achieve
anti-diabetic affects.
[0005] Glutamate decarboxylase (hereafter GAD) is the
pyridoxal-5'-phosphate dependent enzyme that synthesizes
gamma-aminobutyric acid (GABA), the major inhibitory
neurotransmitter in vertebrate brain (Qu et al., Protein Science
7:1092-1105 (1998)). Glutamic acid decarboxylase is of two types,
GAD-65, which is highest in concentrations in the pancreas, and
GAD-67, which is highest in concentration in the central nervous
system. Each GAD is composed of two major domains: a C-terminal
domain of about 500 amino acids, and a 95-100 amino acid n-terminal
domain. The C-terminal domain contains the pyridoxal-P binding site
and lengthy segments that have identical sequences in GAD-65 and
GAD-67. The amino terminal domain of GAD targets membranes and
forms heteromultimers of GAD-65 and GAD-67 (Dirkx et al., J. Biol.
Chem. 270:2241-2246 (1995)). Phosphorylation sites have been found
in GAD-65 (Namchuck et al., J. Biol. Chem. 272:1548-1557 (1997)).
Pyridoxal-P plays a key role in the regulation of GAD activity. GAD
is unusual, if not unique, among pyridoxal-P-dependent enzymes in
the brain because it is present mainly in an inactive apoenzyme
(GAD without bound pyridoxal-P) (Martin et al., J. Neuroscience
11:2725-2731 (1991)). This apoGAD serves as a reservoir of inactive
enzymes that can be converted to active holoGAD when additional
GABA synethesis is required (Porter et al., Biochem. J. 231:705-712
(1985)). The invention disclosed herein found treatment with GAD-65
antibody was most effective but not limited to treating patients
suffering from diabetes while treatment with GAD-67 antibody was
most effective but not limited to treating patients suffering from
CNS disorders such as but not limited to multiple sclerosis,
autism, Parkinson's disease, and pain related neuropathy.
[0006] Of interest to the present application is the disclosure of
co-owned U.S. Pat. No. 6,187,309, which is directed to the
administration of anti-rubella antibodies for the treatment of
symptoms of various central nervous system diseases including
autism, multiple sclerosis, attention deficit disorder (ADD) and
attention deficit hyperactivity disorder (ADHD). Examples therein
demonstrated the efficacy of treating the symptoms of those disease
states with dosages of from 0.1 mg to 1 mg of anti-rubella antibody
per dose.
[0007] Autism is a complex developmental disorder that appears in
the first 3 years of life. It affects the brain's normal
development of social and communication skills. Autism is a
spectrum that encompasses a wide continuum of behavior. Core
features included impaired social interactions, impaired verbal and
nonverbal communication, and restricted and repetitive patterns of
behavior. The symptoms may vary from quite mild to quite severe.
Autisms is a physical condition linked to abnormal biology and
neurochemistry possibly linked to autoimmune disorder of type 1
diabetes and the autoantigen GAD.
[0008] The most distinctive feature of autistic children is that
they appear isolated from the world around them and may appear
detached, aloof, or in a dreamlike world. Autistic children often
appear only vaguely aware of others in their environment, including
family members, and frequently display unusual mannerisms and
engage in ritualistic behavior. Appropriate play with other
children or toys is uncommon and there is often a great interest in
inanimate objects, especially mechanical devices and appliances. In
many cases the disorder is evident during the first 30 months of
life. Autistic children are normal in appearance, physically well
developed and are usually boys (by a ratio of 3:1). Historically,
children were frequently institutionalized by the ages of nine or
ten because their parents were no longer able to control them.
While, the availability and effectiveness of behavioral support
services and advances in treatment and education of treatment of
children with autism have reversed the trend toward
institutionalization autistic children still require significant
resources for their care.
[0009] There are no medical tests that can be used to determine
autism. Instead, the diagnosis of autism is made when a subject
displays six of 12 characteristic behaviors that match the criteria
in the Diagnostic and Statistical Manual, Fourth Edition (DSM IV),
published by the American Psychiatric Association. Subjects with
autism, compared to other disabled persons of commensurate ability,
are more difficult to teach and comparatively have significantly
greater problems acquiring and using language and relating
socially. Historically, about 75 percent of subjects with autism
are classified as mentally retarded.
[0010] Autism was first described by Dr. Leo Kanner, a psychiatrist
at John Hopkins University in the 1940's who examined a group of 11
children who were self-absorbed and who had severe social,
communication, and behavioral problems. It was originally believed
that subjects with autism had good cognitive potentialities and
that autistic children possessed latent genius that could be
unlocked by discovery of the appropriate key for that child.
Associated with that belief was the misconception that autism was
caused by parent's behavior and particularly was the result of
"cold" mothers whose projection of hopelessness, despair and apathy
was projected onto their children. More recently, this
psychoanalytic view of autism was replaced by a neurologically
based approach and continuing study as to the organic causes of the
disease. Of interest to the present invention is the observation
that the incidence of autism may be increasing in the population in
the United States and other developed countries. In a recent report
to the state legislature, the California Department of
Developmental Services has described a three-fold increase in the
number of persons with autism statewide between 1987 and 1998 and a
doubling of the percentage of total mental health client population
accounted for by persons with autism during that time. Similar
observations have been made elsewhere in the United States and in
other developed countries.
