U.S. patent application number 16/275117 was filed with the patent office on 2019-06-13 for sobetirome in the treatment of myelination diseases.
This patent application is currently assigned to Oregon Health & Science University. The applicant listed for this patent is Oregon Health & Science University, The United States Government as respresented by the Department of Veterans Affairs. Invention is credited to Dennis Bourdette, Priya Chaudhary, Meredith Hartley, Gail Marracci, Andrew Placzek, Marco Righi, Thomas S. Scanlan.
Application Number | 20190175531 16/275117 |
Document ID | / |
Family ID | 51843844 |
Filed Date | 2019-06-13 |
United States Patent
Application |
20190175531 |
Kind Code |
A1 |
Scanlan; Thomas S. ; et
al. |
June 13, 2019 |
SOBETIROME IN THE TREATMENT OF MYELINATION DISEASES
Abstract
Methods of treating a subject having or at risk of developing a
neurodegenerative disease or condition associated with
demyelination, insufficient myelination, or underdevelopment of
myelin sheath are described. The methods include administration of
a therapeutically effective amount of sobetirome, or a
pharmaceutically acceptable salt thereof.
Inventors: |
Scanlan; Thomas S.; (San
Francisco, CA) ; Hartley; Meredith; (Portland,
OR) ; Placzek; Andrew; (Portland, OR) ; Righi;
Marco; (Rosignano, IT) ; Bourdette; Dennis;
(Portland, OR) ; Marracci; Gail; (Portland,
OR) ; Chaudhary; Priya; (Portland, OR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Oregon Health & Science University
The United States Government as respresented by the Department of
Veterans Affairs |
Portland
Washington |
OR
DC |
US
US |
|
|
Assignee: |
Oregon Health & Science
University
Portland
OR
The United States Government as respresented by the Department
of Veterans Affairs
Washington
DC
|
Family ID: |
51843844 |
Appl. No.: |
16/275117 |
Filed: |
February 13, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14888577 |
Nov 2, 2015 |
10226438 |
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PCT/US2014/014943 |
Feb 5, 2014 |
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16275117 |
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PCT/US2013/053640 |
Aug 5, 2013 |
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14888577 |
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61819467 |
May 3, 2013 |
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61819467 |
May 3, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 27/16 20180101;
A61P 21/00 20180101; A61P 25/00 20180101; A61P 5/40 20180101; A61P
25/28 20180101; A61P 5/14 20180101; A61P 25/14 20180101; A61K
9/0095 20130101; A61P 25/02 20180101; A61P 5/38 20180101; A61P 1/00
20180101; A61P 13/12 20180101; A61K 31/192 20130101; A61P 15/10
20180101; A61P 27/00 20180101; A61K 9/0053 20130101; A61P 5/00
20180101 |
International
Class: |
A61K 31/192 20060101
A61K031/192; A61K 9/00 20060101 A61K009/00 |
Goverment Interests
ACKNOWLEDGMENT OF GOVERNMENT SUPPORT
[0002] This invention was made with government support under grant
number DK-52798 awarded by the National Institutes of Health. The
government has certain rights in the invention.
Claims
1. A method of treating a subject having or at risk of developing a
disease or condition associated with demyelination, insufficient
myelination, or underdevelopment of myelin sheath, comprising
administering to the subject a therapeutically effective amount of
sobetirome or a pharmaceutically acceptable salt thereof.
2. A method of inhibiting demyelination of a neuron, or promoting
myelination of a neuron, in a patient in need thereof, comprising
contacting the neuron with sobetirome, or a pharmaceutically
acceptable salt thereof, wherein the patient has or is at risk of
developing a disease or condition associated with demyelination,
insufficient myelination, or underdevelopment of myelin sheath.
3. The method of claim 1, wherein the disease or condition is
multiple sclerosis, a leukodystrophy, a leukoencephalopathy, an
idiopathic inflammatory demyelinating disease, or Alzheimer's
disease.
4. The method of claim 3, wherein the multiple sclerosis is
relapsing-remitting multiple sclerosis, primary-progressive
multiple sclerosis, secondary-progressive multiple sclerosis, or
progressive-relapsing multiple sclerosis.
5. The method of claim 1, wherein the disease or condition is
central pontine myelinolysis, acute disseminated encephalomyelitis,
Balo concentric sclerosis, Marburg multiple sclerosis, tumefactive
multiple sclerosis, diffuse myelinoclastic sclerosis, acute
hemorrhagic leukoencephalitis, neuromyelitis optica, a chronic
inflammatory demyelinating polyneuropathy, Leber hereditary optic
neuropathy, multifocal motor neuropathy, paraproteinemic
demyelinating polyneuropathy, tropical spastic paraparesis, a
Guillain-Barre syndrome, infantile Refsum disease, adult Refsum
disease 1, adult Refsum disease 2, Zellweger syndrome, X-linked
adrenoleukodystrophy (X-ALD), metachromatic leukodystrophy, Krabbe
disease, Pelizaeus-Merzbacher disease, Canavan disease, Alexander
disease, peroneal muscular atrophy, cerebrotendineous
xanthomatosis, Binswanger's disease, leukoencephalopathy with
vanishing white matter, toxic leukoencephalopathy, van der Knaap
disease, progressive multifocal leukoencephalopathy,
Marchiafava-Bignami disease or transverse myelitis.
6. The method of claim 5, wherein the X-linked adrenoleukodystrophy
is adrenomyeloneuropathy or Addison's disease.
7. The method of claim 1, wherein the disease or condition is a
chronic axonal neuropathy.
8. The method of claim 1, wherein the disease or condition results
from intraventricular hemorrhage, neonatal hypoxia, or acute
hypoxemic respiratory failure.
9. The method of claim 1, wherein the disease or condition is
cerebral palsy.
10. The method of claim 1, wherein administration of the sobetirome
or pharmaceutically acceptable salt thereof prevents or mitigates
at least one symptom of the disease or condition.
11. The method of claim 10, wherein the symptom is a lack of
sphincter control, erectile dysfunction, paraparesis, ataxia,
adrenocortical insufficiency, progressive neuropathy, paresthesia,
dysarthria, dysphagia, clonus, or any combination thereof.
12. The method of claim 1, wherein administration of the sobetirome
or pharmaceutically acceptable salt thereof prevents or mitigates
damage to central nervous system myelin, peripheral nervous system
myelin, adrenal cortex, testicular Leydig cells, or any combination
thereof.
13. The method of claim 1, wherein the sobetirome, or
pharmaceutically acceptable salt thereof, is administered orally,
parenterally, or topically.
14. The method of claim 13, wherein the sobetirome, or
pharmaceutically acceptable salt thereof, is administered
orally.
15. The method of claim 14, wherein the sobetirome, or
pharmaceutically acceptable salt thereof, is administered
enterally, buccally, sublingually, sublabially, or by
inhalation.
16. The method of claim 13, wherein the sobetirome, or
pharmaceutically acceptable salt thereof, is administered
parenterally.
17. The method of claim 16, wherein the sobetirome, or
pharmaceutically acceptable salt thereof, is administered
intra-arterially, intravenously, intraventricularly,
intramuscularly, subcutaneously, intraspinally, intraorbitally, or
intracranially.
18. The method of claim 1, wherein the sobetirome or
pharmaceutically acceptable salt thereof is administered at a dose
of about 1 .mu.g to about 500 .mu.g daily, or about 10 .mu.g to
about 100 .mu.g daily.
19. The method of claim 1, wherein the disease or condition is not
X-ALD, is not multiple sclerosis, or is not cerebral palsy, or any
combination thereof.
20. A method of treating a patient having or at risk of developing
multiple sclerosis administering to the patient 1 mg/kg/day of
sobetirome, or a pharmaceutically acceptable salt thereof.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This is a continuation of U.S. application Ser. No.
14/888,577, filed Nov. 2, 2015, which is the U.S. National Stage of
International Application No. PCT/US2014/014943, filed Feb. 5,
2014, published in English under PCT Article 21(2), which claims
the benefit of international application PCT/US2013/053640, filed
on Aug. 5, 2013; and claims the benefit of U.S. Provisional
Application 61/819,467, filed on May 3, 2013. The disclosures of
each of the above applications are incorporated herein by
reference.
FIELD
[0003] This disclosure concerns methods for the treatment of
diseases or conditions associated with demyelination, insufficient
myelination or underdevelopment of the myelin sheath. This
disclosure further relates to the use of sobetirome for the
treatment of such diseases and conditions.
PARTIES TO JOINT RESEARCH AGREEMENT
[0004] The inventions described in this application were made by
Oregon Health & Sciences University and The United States
Government as represented by the Department of Veterans Affairs as
a result of activities undertaken within the scope of a joint
research agreement.
BACKGROUND
[0005] Oligodendrocytes (OL) generate and maintain myelin in the
central nervous system (CNS). During development, oligodendrocyte
precursor cells (OPC) differentiate into OL and this
differentiation step depends on the thyroid hormone,
triiodothyronine (T3). Following demyelination, remyelination may
involve T3-dependent differentiation of OPC into OL, which depends
on transcription factors, e.g., Kruppel-like factor 9 (Klf9).
Currently available treatments of demyelinating diseases are
limited in their efficacy. For some demyelinating diseases, there
are no known treatments available. Thus, therapeutic agents capable
of promoting remyelination, without toxic side effects, represent
an unmet medical need.
SUMMARY
[0006] The present disclosure features the use of a CNS active,
non-cardiotoxic drug (sobetirome) capable of reducing demyelination
and promoting myelination without causing thyrotoxicosis.
Sobetirome, and pharmaceutically acceptable salts thereof, provide
a viable treatment for preventing and reversing demyelination in
disorders such as multiple sclerosis (MS) and other diseases or
conditions associated with demyelination, insufficient myelination,
or underdevelopment of the myelin sheath.
[0007] Methods of treating a subject having or at risk of
developing a neurodegenerative disease or condition associated with
demyelination, insufficient myelination, or underdevelopment of
myelin sheath are described herein. The methods include
administration of a therapeutically effective amount of sobetirome,
or a pharmaceutically acceptable salt thereof.
[0008] The foregoing and other objects, features, and advantages of
the invention will become more apparent from the following detailed
description, which proceeds with reference to the accompanying
figures.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1: Sobetirome reduced demyelination in the corpus
callosum of mice following injection of lysolecithin. Top,
BlackGold.RTM. stain is specific for myelin fibers and cresyl
violet is used as a counterstain. Mice received stereotactic
injections of 2 .mu.L, of PBS or 2% lysolecithin in the corpus
callosum. A white arrow indicates the path of the injection needle
and a black box indicates the lesion site. An enlarged image of the
boxed lesion site is shown to the right. Bottom, brain sections of
30 .mu.m were stained with FluoroMyelin.TM., anti-PDGFR-.alpha. and
DAPI. Hypothyroidism was induced with drinking water treatment, and
both hypothyroid and control mice received vehicle injections. T3
(0.4 mg/kg) and sobetirome (1 mg/kg) were administered by daily
i.p. injections starting 7 days before stereotactic injection of
lysolecithin. Mice were euthanized 8 days after stereotactic
injection of 2% lysolecithin, and brains were harvested and
processed for histological analysis.
[0010] FIG. 2: Sobetirome reduces demyelination in mice with EAE.
The dot plot displays the mean percentage area of damage in the
ventrolateral white matter of C57BL/6 mice after 11 days of
treatment with sobetirome and vehicle. EAE was induced in female
mice with MOG 35-55 peptide. On day 17 post immunization, mice were
randomized based on their EAE scores and daily i.p. injections of
sobetirome (n=8) or vehicle (n=8) were started. Mice were
euthanized after 11 days of treatment and spinal cords were
prepared for histological evaluation. The mean percentage of
ventrolateral demyelination for vehicle treated mice was 17.25
(SD+/-7.09) and 9.11 (SD+/-4.96) for sobetirome (p<0.01).
[0011] FIGS. 3A-3D: Sobetirome prevents demyelination and axonal
loss. Representative Black gold II (FIGS. 3A-3B) and toluidine blue
(FIGS. 3B-3C) images from lumbar and thoracic EAE ventral spinal
cord respectively. Sobetirome treated (FIGS. 3A and 3C) and vehicle
(FIGS. 3B and 3D). Demyelination is clearly visible in a
vehicle-treated mouse but not in a sobetirome-treated mouse. Arrows
show unstable myelin; arrowheads show degenerating axon. Scale
bar=20 microns.
DETAILED DESCRIPTION
I. Abbreviations
[0012] ADEM acute disseminated encephalomyelitis
[0013] AIDP acute inflammatory demyelinating polyneuropathy
[0014] CIDP chronic inflammatory demyelinating polyneuropathy
[0015] CNS central nervous system
[0016] EAE experimental autoimmune encephalitis
[0017] IIDD idiopathic inflammatory demyelinating disease
[0018] i.p. intraperitoneal
[0019] MOG myelin oligodendrocyte glycoprotein
[0020] MS multiple sclerosis
[0021] NMO neuromyelitis optica
[0022] OL oligodendrocytes
[0023] OPC oligodendrocyte precursor cells
[0024] PML progressive multifocal leukoencephalopathy
[0025] T3 triiodothyronine
[0026] X-ALD X-linked adrenoleukodystrophy
II. Terms and Methods
[0027] Unless otherwise noted, technical terms are used according
to conventional usage. Definitions of common terms in molecular
biology may be found in Benjamin Lewin, Genes V, published by
Oxford University Press, 1994 (ISBN 0-19-854287-9); Kendrew et al.
(eds.), The Encyclopedia of Molecular Biology, published by
Blackwell Science Ltd., 1994 (ISBN 0-632-02182-9); and Robert A.
Meyers (ed.), Molecular Biology and Biotechnology: a Comprehensive
Desk Reference, published by VCH Publishers, Inc., 1995 (ISBN
1-56081-569-8).
[0028] In order to facilitate review of the various embodiments of
the disclosure, the following explanations of specific terms are
provided:
[0029] Acute disseminated encephalomyelitis (ADEM): An
immune-mediated demyelinating disease of the central nervous
system. ADEM usually occurs following a viral infection, but may
also appear following vaccination or following bacterial or
parasitic infection. In some cases, ADEM develops spontaneously.