[0011] Much speculation concerning the apparent increase in the
incidence of autism has focused on possible links between
immunological causes of the disease. Prenatal and postnatal
infections have been implicated as possible causes of autism. In
particular, congenital rubella and HSV infections have been
associated with incidence of autism.
[0012] Links between a family history of autoimmune disorders such
as type 1 diabetes, adult rheumatoid arthritis, hypothroidism and
systemic lupus erythematosus have also been observed with the
occurrence of autism suggesting that immune dysfunction may
interact with various environmental factors to play a role in
autism pathogenesis. Journal of Child Neurology, vol. 14, number 6
pp. 388-394 (June 1999).
[0013] Other workers have reported an association between autism
and the presence of antibodies against human herpes virus-6, as
well as autoantibodies against tissues of the central nervous
system such as myelin basic protein (MBP). See Warren et al.
Neuropsycholobiology 34:72-75 (1996).
[0014] In addition, Asperger, "Die Pyschopathologie des
coeliakakranken kindes." Ann, Pediatr. 197: 146-151 (1961) reported
an association between intestinal dysfunction and autism. Other
studies including those of Walker-Smith et al. Lancet ii: 883-84
(1972) and D'Eufemia Acta Paediatrica 85: 1076-79 (1996) which show
low concentrations of alpha-1 anti-trypsin and abnormal intestinal
permeability respectively suggest that the consequences of an
inflamed or dysfunctional intestine may play a part in behavioral
changes in some patients.
[0015] Recently, attention has focused on the possibility of an
association between childhood vaccinations and autism. Both,
infection and the immune reaction resulting from immunization would
be consistent with an immunological cause of the disease. In
particular, the combined measles, mumps, and rubella (MMR) vaccine,
rather than the monovalent measles vaccine, has been associated
with the onset of autism. See Gupta Proc. Natl. Autism Assn.
Chicago 1996, 455-460. This observation has led to the suggestion
that some form of immune overload may constitute an aspect of
susceptibility to measles vaccination. As a consequence, some
workers in the field have suggested a suspension of administration
of the combined MMR vaccine in favor of sequential administration
over time of the three vaccine components.
[0016] Wakefield et al. Lancet 351: 637-641 (1998) identified a
chronic enterocolitis in children related to neuropsychiactric
dysfunction and autism. In most cases, the onset of symptoms
occurred after immunization with the MMR vaccine. While Wakefield
et al. stated that they had not proven an association between MMR
vaccine and the syndrome described they suggested that ongoing
virological and epidemiological studies might resolve the issue. At
that time, Wakefield et al. suggested that the published evidence
was inadequate to show whether there was a change in incidence or a
link with MMR vaccine. But see, Peltola, et al. Lancet
351:1327-1328 (1998) which reported work in which children who
received the MMR vaccination in Finland between 1982 and 1996 were
traced but failed to find support for the suggestion that the
vaccination could cause autism or bowel disease. Additional work by
Wakefield and others indicates that there exists live measles
(rubella) vaccine virus in the guts of the vast majority of
autistic children and that autistic patients often have a serum
antibody titer to rubella virus hundreds of times higher than
normal, suggesting continual or oft-repeated exposure and/or
incomplete or failed elimination of the virus by the human
response. Significantly, if rubella virus were present in the gut,
as suggested by photomicrographs by Wakefield, such virus particles
would be protected from the body's immune defenses because
antibodies do not generally travel from the circulatory system to
the lumen of the intestinal tract. Accordingly, massive numbers of
circulating antibodies may be of no real protective value against
rubella virus in the gut.
[0017] While the possibility of a link between MMR vaccination and
autism has prompted suggestions that measles vaccine be applied
singly rather than as a component of a multi-component vaccine as a
means for reducing the incidence of autism there remains a need for
method of treating the symptoms of autism in subjects who already
affected by the condition.
[0018] Multiple sclerosis (MS) is a slowly progressing
demyelinating disease of the central nervous system which is
insidious and characterized by multiple and varied neurological
symptoms characterized by remissions and exacerbations. These
repeated episodes of inflammation of the nervous tissue generally
occur in the area of the central nervous system like the brain and
spinal cord. The location of the inflammation varies from person to
person and from episode to episode. The inflammation destroys the
covering of the nerve cells in that area (myelin sheath), leaving
multiple areas of scar tissue (sclerosis) along the covering of the
nerve cells. This results in slowing or blocking the transmission
of nerve impulses in that area, leading to the symptoms of multiple
sclerosis. Symptoms vary because the location and extent of each
attack varies. There is usually a stepwise progression of the
disorder, with episodes that last days, weeks, or months
alternating with times of reduced or no symptoms (remission). The
onset of the disease usually occurs between 20 and 50 years of age
with a peak occurring in people 30 years old. MS is believed to be
immunological in nature but treatment with immuno-suppressive
agents is not advised. The prevalence of MS varies widely with
location with the highest prevalence found at higher latitudes in
northern Europe and northern North America. The geographic
variation suggests that MS may in part be caused by the action of
some environmental factor that is more common in high
latitudes.
[0019] Symptoms of multiple sclerosis include, but are not limited
to, weakness of one or more extremities, paralysis of one or more
extremities, tremors of one or more extremities, muscle spasticity,
muscle atrophy, dysfunctional movement beginning in the legs,
numbness, tingling, facial pain, loss of vision, double vision, eye
discomfort, rapid eye movements, decreased coordination, loss of
balance, dizziness, vertigo, urinary hesitancy, strong urge to
urinate, frequent need to urinate, decreased memory, decreased
spontaneity, decreased judgment, loss of ability to think
abstractly, depression, decreased attention span, slurred speech,
and fatigue. Symptoms vary with each attack. They may last days to
months, then reduce or disappear, then reoccur periodically.
[0020] There is no known cure for multiple sclerosis. There are,
however, promising new therapies that may decrease exacerbations
and delay progression of the disease. Treatment is aimed at
controlling symptoms and maintaining function to give the maximum
quality of life. Patients with a relapsing-remitting course are now
placed on immune modulating therapy that requires injection under
the skin or in the muscle once or several times a week. This
treatment is in the form of interferon (such as Avonex or
Betaseron) or another medicine called glatiramer acetate
(Copaxone). Other than protective therapies, steroids are given to
decrease the severity of an attack if it occurs. Other medicines
include Baclofen, Tizanidine, or Diazepammay may be used to reduce
muscle spasticity. Cholinergic medications may be helpful to reduce
urinary problems. Antidepressant medications may be helpful for
mood or behavior symptoms. Amantadine may be given for fatigue.
There is a need, however, in the art for more effective treatment
for multiple sclerosis.
[0021] Huntington's disease is an inherited condition characterized
by abnormal body movements, dementia, and psychiatric problems.
This progressive disease involves wasting (degeneration) of nerve
cells in the brain. Huntington's disease is inherited as a single
faulty gene on chromosome #4. There is a part of the gene that is
repeated in multiple copies. The greater number of repeats, the
more likely it is that the person will develop symptoms and the
greater the chance they will occur at a younger age. The disease
may occur earlier and more severely in each succeeding affected
generation because the number of repeats can increase.
[0022] The molecular mechanisms responsible for delayed onset,
selective pattern of neuropathology, and cell death in Huntington's
disease is unknown. However, insoluble huntington protein
aggregates have been detected in an in vitro model system as well
as in transgenic animals, fly models, cell culture systems, and
brains of Huntington disease patients (DiFiglia et al., Science
277:1990-1993 (1998)). This study demonstrated that mAb 1C2 as well
as the chemical compounds Congo red, thioflavine S, Direct fast
yellow, and chrysamine G are capable of preventing Huntington
aggregation in vitro, at least partially (Id., at 6743). Another
antibody treatment method that is being developed is using
intracellular intrabodies as a means of blocking the pathogenesis
of Huntington's disease (Lecerf et al., Proc. Natl. Acad. Sci. USA
98:4764-4769 (2001)).
[0023] Symptoms do not usually appear until adulthood, typically
between ages 35 and 50 years old, but this depends on the number of
repeats found in the gene so it may appear in younger people as
well. In children, symptoms may appear to be Parkinson's Disease
with rigidity, slow movements, and tremors. There is a progressive
loss of mental function, including personality changes, and loss of
cognitive functions such as judgment and speech. Abnormal facial
and body movements develop, including jerking movements. Symptoms
of the disease also include irritability, restlessness, antisocial
behavior, psychosis, paranoia, hallucinations, facial movements,
progressive dementia, loss of memory, loss of judgment, speech
changes, loss of other functions, personality changes,
disorientation and confusion, unsteady gait, abnormal (choreiform)
movements including jerking movements of the arms, legs, face, and
trunk, speech impairment, anxiety, stress, tension and difficulty
in swallowing.
[0024] There is no cure for Huntington's disease and there is no
known way to stop progression of the disorder. Genetic counseling
is advised if there is a family history of Huntington's disease.
This may include DNA analysis of multiple family members. Treatment
is aimed at slowing progression and maximizing ability to function
for as long as possible. Medications vary depending on the
symptoms. Dopamine blockers such as haloperidol or phenothiazine
medications may reduce abnormal behaviors and movements. Reserpine
and other medications have been used, with varying success. Drugs
like Tetrabenazine and Amantidine are used to try to control extra
movements. There has been some evidence to suggest that Co-Enzyme
Q10 may minimally decrease progression of the disease.
[0025] Alternative therapies such as using antibodies to treat
Huntington's disease began when antibodies directed against the
transferring receptor (OX-26) were fused to nerve growth factor.
This preventative fusion neurotrophic factor-antibody conjugate was
shown to prevent degeneration of central nerve growth factor
responsive neurons following systemic administration (Kordower et
al., Proc. Natl. Acad. Sci. 91:9077-9080 (1994). Other antibodies
that may prevent neuron degeneration include the antibody 1C2,
which selectively recognizes elongated polyQ chains which
suppresses the aggregation of HD exon 1 protein (Heiser et al.,
Proc. Natl. Acad. Sci. 97:6739-6744 (2000)). In addition, the use
of intracellular antibodies (intrabodies) has helped to better
understand the mechanisms of Huntingtons disease. For example,
intrabodies have been developed wherein they target the 17
N-terminal residue of the huntingtin protein, adjacent to the
polyglutamine in HD exon 1. This interaction suggests
intrabody-mediated modulation of abnormal neuronal proteins may
contribute to the treatment of neurodegenerative diseases such as
Huntington disease, Alzheimer's, Parkinson's, prion disease, and
the spinocerebellar ataxis (Lecerf et al., Proc. Natl. Acad. Sci.