The disease involves autoimmune demyelination, similar to multiple
sclerosis, and is therefore considered a multiple sclerosis
borderline disease. ADEM produces multiple inflammatory lesions in
the brain and spinal cord, particularly in the white matter. The
lesions are typically found in the subcortical and central white
matter and cortical gray-white junction of both cerebral
hemispheres, cerebellum, brainstem, and spinal cord, but
periventricular white matter and gray matter of the cortex, thalami
and basal ganglia may also be involved. When a patient suffers more
than one demyelinating episode, the disease is referred to as
recurrent disseminated encephalomyelitis or multiphasic
disseminated encephalomyelitis.
[0030] Acute hemorrhagic leukoencephalitis (AHL or AHLE): A
hyperacute and frequently fatal form of ADEM. This disease is also
known as acute necrotizing encephalopathy (ANE), acute hemorrhagic
encephalomyelitis (AHEM), acute necrotizing hemorrhagic
leukoencephalitis (ANHLE), Weston-Hurst syndrome, or Hurst's
disease.
[0031] Administration: To provide or give a subject an agent, such
as a therapeutic agent (e.g. sobetirome or a pharmaceutically
acceptable salt thereof), by any effective route. Exemplary routes
of administration are described hereinbelow.
[0032] Adult Refsum disease: An autosomal recessive neurological
disease that is associated with the over-accumulation of phytanic
acid in cells and tissues. Adult Refsum disease is divided into the
adult Refsum disease 1 and adult Refsum disease 2 subtypes.
Individuals with Refsum disease present with neurologic damage,
cerebellar degeneration, and peripheral neuropathy. Onset is most
commonly in childhood/adolescence with a progressive course,
although periods of stagnation or remission occur. Symptoms also
include ataxia, scaly skin (ichthyosis), difficulty hearing, and
eye problems including cataracts and night blindness.
[0033] Alexander disease: A very rare, congenital demyelinating
disease. The disease primarily affects infants and children,
causing developmental delay and changes in physical
characteristics. Alexander disease is a type of leukodystrophy.
[0034] Alzheimer's disease: The most common form of dementia.
Symptoms of Alzheimer's disease include memory loss, confusion,
irritability, aggression, mood swings and trouble with language.
This disease is characterized by the loss of neurons and synapses
in the cerebral cortex and certain subcortical regions. The loss
results in gross atrophy of the affected regions, including
degeneration in the temporal lobe, and parts of the frontal cortex
and cingulate gyrus. Amyloid plaques and neurofibrillary tangles
are visible by microscopy in brains of those afflicted with this
disease. The cause of Alzheimer's disease is unknown; however,
several hypothesis exist, including that the disease is caused by
age-related myelin breakdown in the brain.
[0035] Balo concentric sclerosis: A demyelinating disease similar
to standard multiple sclerosis, but with the particularity that the
demyelinated tissues form concentric layers. Patients with this
disease can survive and/or have spontaneous remission. Typically,
the clinical course is primary progressive, but a
relapsing-remitting course has been reported.
[0036] Canavan disease: An autosomal recessive degenerative
disorder that causes progressive damage to nerve cells in the
brain. Canavan disease is a leukodystrophy and is one of the most
common degenerative cerebral diseases of infancy. This disease is
also called Canavan-Van Bogaert-Bertrand disease, aspartoacylase
deficiency and aminoacylase 2 deficiency.
[0037] Central pontine myelinolysis (CPM): A neurologic disease
caused by severe damage of the myelin sheath of nerve cells in the
brainstem, more precisely in the area termed the pons. The most
common cause is the rapid correction of low blood sodium levels
(hyponatremia). Frequently observed symptoms in this disorder are
sudden para or quadraparesis, dysphagia, dysarthria, diplopia and
loss of consciousness. The patient may experience locked-in
syndrome where cognitive function is intact, but all muscles are
paralyzed with the exception of eye blinking.
[0038] Cerebral palsy: A term used for a group of permanent,
non-progressive movement disorders that cause physical disability.
Cerebral palsy is caused by damage to the motor control centers of
the developing brain and can occur during pregnancy, during
childbirth, or after birth up to about age three. Patients with
cerebral palsy exhibit damage to myelin sheaths.
[0039] Cerebrotendineous xanthomatosis: An inherited disorder
associated with the deposition of a form of cholesterol
(cholestanol) in the brain and other tissues and with elevated
levels of cholesterol in plasma but with normal total cholesterol
level. It is characterized by progressive cerebellar ataxia
beginning after puberty and by juvenile cataracts, juvenile or
infantile onset chronic diarrhea, childhood neurological deficit,
and tendineous or tuberous xanthomas. This disorder is an autosomal
recessive form of xanthomatosis. It falls within a group of genetic
disorders called the leukodystrophies.
[0040] Chronic inflammatory demyelinating polyneuropathy (CIDP): An
acquired immune-mediated inflammatory disorder of the peripheral
nervous system. The disorder is sometimes called chronic relapsing
polyneuropathy (CRP) or chronic inflammatory demyelinating
polyradiculoneuropathy (because it involves the nerve roots). CIDP
is closely related to Guillain-Barre syndrome and it is considered
the chronic counterpart of that acute disease. Its symptoms are
also similar to progressive inflammatory neuropathy. An
asymmetrical variant of CIDP is known as Lewis-Sumner syndrome. The
pathologic hallmark of the disease is loss of the myelin
sheath.
[0041] Demyelinating disease: Includes any disease of the nervous
system in which myelin is damaged or lost, or in which the growth
or development of the myelin sheath is impaired. Demyelination
inhibits the conduction of signals in the affected nerves, causing
impairment in sensation, movement, cognition, or other functions
for which nerves are involved.
[0042] Demyelinating diseases have a number of different causes and
can be hereditary or acquired. In some cases, a demyelinating
disease is caused by an infectious agent, an autoimmune response, a
toxic agent or traumatic injury. In other cases, the cause of the
demyelinating disease is unknown ("idiopathic") or develops from a
combination of factors.
[0043] Devic's syndrome: An autoimmune, inflammatory disorder in
which a person's immune system attacks the optic nerves and spinal
cord, which results in inflammation of the optic nerve (optic
neuritis) and the spinal cord (myelitis). Spinal cord lesions lead
to varying degrees of weakness or paralysis in the legs or arms,
loss of sensation, and/or bladder and bowel dysfunction. Although
inflammation may also affect the brain, the lesions are different
from those observed in MS. Devic's disease is similar to MS in that
the body's immune system attacks the myelin surrounding nerve
cells. Unlike standard MS, the attacks are not believed to be
mediated by the immune system's T cells but rather by antibodies
called NMO-IgG. These antibodies target a protein called aquaporin
4 in the cell membranes of astrocytes which acts as a channel for
the transport of water across the cell membrane. Devic's syndrome
is also known as Devic's disease or neuromyelitis optica (NMO).
[0044] Diffuse myelinoclastic sclerosis: An uncommon
neurodegenerative disease that presents clinically as pseudotumoral
demyelinating lesions. It usually begins in childhood, affecting
children between 5 and 14 years old; however, cases in adults are
possible. This disease is considered one of the borderline forms of
MS and is sometimes referred to as Schilder's disease.
[0045] Encephalomyelitis: Inflammation of the brain and spinal
cord.