98:4764-4769 (2001)). However, these treatments are just in their
experimental stages, are designed to prevent further wasting of
neurons, and only provide a small amount of insight into the
possible pathology of Huntington's disease. Therefore, there is a
need in the art for alternative therapies that provide effective
treatment of Huntington's disease.
[0026] Parkinson's disease is a disorder of the brain characterized
by shaking and difficulty with walking, movement, and coordination.
The disease is associated with damage to a part of the brain that
is involved in the execution of movement. Parkinson's disease
affects approximately 2 out 1000 people, and most often develops
after age 50. It does occasionally occur in younger adults and
rarely in children. It affects both men and women and is one of the
most common neurologic disorders of the elderly. In some cases, the
disease occurs within families, especially when it affects young
people. Most late onset cases are sporadic. The term "parkinsonism"
refers to any condition that involves a combination of the types of
changes in movement seen in Parkinson's disease, which happens to
be the most common condition causing this group of symptoms.
Parkinsonism may be caused by other disorders or by external
factors.
[0027] Parkinson's disease is caused by progressive deterioration
of the nerve cells of the part of the brain that controls muscle
movement (the basal ganglia and the extra pyramidal area).
Dopamine, which is one of the substances used by cells to transmit
impulses (transmitters), is normally produced in this area.
Deterioration of this area of the brain reduces the amount of
dopamine available to the body. Insufficient dopamine disturbs the
balance between dopamine and other transmitters, such as
acetylcholine. Without dopamine, the nerve cells cannot properly
transmit messages, and this result in the loss of muscle function.
The exact reason that the cells of the brain deteriorate is
unknown. The disorder may affect one or both sides of the body,
with varying degrees of loss of function. Depression also
accompanies this disease due to the person's slow loss of muscle
function. Symptoms include muscle rigidity, loss of balance,
shuffling walk, slow movements, difficulty beginning to walk,
freezing of movement, muscle aches, shaking and tremors, changes in
facial expression, voice/speech changes, and loss of fine motor
skills, frequent falls, and decline in intellectual function.
[0028] There is no known cure for Parkinson's disease. Treatment is
aimed at controlling the symptoms. Medications control symptoms
primarily by controlling the imbalance of transmitters. Many of the
current medications require monitoring due to severe side effects.
Deprenyl may provide some improvements to mildly affected patients.
Amantadine and/or anticholinergic medications may be used to reduce
early or mild tremors. Levodopa is a medication that the body
converts to dopamine. It may be used to increase the body's supply
of dopamine, which may improve balance and movement. Carbidopa is a
medication that reduces the side effects of Levodopa and makes
Levodopa work well. Additional medications that reduce symptoms and
control side effects of primary treatment medications include
antihistamines, antidepressants, dopamine agonists, monoamine
oxidase inhibitors, and others. One alternative treatment in the
experimental stage is allotransplantation of embryonic neural
tissue into the disease CNS. Good clinical results have been shown
for Parkinson's disease (Fahn et al., Neurology 52 [Suppl 2]:A405;
Kopyov et al., Exp. Neurol. 149:97-108 (1998)). Problems with this
alternative treatment are xenografts are rejected and the ethical
issues of using suitable donor tissues. The use of embryonic neural
tissue from pig has been experimented and offers their own problems
of zoonotic infection as well as rejection (Weiss, R. A., Science
285:1221-1222 (1999)). The role of complement appears to be a major
player in porcine tissue rejection (Baker et al., J. of
Neuroscience 20:3415-3424 (2000)). Therefore, due the present state
of treatment of Parkinson's wherein the medications either entail
many side effects or the use of grafts is still in its infancy,
there is a need in the art for more effective treatment for
Parkinson's disease.
[0029] Attention Deficit Disorder (ADD) is the most commonly
diagnosed psychological disorder of childhood, affecting 3% to 5%
of school aged children. Symptoms include developmentally
inappropriate levels of attention, concentration, activity,
distractibility, and impulsivity. There are three sub-categories of
attention deficit disorder: (1) attention deficit/hyperactivity
disorder of the combined type; (2) attention deficit/hyperactivity
disorder of the predominantly inattentive type; and (3) attention
deficit/hyperactivity disorder of the predominantly hyperactive or
impulsive type. Despite much progress in the diagnosis and
treatment of ADD, the treatment for this disorder remains highly
controversial. While the cause of attention deficit disorder is
unknown, scientists have determined a neurological basis for the
disease and genes have been identified that are thought to be
involved in ADD.
[0030] The most effective treatment strategy for ADD is using
psychotropic medications such as Dexedine (dextroamphetamine),
Ritalin (methylphenidate), and Cylert (magnesium pemoline).
Antidepressants (such as amitriptyline or fluoxetine),
tranquilizers (such as thioridazine), alpha-adrenergic agonist
(clonidine), and caffeine have also been tried to treat ADD. The
disadvantage of these drugs is the lack of long term information on
the affect these drugs have on the cognitive and emotional
development of ADD children. In addition, medications such as
antidepressants, tranquilizers, and caffeine have met with little
success. A significant amount of research has been carried out
studying psychological therapeutic treatments such as contingency
management (e.g. time out), cognitive-behavioral treatment (e.g.
self monitoring, verbal self instruction, problem solving
strategies, and self reinforcement), parent counseling, and
individual psychotherapy. Studies using these techniques have
yielded mixed results and no studies have been carried out
combining psychological interventions with stimulant medications.
Therefore, parents are directed to manage the symptoms and direct
the child's energy to constructive and educational paths.