[0046] Experimental autoimmune encephalomyelitis (EAE): An animal
model of MS (for example, see Gold et al., Brain 129:1953-1971,
2006). EAE animals exhibit characteristic plaques of tissue injury
disseminated throughout the central nervous system. Plaques show
infiltration of nervous tissue by lymphocytes, plasma cells, and
macrophages, which cause destruction of the myelin sheaths that
surround nerve cell axons in the brain and spinal cord. In some
cases, EAE is induced by immunization of susceptible animals, such
as mice, rats, guinea pigs, or non-human primates, with either
myelin or various components of myelin. For example, EAE can be
induced by immunization with components of the myelin sheath, such
as myelin basic protein, proteolipid protein, or myelin
oligodendrocyte glycoprotein (MOG). EAE is a useful and widely
accepted model for studying mechanisms of autoimmune CNS tissue
injury and for testing potential therapies for MS. EAE also
includes "passive EAE" which is induced in the same manner in donor
animals, but involves the transfer of activated T-cells harvested
from the donor animal's lymph nodes to naive recipient animals.
[0047] Guillain-Barre syndrome: An acute polyneuropathy, a disorder
affecting the peripheral nervous system. Ascending paralysis,
weakness beginning in the feet and hands and migrating towards the
trunk, is the most typical symptom, and some subtypes cause change
in sensation or pain, as well as dysfunction of the autonomic
nervous system. It can cause life-threatening complications, in
particular if the respiratory muscles are affected or if the
autonomic nervous system is involved. This disease is usually
triggered by an infection. Acute inflammatory demyelinating
polyneuropathy (AIDP) is the most common subtype of this disease.
Other subtypes of Guillain-Barre syndrome include Miller Fischer
syndrome, acute motor axonal neuropathy (Chinese paralytic
syndrome), acute motor sensory axonal neuropathy, acute
panautonomic neuropathy, and Bickerstaff's brainstem
encephalitis.
[0048] Hemorrhage: Bleeding or escape of blood from a vessel.
[0049] Hypoxia: The lack of oxygen supply to the tissues of the
body below the normal level.
[0050] Idiopathic inflammatory demyelinating disease (IIDD): A
broad spectrum of central nervous system disorders that can usually
be differentiated on the basis of clinical, imaging, laboratory and
pathological findings. Idiopathic inflammatory demyelinating
diseases are sometimes known as borderline forms of multiple
sclerosis. IIDD generally refers to a collection of multiple
sclerosis variant diseases, including but not limited to,
optic-spinal MS, Devic's disease, ADEM, acute hemorrhagic
leukoencephalitis, Balo concentric sclerosis, Schilder disease,
Marburg multiple sclerosis, tumefactive multiple sclerosis and
solitary sclerosis.
[0051] Infantile Refsum disease: A peroxisome biogenesis disorder
associated with deficiencies in the catabolism of very long chain
fatty acids and branched chain fatty acids (such as phytanic acid)
and plasmalogen biosynthesis. Infantile Refsum disease is a rare,
autosomal recessive congenital disorder, and one of three
peroxisome biogenesis disorders that belong to the Zellweger
spectrum of peroxisome biogenesis disorders.
[0052] Injury: Refers to any type of physical damage to cells,
tissues, or the body. In some cases, nervous system (e.g., CNS or
PNS) injury results in demyelination and/or a demyelinating
disease.
[0053] Ischemia: A vascular phenomenon in which a decrease in the
blood supply to a bodily organ, tissue, or part is caused, for
instance, by constriction or obstruction of one or more blood
vessels. Ischemia sometimes results from vasoconstriction,
thrombosis or embolism. Ischemia can lead to direct ischemic
injury, tissue damage due to cell death caused by reduced oxygen
supply. In some cases, ischemia can lead to demyelination.
[0054] Krabbe disease: A rare, often fatal degenerative disorder
that affects the myelin sheath of the nervous system. It is a form
of sphingolipidosis, as it involves dysfunctional metabolism of
sphingolipids. This condition is inherited in an autosomal
recessive pattern. Krabbe disease is also known as globoid cell
leukodystrophy or galactosylceramide lipidosis.
[0055] Leber hereditary optic neuropathy: A mitochondrially
inherited (transmitted from mother to offspring) degeneration of
retinal ganglion cells (RGCs) and their axons that leads to an
acute or subacute loss of central vision; this affects
predominantly young adult males.
[0056] Leukodystrophy: Refers to a group of diseases that affects
the growth or development of the myelin sheath.
[0057] Leukoencephalopathy: Any of a group of diseases affecting
the white substance of the brain; can refer specifically to several
diseases including, for example, "leukoencephalopathy with
vanishing white matter" and "toxic leukoencephalopathy."
Leukoencephalopathies are leukodystrophy-like diseases.
[0058] Marburg multiple sclerosis: A condition in which the central
nervous system has multiple demyelinating lesions with atypical
characteristics for those of standard multiple sclerosis. This
disease is a borderline form of multiple sclerosis and is also
known as tumefactive multiple sclerosis or fulminant multiple
sclerosis. It is called tumefactive because the lesions are
"tumor-like" and they mimic tumors clinically, radiologically and
sometimes pathologically.
[0059] Marchiafava-Bignami disease: A progressive neurological
disease characterized by corpus callosum demyelination and necrosis
and subsequent atrophy. It is classically associated with chronic
alcoholics.
[0060] Metachromatic leukodystrophy (MLD): A lysosomal storage
disease that is commonly listed in the family of leukodystrophies,
as well as in the sphingolipidoses as it affects the metabolism of
sphingolipids. MLD is directly caused by a deficiency of the enzyme
arylsulfatase A.
[0061] Multifocal motor neuropathy (MMN): A progressively worsening
condition where muscles in the extremities gradually weaken. This
disorder, a motor neuropathy syndrome, is sometimes mistaken for
amyotrophic lateral sclerosis (ALS) because of the similarity in
the clinical picture, especially if muscle fasciculations are
present. MMN is usually asymmetric and is thought to be
autoimmune.
[0062] Multiple sclerosis (MS): A slowly progressive CNS disease
characterized by disseminated patches of demyelination in the brain
and spinal cord, resulting in multiple and varied neurological
symptoms and signs, usually with remissions and exacerbation. The
cause of MS is unknown but an immunological abnormality is
suspected. An increased family incidence suggests genetic
susceptibility, and women are somewhat more often affected than
men. The symptoms of MS include weakness, lack of coordination,
paresthesias, speech disturbances, and visual disturbances, most
commonly double vision. More specific signs and symptoms depend on
the location of the lesions and the severity and destructiveness of
the inflammatory and sclerotic processes. Relapsing-remitting
multiple sclerosis (RRMS) is a clinical course of MS that is
characterized by clearly defined, acute attacks with full or
partial recovery and no disease progression between attacks.
Secondary-progressive multiple sclerosis (SPMS) is a clinical
course of MS that initially is relapsing-remitting, and then
becomes progressive at a variable rate, possibly with an occasional
relapse and minor remission. Primary-progressive multiple sclerosis
(PPMS) presents initially in the progressive form. A clinically
isolated syndrome is the first neurologic episode, which is caused
by inflammation/demyelination at one or more sites in the CNS.
Progressive-relapsing multiple sclerosis (PRMS) is a rare form of
MS (.about.5%) characterized by a steadily worsening disease state
from onset, with acute relapses but no remissions.
[0063] Myelin: A lipid substance forming a sheath (known as the
myelin sheath) around the axons of certain nerve fibers. Myelin is
an electrical insulator that serves to speed the conduction of
nerve impulses in nerve fibers. "Myelination" (also
"myelinization") refers to the development or formation of a myelin
sheath around a nerve fiber. Similarly, "remyelination" (also,
"remyelinization") refers to the repair or reformation of the
myelin sheath, such as following injury, exposure to a toxic agent,
or an inflammatory response, or during the course of a
demyelinating disease.
[0064] Neurodegenerative disease: Refers to any type of disease
that is characterized by the progressive deterioration of the
nervous system.
[0065] Neuropathy: A functional disturbance or pathological change
in the peripheral nervous system. Axonal neuropathy refers to a
disorder disrupting the normal functioning of the axons.
[0066] Paraproteinemic demyelinating polyneuropathy: A type of
peripheral neuropathy characterized by auto antibodies directed
against myelin associated glycoproteins (MAG). Anti-MAG antibodies
inhibit the production of myelin, thereby leading to
neuropathy.
[0067] Pelizaeus-Merzbacher disease (PMD): A rare central nervous
system disorder in which coordination, motor abilities, and
intellectual function are delayed to variable extents. The disease
is one in a group of genetic disorders collectively known as
leukodystrophies.
[0068] Peroneal muscular atrophy (PMA): A genetically and
clinically heterogeneous group of inherited disorders of the
peripheral nervous system characterized by progressive loss of
muscle tissue and touch sensation across various parts of the body.
This disease is also known as Charcot-Marie-Tooth disease (CMT),
Charcot-Marie-Tooth neuropathy and hereditary motor and sensory
neuropathy (HMSN).
[0069] Pharmaceutical composition: A composition containing
sobetirome, or a pharmaceutically acceptable salt thereof,
formulated with a pharmaceutically acceptable excipient, and
manufactured or sold with the approval of a governmental regulatory
agency as part of a therapeutic regimen for the treatment of
disease in a mammal. Pharmaceutical compositions can be formulated,
for example, for oral administration in unit dosage form (e.g., a
tablet, capsule, caplet, gelcap, or syrup); for topical
administration (e.g., as a cream, gel, lotion, or ointment); for
intravenous administration (e.g., as a sterile solution free of
particulate emboli and in a solvent system suitable for intravenous
use); or in any other formulation described herein.
[0070] Pharmaceutically acceptable salt: A salt of sobetirome which
is, within the scope of sound medical judgment, suitable for use in
contact with the tissues of humans and animals without undue
toxicity, irritation, allergic response and the like and are
commensurate with a reasonable benefit/risk ratio. Pharmaceutically
acceptable salts are well known in the art. For example,
pharmaceutically acceptable salts are described in: Berge et al.,
J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical
Salts: Properties, Selection, and Use, (Eds. P. H. Stahl and C. G.
Wermuth), Wiley-VCH, 2008. The salts can be prepared in situ during
the final isolation and purification of the compounds described
herein or separately by reacting the free carboxylic acid group
with a suitable base. Representative alkali or alkaline earth metal
salts include sodium, lithium, potassium, calcium, magnesium, and
the like, as well as nontoxic ammonium, primary ammonium, secondary
ammonium, tertiary ammonium, or quaternary ammonium cations,
including, but not limited to ammonium, tetramethylammonium,
tetraethylammonium, methylammonium, dimethylammonium,
trimethylammonium, triethylammonium, ethylammonium, and the
like.
[0071] Pharmaceutically acceptable excipient (pharmaceutically
acceptable carrier): Any ingredient other than sobetirome, or a
pharmaceutically acceptable salt thereof (e.g., a vehicle capable
of suspending or dissolving the active compound) and having the
properties of being nontoxic and non-inflammatory in a patient.
Excipients may include, for example: antiadherents, antioxidants,
binders, coatings, compression aids, disintegrants, dyes (colors),
emollients, emulsifiers, fillers (diluents), film formers or
coatings, flavors, fragrances, glidants (flow enhancers),
lubricants, preservatives, printing inks, sorbents, suspensing or
dispersing agents, sweeteners, or waters of hydration. Exemplary
excipients include, but are not limited to: butylated
hydroxytoluene (BHT), calcium carbonate, calcium phosphate
(dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl
pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose,
gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose,
lactose, magnesium stearate, maltitol, mannitol, methionine,
methylcellulose, methyl paraben, microcrystalline cellulose,
polyethylene glycol, polyvinyl pyrrolidone, povidone,
pregelatinized starch, propyl paraben, retinyl palmitate, shellac,
silicon dioxide, sodium carboxymethyl cellulose, sodium citrate,
sodium starch glycolate, sorbitol, starch (corn), stearic acid,
stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin
E, vitamin C, and xylitol.
[0072] The pharmaceutically acceptable excipients or carriers
useful for each specific mode of administration are described
hereinbelow.
[0073] Preventing, treating or ameliorating a disease: "Preventing"
refers to a prophylactic treatment or treatment that prevents one
or more symptoms or conditions of a disease, disorder, or
conditions described herein. Preventive treatment that includes
administration of sobetirome, or a pharmaceutically acceptable salt
thereof, or a pharmaceutical composition thereof, can be acute,
short-term, or chronic. The doses administered may be varied during
the course of preventative treatment. "Treating" refers to an
approach for obtaining beneficial or desired results, e.g.,
clinical results. Beneficial or desired results can include, but
are not limited to, alleviation or amelioration of one or more
symptoms or conditions; diminishment of extent of disease or
condition; stabilized (i.e., not worsening) state of disease,
disorder, or condition; preventing spread of disease or condition;
delay or slowing the progress of the disease or condition;
amelioration or palliation of the disease or condition; and
remission (whether partial or total), whether detectable or
undetectable. "Ameliorating (palliating)" a disease or condition
means that the extent and/or undesirable clinical manifestations of
the disease, disorder, or condition are lessened and/or time course
of the progression is slowed or lengthened, as compared to the
extent or time course in the absence of treatment.
[0074] Progressive multifocal leukoencephalopathy (PML): A rare and
usually fatal viral disease that is characterized by progressive
damage or inflammation of the white matter of the brain in multiple
locations. PML occurs almost exclusively in people with severe
immune deficiency. The cause of PML is a type of polyomavirus
called the JC virus. The virus is widespread, with 86% of the
general population presenting antibodies, but it usually remains
latent, causing disease only when the immune system has been
severely weakened. PML is a demyelinating disease, in which the
myelin sheath covering the axons of nerve cells is gradually
destroyed, impairing the transmission of nerve impulses. The
disease may occur in subjects (e.g., humans) with severe immune
deficiency, such as transplant patients on immunosuppressive
medications or those receiving certain kinds of medications. For
example, PML has been associated with administration of rituximab
(off-label use in the treatment of multiple sclerosis). It affects
the white matter, which is mostly composed of axons from the
outermost parts of the brain (cortex). Symptoms include weakness or
paralysis, vision loss, impaired speech, and cognitive
deterioration.
[0075] Sobetirome: A synthetic diarylmethane derivative that was
investigated clinically as a potential therapeutic for
hypercholesterolemia (see U.S. Pat. No. 5,883,294, which is herein
incorporated by reference). Other names for sobetirome found in the
literature and regulatory filings include QRX-431 and GC-1.