[0031] While the administration of larger quantities of
immunoglobulins is effective in the treatment of many disease
states, there remains a desire in the art for methods for the
treatment and prevention of diabetes, or neuropathic disorders such
as autism, multiple sclerosis, Huntington's disease, Parkinson's
disease, attention deficit disorder, diabetes neuropathy, and pain
neuropathy following chemotherapy.
SUMMARY OF THE INVENTION
[0032] The present invention is directed to the discovery that the
symptoms of neuropathic conditions including, but not limited to
those symptoms associated with diabetes which may be effectively
treated by administration of very low levels of anti-glutamic acid
decarboxylase (anti-GAD) antibodies. Specifically, the antibodies
may be administered in one or in multiple dosages, but the sum of
antibodies administered in any 24 hour period (or daily period) is
less than 10 mg each of anti-GAD, with preferred daily dosages
being less than 1.0 mg and more preferably less than 0.1 mg.
[0033] While the antibody may be monoclonal or polyclonal, it is
preferably monoclonal according to one aspect of the invention. The
antibody may be administered by a variety of manners but is
preferably administered subcutaneously and orally. Suitable methods
of oral administration include oral drench and sublingual
administration. According to another aspect of the invention the
antibody is administered in an enterically protected form.
[0034] The invention provides methods for alleviating symptoms of
neuropathic disorders by administering anti-glutamic acid
decarboxylase (anti-GAD) antibody. Specifically, the invention
provides methods for alleviating symptoms of a neuropathic
condition such as autism, multiple sclerosis, Huntington's disease,
Parkinson's disease, attention deficit disorder, diabetes
neuropathy, and pain neuropathy following chemotherapy by
administering to a patient in need thereof, anti-glutamic acid
decarboxylase (anti-GAD) antibody in an amount effective to treat
one or more symptoms of the neuropathic condition.
[0035] Methods of the invention comprise administration to a
patient suffering from a neuropathic disorders such as autism,
multiple sclerosis, Huntington's disease, Parkinson's disease,
attention deficit disorder, diabetes neuropathy, and pain
neuropathy following chemotherapy an effective amount of
anti-glutamic acid decarboxylase (anti-GAD) antibody. The
anti-glutanic acid decarboxylase is preferably administered in an
amount ranging from about 1.times.10.sup.-1 to 1.times.10.sup.-6
microgram (.mu.g) per day and is preferable formulated in a liquid
vehicle and provided at a concentration of approximately
2.times.10.sup.-2 .mu.g as a single drop. A single drop of
anti-glutamic acid decarboxylase antibody is within the range of
1.times.10.sup.=2 to 1.times.10.sup.-4 micrograms (.mu.g). More
preferably, a drop of anti-glutamic acid decarboxylase antibody is
in the amount of 1.2.times.10.sup.-3 micrograms (.mu.g) per drop.
The anti-glutamic acid decarboxylase antibody is more preferably
administered in an amount ranging from about 1.times.10.sup.-5 to
1.times.10.sup.-2 microgram (.mu.g) or from 1.times.10.sup.-4 to
1.times.10.sup.-2 .mu.g or about 1.times.10.sup.-3 .mu.g per day. A
preferred route of administration is sublingual, but other routes,
such as bucal, oral drench, subcutaneous, intradermal, and
intravenous, are expected to work.
[0036] The invention also provides methods for treating the
symptoms of diabetes comprising the method of administering an
effective amount of a combination of an antibody directed against
GAD. The term "effective amounts of an antibody" is used herein to
describe the amount of antibody administered to a subject to result
in the reduction or elimination of the pathogenic autoimmune
response associated with the onset of diabetes, thereby alleviating
symptoms of diabetes. Preferred amounts of anti-GAD and
anti-insulin antibodies for use according to the disclosed method
are less than 1.0 mg of anti-GAD antibodies, and more preferably
less than 0.5 mg of anti-GAD antibodies. A still more preferred
daily dosage ranges from 1.times.10.sup.-6 to 1.times.10.sup.-2 mg
of anti-GAD antibodies. An even more preferred daily dosage ranges
from 1.times.10.sup.-5 to 1.times.10.sup.-3 mg of anti-GAD
antibodies.
[0037] The invention also provides methods patients suffering for
neuropathic disorders such as autism, multiple sclerosis,
Huntington's disease, Parkinson's disease, attention deficit
disorder, diabetes neuropathy, and pain neuropathy following
chemotherapy comprising the method of administering an effective
amount of anti-glutamic acid decarboxylase (anti-GAD) antibodies
against GAD-65 or GAD-67. The anti-GAD antibodies can be directed
against either GAD-65 or GAD-67 alone or in combination.
[0038] The invention also provides pharmaceutical compositions for
administration to subjects for treatment of the symptoms of
neuropathic conditions such as diabetic neuropathy, Huntington's
disease, Parkinson's disease, autism, multiple sclerosis, attention
deficit disorder (ADD), and pain neuropathy after chemotherapy,
comprising a dosage unit of less than 1.0 mg of anti-GAD antibodies
and preferably less than 1.0 .mu.g of anti-GAD antibody. A still
more preferred dosage unit is less than 0.5 .mu.g of anti-GAD
antibodies, and more preferably less than 0.1 .mu.g of anti-GAD
antibodies. A still more preferred dosage unit ranges from
1.times.10.sup.-6 to 1.times.10.sup.-2 .mu.g of anti-GAD antibodies
with dosage unit ranges of 1.times.10.sup.-5 to 1.times.10.sup.-2
.mu.g or from 1.times.10.sup.4 to 1.times.10.sup.-2 .mu.g or about
1.times.10.sup.-3 .mu.g of anti-GAD antibodies being more
preferred.
[0039] The invention also provides pharmaceutical compositions for
administration to patients for treatment of symptoms of patients
suffering from neuropathic disorders such as autism, multiple
sclerosis, Huntington's disease, Parkinson's disease, attention
deficit disorder, diabetes neuropathy, and pain neuropathy
following chemotherapy comprising an effective amount of
anti-glutamic acid decarboxylase (anti-GAD) antibodies against
GAD-65 or GAD-67. The anti-GAD antibodies can be directed against
either GAD-65 or GAD-67 alone or in combination.
DETAILED DESCRIPTION
[0040] The methods and compositions described herein relate to low
levels of antibodies specific for the autoantigens of pancreatic
beta cells that can reduce or eliminate the pathological
consequences caused by the autoimmune response against the
pancreatic beta cells. The mechanism by which this is accomplished
is not completely understood and is the focus of ongoing research.
Without intending to be bound by any particular theory of the
invention, it is thought that the low levels of the antibodies
specific for the autoantigens are able to prevent the pathogenic
cascade that results from the destruction of the autoantigens by
the immune system, possibly by redirecting the host immune system
or by providing a negative feedback to prevent further autoimmune
response. Particularly, the use of antibodies against GAD and
insulin can be used as a systemic signal to specifically inhibit
the body's aberrant, pathogenic response to the autoimmune response
against GAD and insulin. In addition to the use of the disclosed
method to alleviate symptoms of diabetes, it is further
contemplated that practice of the methods disclosed herein will
prove useful in the prevention of diabetes.
[0041] Symptoms of diabetes which can be treated according to the
methods of the invention include elevated blood sugar level,
elevated hemoglobin A1c level, neuropathy, retinopathy,
ketoacidosis, and glycosuria. With respect to blood sugar levels,
normal levels are <140 mg/dl and diabetic levels are considered
to be levels >140 mg/dl.
[0042] The present invention also provides methods for treating
patients with symptoms of autism by sublingual, or subcutaneously
administering a small amount of anti-GAD antibody. Methods of the
invention are also useful for treating, but not limited to, the
symptoms of autism. In those cases, methods of the invention allow
an autism patient to increase their attention span, sustain a
conversation, develop language skills, communicate with words,
socially interact, decrease repetitive body movements, decrease
tantrums, expand interests, reduce preservation, reduce aggression
to others or self, and increase social skills.
[0043] The present invention also provides methods for treating
patients with symptoms of multiple sclerosis by sublingual or
subcutaneous administration of a small amount of anti-GAD antibody.
Methods of the invention are also useful for treating, but are not
limited to, the symptoms of multiple sclerosis. In those cases,
methods of the invention control or alleviate weakness of one or
more extremities, paralysis of one or more extremities, tremors of
one or more extremities, muscle spasticity, muscle atrophy,
dysfunctional movement beginning in the legs, numbness, tingling,
facial pain, loss of vision, double vision, eye discomfort, rapid
eye movements, decreased coordination, loss of balance, dizziness,
vertigo, urinary hesitancy, strong urge to urinate, frequent need
to urinate, decreased memory, decreased spontaneity, decreased
judgment, loss of ability to think abstractly, depression,
decreased attention span, slurred speech, and fatigue.
[0044] The present invention also provides methods for treating
patients with symptoms of Huntington's disease by sublingual or
subcutaneous administration of a small amount of anti-GAD antibody.
Methods of the invention are also useful for treating, but are not
limited to, the symptoms of Huntington's disease. In those cases,
methods of the invention control or alleviate the symptoms of
irritability, restlessness, antisocial behavior, psychosis,
paranoia, hallucinations, facial movements, progressive dementia,
loss of memory, loss of judgment, speech changes, loss of other
functions, personality changes, disorientation and confusion,
unsteady gait, abnormal (choreiform) movements including jerking
movements of the arms, legs, face, and trunk, speech impairment,
anxiety, stress, tension and difficulty in swallowing that are
associated with Huntington's disease.
[0045] The present invention also provides methods for treating
patients with symptoms of Parkinson's disease by sublingual or
subcutaneous administration of a small amount of anti-GAD antibody.
Methods of the invention are also useful for treating, but are not
limited to, the symptoms of Parkinson's disease. In those cases,
methods of the invention control or alleviate the symptoms of
muscle rigidity, loss of balance, shuffling walk, slow movements,
difficulty beginning to walk, freezing of movement, muscle aches,
shaking and tremors, changes in facial expression, voice/speech
changes, loss of fine motor skills, frequent falls, and decline in
intellectual function associated with Parkinson's disease.
[0046] The present invention also provides methods for treating
patients with symptoms of pain neuropathy that is associated with
chemotherapy by sublingual or subcutaneous administration of a
small amount of anti-GAD antibody. Methods of the invention are
useful for alleviating such pain associated with chemotherapy
treatment.