##STR00001##
[0076] Subject: An animal (e.g., a mammal, such as a human). A
subject to be treated according to the methods described herein may
be one who has been diagnosed with a neurodegenerative disease
involving demyelination, insufficient myelination, or
underdevelopment of a myelin sheath, e.g., a subject diagnosed with
multiple sclerosis or cerebral palsy, or one at risk of developing
the condition. Diagnosis may be performed by any method or
technique known in the art. One skilled in the art will understand
that a subject to be treated according to the present disclosure
may have been subjected to standard tests or may have been
identified, without examination, as one at risk due to the presence
of one or more risk factors associated with the disease or
condition.
[0077] Therapeutically effective amount: A quantity of sobetirome,
or a pharmaceutically acceptable salt thereof, sufficient to
achieve a desired effect in a subject, or in a cell, being treated
with sobetirome. The effective amount of sobetirome depends on
several factors, including, but not limited to the subject or cells
being treated, and the manner of administration of the therapeutic
composition. In some embodiments, a "therapeutically effective
amount" of sobetirome, or a pharmaceutically acceptable salt
thereof, is the amount sufficient to promote myelination in a
subject. In other embodiments, a "therapeutically effective amount"
of sobetirome, or a pharmaceutically acceptable salt thereof, is
the amount sufficient to inhibit demyelination in a subject.
[0078] Transverse myelitis: A neurological disorder caused by an
inflammatory process of the grey and white matter of the spinal
cord, leading to axonal demyelination. Demyelination arises
idiopathically following infections or vaccination, or due to
multiple sclerosis. Symptoms include weakness and numbness of the
limbs as well as motor, sensory, and sphincter deficits. Severe
back pain may occur in some patients at the onset of the
disease.
[0079] Tropical spastic paraparesis (TSP): An infection of the
spinal cord by human T-lymphotropic virus resulting in paraparesis,
weakness of the legs. TSP is also known as HTLV-associated
myelopathy or chronic progressive myelopathy. As the name suggests,
this disease is most common in tropical regions, including the
Caribbean and Africa.
[0080] Van der Knaap disease: A form of hereditary CNS
demyelinating disease. This disease is a type of leukodystrophy and
is also known as megalencephalic leukoencephalopathy with
subcortical cysts (MLC).
[0081] X-linked adrenoleukodystrophy (X-ALD, ALD, or X-linked ALD):
A rare, inherited metabolic disorder that leads to progressive
brain damage, mental deterioration, failure of the adrenal glands,
muscle spasms, blindness and eventually death. ALD is one disease
in a group of inherited disorders called leukodystrophies.
Adrenoleukodystrophy progressively damages myelin. X-linked ALD
male patients may be divided into 7 phenotypes: childhood cerebral
(progressive neurodegenerative decline leading to a vegetative
state), adolescent (similar to childhood cerebral form but with a
slower progression), adrenomyeloneuropathy (progressive neuropathy,
paraparesis, may progress to cerebral involvement), adult cerebral
(dementia, similar progression to childhood cerebral form),
olivo-ponto-cerebellar (cerebral and brain stem involvement),
Addison disease (adrenal insufficiency), asymptomatic (no clinical
presentation, subclinical adrenal insufficiency, or AMN phenotype).
X-linked ALD female patients may be divided into 5 phenotypes:
asymptomatic (no neurologic or adrenal involvement), mild
myelopathy, moderate to severe myelopathy (similar to male AMN
phenotype), cerebral (progressive dementia and decline), and
adrenal (primary adrenal insufficiency). X-linked ALD patients may
progress from one phenotype to another over the course of their
life. ALD is also known as Addison-Schilder disease or
Siemerling-Creutzfeldt disease.
[0082] Zellweger syndrome: A rare congenital disorder,
characterized by the reduction or absence of functional peroxisomes
in the cells of an individual. This disease is classified as a
leukodystrophy and is one of three peroxisome biogenesis disorders
that belong to the Zellweger spectrum of peroxisome biogenesis
disorders.
[0083] Unless otherwise explained, all technical and scientific
terms used herein have the same meaning as commonly understood by
one of ordinary skill in the art to which this disclosure belongs.
The singular terms "a," "an," and "the" include plural referents
unless context clearly indicates otherwise. "Comprising A or B"
means including A, or B, or A and B. It is further to be understood
that all base sizes or amino acid sizes, and all molecular weight
or molecular mass values, given for nucleic acids or polypeptides
are approximate, and are provided for description. Although methods
and materials similar or equivalent to those described herein can
be used in the practice or testing of the present disclosure,
suitable methods and materials are described below. In case of
conflict, the present specification, including explanations of
terms, will control. In addition, the materials, methods, and
examples are illustrative only and not intended to be limiting.
III. Overview of Several Embodiments
[0084] Sobetirome, or a pharmaceutically acceptable salt thereof,
provides a viable treatment for preventing and reversing
demyelination and/or promoting myelination in diseases or
conditions associated with demyelination, insufficient myelination,
or underdevelopment of the myelin sheath.
[0085] The present disclosure features a method of treating a
subject having or at risk of developing X-linked
adrenoleukodystrophy by administering to the subject in need
thereof a therapeutically effective amount of sobetirome or a
pharmaceutically acceptable salt thereof. The present disclosure
also features a method of inhibiting accumulation of very-long
chain fatty acids in a cell in a patient that has or is at risk of
developing X-linked adrenoleukodystrophy, by contacting the neuron
with sobetirome, or a pharmaceutically acceptable salt thereof.
[0086] In some embodiments, the phenotype of X-linked
adrenoleukodystrophy is childhood cerebral, adolescent,
adrenomyeloneuropathy, adult cerebral, olivo-ponto-cerebellar,
Addison disease, or asymptomatic. In other embodiments, the
phenotype of X-linked adrenoleukodystrophy is asymptomatic, mild
myelopathy, moderate to severe myelopathy (e.g.,
adrenomyeloneuropathy), cerebral, and adrenal. In certain
embodiments, the phenotype of X-linked adrenoleukodystrophy is
cerebral. In other embodiments, the phenotype of X-linked
adrenoleukodystrophy is myelopathy (e.g., moderate to severe
myelopathy). In certain other embodiments, the phenotype of
X-linked adrenoleukodystrophy is asymptomatic. In yet other
embodiments, the phenotype of X-linked adrenoleukodystrophy is
Addison disease. In certain embodiments, the phenotype of X-linked
adrenoleukodystrophy is olivo-ponto-cerebellar.
[0087] The present disclosure features a method of treating a
subject having or at risk of developing a disease or condition
associated with demyelination, insufficient myelination, or
underdevelopment of myelin sheath. The method involves
administration of a therapeutically effective amount of sobetirome,
or a pharmaceutically acceptable salt thereof.
[0088] The present disclosure features a method of inhibiting
demyelination of a neuron in a patient that has or is at risk of
developing a disease or condition associated with demyelination,
insufficient myelination, or underdevelopment of myelin sheath, by
contacting the neuron with sobetirome, or a pharmaceutically
acceptable salt thereof.
[0089] The present disclosure also features a method of promoting
myelination of a neuron in a patient that has or is at risk of
developing a disease or condition associated with demyelination,
insufficient myelination, or underdevelopment of myelin sheath, by
contacting the neuron with sobetirome, or a pharmaceutically
acceptable salt thereof.
[0090] The disease or condition to be treated can be any disease or
condition associated with demyelination, insufficient myelination
or underdevelopment of myelin sheath. In some embodiments, the
disease or condition is multiple sclerosis, a leukodystrophy, a
leukoencephalopathy, an idiopathic inflammatory demyelinating
disease, or Alzheimer's disease. In some examples in which the
disease or condition is multiple sclerosis, the multiple sclerosis
is relapsing-remitting multiple sclerosis, primary-progressive
multiple sclerosis, secondary-progressive multiple sclerosis, or
progressive-relapsing multiple sclerosis.
[0091] In some embodiments, the disease or condition is central
pontine myelinolysis, acute disseminated encephalomyelitis, Balo
concentric sclerosis, Marburg multiple sclerosis, tumefactive
multiple sclerosis, diffuse myelinoclastic sclerosis, acute
hemorrhagic leukoencephalitis, neuromyelitis optica, a chronic
inflammatory demyelinating polyneuropathy, Leber hereditary optic
neuropathy, multifocal motor neuropathy, paraproteinemic
demyelinating polyneuropathy, tropical spastic paraparesis, a
Guillain-Barre syndrome, infantile Refsum disease, adult Refsum
disease 1, adult Refsum disease 2, Zellweger syndrome, X-linked
adrenoleukodystrophy (X-ALD), metachromatic leukodystrophy, Krabbe
disease, Pelizaeus-Merzbacher disease, Canavan disease, Alexander
disease, Binswanger's disease, peroneal muscular atrophy,
cerebrotendineous xanthomatosis, leukoencephalopathy with vanishing
white matter, toxic leukoencephalopathy, van der Knaap disease,
progressive multifocal leukoencephalopathy, Marchiafava-Bignami
disease or transverse myelitis.
[0092] In some examples, the Guillain-Barre syndrome is acute
inflammatory demyelinating polyneuropathy.
[0093] In some examples, the chronic inflammatory demyelinating
polyneuropathy is multifocal acquired demyelinating sensory and
motor neuropathy. In some examples, the chronic inflammatory
demyelinating polyneuropathy is induced by HIV infection.
[0094] In some embodiments, the disease or condition is a chronic
axonal neuropathy.
[0095] In some embodiments, the disease or condition results from
intraventricular hemorrhage, neonatal hypoxia, or acute hypoxemic
respiratory failure.
[0096] In some embodiments, the disease or condition is cerebral
palsy.
[0097] In one embodiment, the disease or condition is not X-ALD. In
another embodiment, the disease or condition is not multiple
sclerosis. In another embodiment, the disease or condition is not
cerebral palsy. In another embodiment, the disease or condition is
not a leukodystrophy.
[0098] In some embodiments of the disclosed method, administration
of the sobetirome or pharmaceutically acceptable salt thereof
prevents or mitigates at least one symptom of the disease or
condition. In some examples, the symptom is a lack of sphincter
control, erectile dysfunction, paraparesis, ataxia, adrenocortical
insufficiency, progressive neuropathy, paresthesia, dysarthria,
dysphagia, clonus, or any combination thereof.
[0099] In some embodiments, administration of the sobetirome or
pharmaceutically acceptable salt thereof prevents or mitigates
damage to central nervous system myelin, peripheral nervous system
myelin, adrenal cortex, testicular Leydig cells, or any combination
thereof.
[0100] In certain embodiments, sobetirome, or a pharmaceutically
acceptable salt thereof, is administered orally, parenterally, or
topically. In particular embodiments, sobetirome, or a
pharmaceutically acceptable salt thereof, is administered orally.
In certain embodiments, sobetirome, or a pharmaceutically
acceptable salt thereof, is administered enterally. In some
embodiments, sobetirome, or a pharmaceutically acceptable salt
thereof, is administered buccally, sublingually, sublabially, or by
inhalation. In other embodiments, sobetirome, or a pharmaceutically
acceptable salt thereof, is administered sublingually. In yet other
embodiments, sobetirome, or a pharmaceutically acceptable salt
thereof, is administered parenterally. In particular embodiments,
sobetirome, or a pharmaceutically acceptable salt thereof, is
administered intra-arterially, intravenously, intraventricularly,
intramuscularly, subcutaneously, intraspinally, intraorbitally,
intracranially or intrathecally.
[0101] In some embodiments, the sobetirome or pharmaceutically
acceptable salt thereof is administered at a dose of about 1 .mu.g
to about 500 .mu.g. In some examples, the sobetirome or
pharmaceutically acceptable salt thereof is administered at a dose
of about 10 .mu.g to about 100 .mu.g.
[0102] In some embodiments, the sobetirome or pharmaceutically
acceptable salt thereof is administered daily.
[0103] In particular embodiments, the compound is administered to
the subject once daily, twice daily, three times daily, once every
two days, once weekly, twice weekly, three times weekly, once
biweekly, once monthly, or once bimonthly. In certain embodiments,
the compound is administered to the subject once daily. In other
embodiments, the effective amount is more than 30 .mu.g (e.g., more
than 50 .mu.g, such as more than 100 .mu.g). In some embodiments,
the effective amount is more than 30 .mu.g (e.g., more than 50
.mu.g, such as more than 100 .mu.g) daily. In certain embodiments,
the effective amount is more than 30 .mu.g (e.g., more than 50
.mu.g, such as more than 100 .mu.g) twice daily. In particular
embodiments, the effective amount is more than 30 .mu.g (e.g., more
than 50 .mu.g, such as more than 100 .mu.g) once weekly. In other
embodiments, the effective amount is more than 30 .mu.g (e.g., more
than 50 .mu.g, such as more than 100 .mu.g) twice weekly. In
certain embodiments, the effective amount is at least 30 .mu.g
(e.g., more than 50 .mu.g, such as more than 100 .mu.g) three times
weekly. In some embodiments, the effective amount is less than 1 mg
(e.g., less than 500 .mu.g, such as less than 200 .mu.g).
[0104] In some embodiments, the methods of the present disclosure
involve administering a unit dosage form containing from 10 .mu.g
to 100 .mu.g of sobetirome, or a pharmaceutically acceptable salt
thereof, once, twice or three times per day. In some embodiments,
the methods of the present disclosure involve administering a unit
dosage form containing from 10 .mu.g to 75 .mu.g of sobetirome, or
a pharmaceutically acceptable salt thereof, once, twice or three
times per day. In other embodiments, the methods of the present
disclosure involve administering a unit dosage form containing from
30 .mu.g to 75 .mu.g of sobetirome, or a pharmaceutically
acceptable salt thereof, once, twice or three times per day. In
particular embodiments, the methods of the present disclosure
involve administering a unit dosage form containing from 10 .mu.g
to 50 .mu.g of sobetirome, or a pharmaceutically acceptable salt
thereof, once, twice or three times per day. In yet other
embodiments, the methods of the present disclosure involve
administering a unit dosage form containing from 30 .mu.g to 50
.mu.g of sobetirome, or a pharmaceutically acceptable salt thereof,
once, twice or three times per day. In still other embodiments, the
methods of the present disclosure involve administering a unit
dosage form containing from 50 .mu.g to 75 .mu.g of sobetirome, or
a pharmaceutically acceptable salt thereof, once, twice or three
times per day.