[0047] The present invention also provides methods for treating
various anxiety disorders by topically, sublingually, or
subcutaneously administering to humans a small amount of anti-GAD
antibody. These methods are also useful for treating panic
disorders, and agoraphobia including, but not limited to, those
involving shortness of breath, dizziness, palpitations, trembling,
sweating, choking, nausea, chest pain, hot flashes or chills, fear
of dying, fear of losing control, numbness, fear of going insane,
feelings of detachment, feelings of helplessness, and avoidance of
crowds, especially if escape or assistances is not immediately
available. Other disorders subject to therapeutic treatment using
anti-GAD antibody include attention deficit disorder (ADD) and
obsessive/compulsive behavior.
[0048] Antibodies of the invention can be produced using any method
well known and routinely practiced in the art. Such antibodies
include monoclonal and polyclonal antibodies, single chain
antibodies, chimeric antibodies, bifunctional/bispecific
antibodies, humanized antibodies, human antibodies, and
complementary determining region (CDR)-grafted antibodies,
including compounds which include CDR and/or antigen-binding
sequences, which specifically recognize a polypeptide of the
invention. A preferred anti-GAD antibody and anti-insulin antibody
is available from Chemicon International Inc., Temecula, Calif.
[0049] The invention also provides a pharmaceutical composition for
administering to a subject or patient for alleviating symptoms of a
neuropathic condition selected from a group consisting of
neuropathy diabetes, Huntington's disease, Parkinson's disease,
autism, multiple sclerosis, attention deficit disorder (ADD), and
pain neuropathy after chemotherapy, wherein the anti-GAD is in an
amount effective to treat one or more symptoms of said
psychological condition. An effective dosage comprises a dosage
unit of less than 1.0 mg of anti-GAD antibodies and preferably less
than 1.0 .mu.g of anti-GAD antibody. A still more preferred dosage
unit is less than 0.5 .mu.g of anti-GAD antibodies, and more
preferably less than 0.1 .mu.g of anti-GAD antibodies. A still more
preferred dosage unit ranges from 1.times.10.sup.-6 to
1.times.10.sup.-2 .mu.g of anti-GAD antibodies with dosage unit
ranges of 1.times.10.sup.-5 to 1.times.10.sup.-2 .mu.g or from
1.times.10.sup.-4 to 1.times.10.sup.-2 .mu.g or about
1.times.10.sup.-3 .mu.g of anti-GAD antibodies being more
preferred. The anti-GAD antibodies can be directed against GAD-65
or GAD-67 alone or in combination of each other. The following
examples are illustrative and are not intended to limit either the
scope or spirit of the invention.
EXAMPLES
Example I
[0050] A male patient, who suffered uncontrolled lower limb pain
associated with diabetes (diabetes neuropathy), as diagnosed by his
physician, had been treated with a wide range of analgesics and
narcotics with only limited relief over a two year period. Patient
was then placed on treatments of one sublingual drop (0.05
ml)(0.006 .mu.g/drop) of anti-GAD (Ab directed against combination
of GAD-65 and GAD-67) 3-4 times daily. During three months of
treatment, patient experienced resolution of his pain and has been
able to discontinue narcotic treatments and was able to reduce
treatment dosages to one sublingual drop per day.
Example II
[0051] A 60-year old male who suffered from advanced Parkinson's,
as diagnosed by his physician, was treated with a sublingual dose
of one drop (0.05 ml)(0.0012 .mu.g/drop) of anti-GAD (Ab directed
against GAD-67) 3-4 times daily. After 9-10 weeks of treatment,
patient experienced improved mobility, ability to speak, and
positive attitude. No adverse effects of the anti-GAD treatment
were experienced by the patient.
Example III
[0052] A patient, who suffered from Parkinson's disease, as
diagnosed by his physician, was treated with a sublingual dose of
one drop (0.05 ml)(0.0012 .mu.g/drop) of anti-GAD (Ab directed
against GAD-67) 3-4 times daily. After 4 weeks of treatment,
patient experienced complete resolution of lower extremity tremors
and elimination of incidents of falling due to the Parkinson
tremors. In addition, the patient experiences a 40% improvement in
tremors of the upper extremities. No adverse effects of the
anti-GAD treatment were experienced by the patient and the patient
was able to reduce administration to one drop daily.
Example IV
[0053] A 28-year old male who suffered from autism, as diagnosed by
his physician, was treated with a sublingual dose of one drop (0.05
ml)(0.006 .mu.g/drop) of anti-GAD (Ab directed against GAD-67) once
daily. Upon initiation of treatment, patient experienced improved
tolerance to foods permitting a wider choice of diet, decreased
anxiety, improved sleep patterns, improved bladder control,
improved cognition and attention, and increased efforts to speak.
Therefore, the anti-GAD treatments appear to improve both
neurological and auto-immunological disorders associated with
autism. No adverse affects of the anti-GAD treatment was
experienced by the patient. In fact, patient had developed
allergies to many other treatment regiments for his autism.
Example V
[0054] A 9-year old male who suffered from autism, as diagnosed by
his physician, was treated with a sublingual dose of one drop (0.05
ml)(0.006 .mu.g/drop) of anti-GAD (Ab directed against GAD-67) once
daily. Upon treatment for four weeks, patient experienced improved
school work, greater attention span to teachers and parents,
appropriately entertained him, and had a more controlled behavioral
pattern.
Example VI
[0055] A 54-year old male who suffered from multiple sclerosis for
over 30 years was treated with a sublingual dose of one drop (0.05
ml)(0.0012 .mu.g/drop) of anti-GAD(Ab directed against GAD-67) 3
times daily for several months. Upon initiation of treatment,
patient experienced feeling in his lower extremities, specifically
patient could feel the carpet with his feet. Physical capabilities
have improved as well. Patient was able to walk unassisted for at
least 100 yards. The patient also experienced improved bladder
function and vision and reduced dosage rate to one drop daily.
Example VII
[0056] A 45-year old female patient who suffered from multiple
sclerosis for over 20 years was treated with a sublingual dose of
one drop (0.05 ml)(0.0012 .mu.g/drop) of anti-GAD (Ab directed
against GAD-67) 2-3 times daily. Upon initiation of treatment,
patient experienced improved vision, less fatigue, sleeps through
the night, and a decreased numbness in the mid-calf down
bilaterally thus improving his overall balance.
Example VIII
[0057] A 53-year old female patient who sufferance from multiple
sclerosis was treated with one sublingual drop (0.05 ml)(0.0012
.mu.g/drop) of anti-GAD (Ab directed against GAD-67) twice daily.
After one month of treatment, patient experienced less spasms and
tremors, a moderate increase in energy level, and a return of her
balance.
Example IX
[0058] A middle age female patient diagnosed with anxiety disorder
and obsessive/compulsive behavior by her physician was treated with
one sublingual drop (0.05 ml)(0.006 .mu.g/drop) of anti-GAD (Ab
directed against GAD-67) twice daily over a two week period. During
treatment period, patient was able to control anger and anxiety.
These feelings, however, returned after administration of the
anti-GAD has ended. Patient continued to be administer anti-GAD,
but reduced the dosage to one drop at an "at need basis."
Example X
[0059] According to this example, a 45 year old female diagnosed
with insulin-dependent diabetes was treated with low level
antibodies (Abs directed against combination of GAD-65 and GAD-67).
The subject was determined to have a hemoglobin A1C level of 11%,
which is typically at a level of 4-6% in non-diabetic individuals.
The subject experienced neuropathy characterized by numbness and
poor circulation as determined by the subject in response to a
tuning fork test. The subject underwent antibody therapy by
sublingual administration, via drops, twice daily of one dose of
anti-GAD (8.times.10.sup.-4 mg) and anti-insulin antibodies
(4.times.10.sup.-4 mg). The antibodies used in this example are the
same as that used above in Example I. The subject was tested for
hemoglobin A1C levels after 2 weeks of therapy and the levels were
reduced to 7%. The subject was free from any other therapies during
the low level antibody therapy. After one week the subject
experienced a disappearance of neuropathy in the subject's lower
extremities. The low level antibody treatment was stopped and the
subject's previously experienced neuropathy returned after
approximately one week.
Example XI
[0060] According to this example, a 42 year old female with a 20
year history of diabetes mellitus was treated with low level
antibodies. The subject was treated with antibody therapy by
sublingual administration in the form of 1 drop (or dose),
4.times.per day. Each dose contained 8.times.10.sup.-4 mg of
anti-GAD and 4.times.10.sup.-4 mg of anti-insulin antibodies. The
antibodies used in this example are the same as that used above in
Example I. After approximately one week, the subject experienced an
abatement of pain from diabetic neuropathy and a reduction in blood
sugar levels. Following a one week period in which the subject
experiences no pain, the subject was discontinued from low level
antibody treatment. The discontinuation resulted in reoccurrence of
diabetic neuropathy and elevated blood sugar levels, which were the
symptoms experience by the subject prior to low level antibody
treatment. Subsequently, the subject was, again, treated with low
level antibody therapy, which resulted in abatement of pain from
diabetic neuropathy and a reduction in blood sugar levels similar
to the result from the initial therapy with low level
antibodies.
Example XII
[0061] According to this example, a white male diagnosed with
diabetes was treated with low level antibodies. The subject was
treated with antibody therapy by sublingual administration in the
form of 1 drop (or dose), 2.times.per day. Each dose contained
8.times.10.sup.-4 mg of anti-GAD (Ab directed against combination
of GAD-65 and GAD-67) and 4.times.10.sup.-4 mg of anti-insulin
antibodies. The antibodies used in this example are the same as
that used above in Example I. After approximately eight weeks the
subject experienced a reduction in diabetic neuropathy of
approximately 60%. This reduction in diabetic neuropathy was
determined by having the patient assess the sensations resulting
from a tuning fork on the subject's lower extremities just prior to
treatment and after the eight weeks of treatment. Additionally, the
subject experienced a loss in weight (approximately 12 lbs),
increased energy and a reduction in levels of blood sugar of about
40 mg/dl.
Example XIII
[0062] A 55-year old female patient who suffers pain neuropathy due
to her recovery efforts from chemotherapy and surgery to the
mandible jaw bone in efforts to treat osteocarcinoma. Patient was
treated with numerous narcotics to control the pain but patient
continues to suffer despite prescribed narcotics. Patient was
administered a sublingual dosage of one drop (0.05 ml)(0.0012
.mu.g/drop) of anti-GAD (Ab directed against GAD-67) 3 to 4 times
daily. After 2 weeks of treatment, patient experienced complete
elimination of the pain neuropathy and reduced the dosage of
anti-GAD to one drop daily.
[0063] Numerous modifications and variations in the practice of the
invention are expected to occur to those skilled in the art upon
consideration of the presently preferred embodiments thereof.
Consequently, the only limitations which should be placed upon the
scope of the invention are those which appear in the appended
claims.
* * * * *