[0105] The present disclosure also features a method of treating a
patient having or at risk of developing multiple sclerosis by
administering to the patient a therapeutically effective amount of
sobetirome, or a pharmaceutically acceptable salt thereof. In one
example, provided is a method of treating a patient having or at
risk of developing multiple sclerosis, comprising administering to
the patient 1 mg/(kg of the weight of said patient)/day of
sobetirome, or a pharmaceutically acceptable salt thereof.
[0106] Administration of sobetirome and pharmaceutically acceptable
salts thereof is further discussed in the section below.
IV. Administration of Sobetirome or Pharmaceutical Compositions
Thereof
[0107] Sobetirome and pharmaceutically acceptable salts thereof can
be administered according to any suitable route of administration
for the treatment of a disease or condition associated with
demyelination, insufficient myelination, or underdevelopment of
myelin sheath. For example, standard routes of administration
include oral, parenteral, or topical routes of administration. In
particular, the route of administration of sobetirome or a
pharmaceutically acceptable salt thereof may be oral (e.g.,
enteral, buccal, sublingual, sublabial, or by inhalation).
Parenteral route of administration of sobetirome, or a
pharmaceutical composition thereof, may be, e.g., intra-arterial,
intravenous, intraventricular, intramuscular, subcutaneous,
intraspinal, intraorbital, or intracranial. Topical route of
administration may be, e.g., cutaneous, intranasal, or
ophthalmic.
[0108] Pharmaceutical compositions comprising sobetirome have been
described in the art (see, e.g., U.S. Pat. No. 5,883,294, which is
herein incorporated by reference).
[0109] Sobetirome and pharmaceutically acceptable salts thereof
that are to be administered orally can be formulated as liquids,
for example syrups, suspensions or emulsions, or as tablets,
capsules or lozenges.
[0110] A liquid composition will generally include a suspension or
solution of sobetirome or pharmaceutically acceptable salt in a
suitable liquid carrier, for example ethanol, glycerine, sorbitol,
non-aqueous solvent such as polyethylene glycol, oils or water,
with a suspending agent, preservative, surfactant, wetting agent,
flavoring or coloring agent. Alternatively, a liquid formulation
can be prepared from a reconstitutable powder.
[0111] In some cases, a powder containing active compound,
suspending agent, sucrose and a sweetener can be reconstituted with
water to form a suspension; and a syrup can be prepared from a
powder containing active ingredient, sucrose and a sweetener.
[0112] A composition in the form of a tablet can be prepared using
any suitable pharmaceutical carrier(s) routinely used for preparing
solid compositions. Examples of such carriers include magnesium
stearate, starch, lactose, sucrose, microcrystalline cellulose and
binders, for example polyvinylpyrrolidone. The tablet can also be
provided with a color film coating, or color included as part of
the carrier(s). In addition, active compound can be formulated in a
controlled release dosage form as a tablet comprising a hydrophilic
or hydrophobic matrix.
[0113] A composition in the form of a capsule can be prepared using
routine encapsulation procedures, for example by incorporation of
active compound and excipients into a hard gelatin capsule.
Alternatively, a semi-solid matrix of active compound and high
molecular weight polyethylene glycol can be prepared and filled
into a hard gelatin capsule; or a solution of active compound in
polyethylene glycol or a suspension in edible oil, for example
liquid paraffin or fractionated coconut oil can be prepared and
filled into a soft gelatin capsule. Sobetirome and pharmaceutically
acceptable salts thereof to be administered parenterally can be
formulated, for example, for intramuscular or intravenous
administration.
[0114] In some instances, a composition for intramuscular
administration contains a suspension or solution of active
ingredient in an oil, for example arachis oil or sesame oil. A
composition for intravenous administration can include a sterile
isotonic aqueous solution containing, for example active
ingredient, dextrose, sodium chloride, a co-solvent, for example
polyethylene glycol and, optionally, a chelating agent, for example
ethylenediamine tetracetic acid and an anti-oxidant, for example,
sodium metabisulphite. Alternatively, the solution can be freeze
dried and then reconstituted with a suitable solvent just prior to
administration.
[0115] Sobetirome and pharmaceutically acceptable salts thereof for
rectal administration can be formulated as suppositories. A typical
suppository formulation will generally include active ingredient
with a binding and/or lubricating agent such as a gelatin or cocoa
butter or other low melting vegetable or synthetic wax or fat.
[0116] Sobetirome and pharmaceutically acceptable salts thereof to
be administered topically can be formulated as transdermal
compositions. Such compositions include, for example, a backing,
active compound reservoir, a control membrane, liner and contact
adhesive.
[0117] Non-limiting examples of formulations for buccal,
sublingual, and/or sublabial administration may be found in U.S.
Pre-grant Publication No. 2012/0058962, U.S. Pre-grant Publication
No. 2013/0225626, U.S. Pre-grant Publication No. 2009/0117054, and
U.S. Pat. No. 8,252,329; the disclosure of each of which is
incorporated herein by reference.
[0118] For buccal, sublingual, or sublabial administration, the
compositions may take the form of tablets, lozenges, etc.
formulated in a conventional manner, as described for oral dosage
forms. In some embodiments, the formulation for buccal, sublingual,
or sublabial administration includes one or more of taste masking
agents, enhancers, complexing agents, and other described above
pharmaceutically acceptable excipients and carriers.
[0119] Taste masking agents include, for example, taste receptor
blockers, compounds which mask the chalkiness, grittiness, dryness,
and/or astringent taste properties of an active compound, compounds
which reduce throat catch as well as compounds which add a flavor.
A taste receptor blocker used in the formulation of the present
disclosure may include Kyron T-134, a glycoprotein extract called
miraculin from the fruit of the plant synsepalum dulcifcum, ethyl
cellulose, hydroxypropyl methylcellulose, arginine, sodium
carbonate, sodium bicarbonate, gustducin blockers and mixtures
thereof. Compounds which mask the chalkiness, grittiness, dryness
and/or astringent taste properties of an active compound include
those of a natural or synthetic fatty type or other flavorant such
as cocoa, chocolate (e.g., mint chocolate), cocoa butter, milk
fractions, vanillin butter fat, egg or egg white, peppermint oil,
wintergreen oil, spearmint oil, and similar oils. Compounds which
reduce throat catch include combinations of high and low solubility
acids. For example, high solubility acids suitable for use here
include amino acids (e.g., alanine, arginine etc.), glutaric,
ascorbic, malic, oxalic, tartaric, malonic, acetic, citric acids
and mixtures thereof. Low solubility acids suitable for use include
oleic, stearic and aspartic acids plus certain amino acids such as
glutamic acid, glutamine, histidine, isoleucine, leucine,
methionine, phenylalanine, serine, tryptophan, tyrosine, valine and
fumaric acid. Actual amounts used will vary depending on the amount
of throat catch or burn exhibited by the active used but will
generally be in the range of 1 to 40%. Flavoring agents include
sweeteners and flavors. Examples of suitable sweeteners and flavors
include mannitol, sorbitol, maltitol, lactitol, isomaltitol,
erythritol, xylitol, sucrose, ammonium glycyrrhizinate, mango
aroma, black cherry aroma, sodium citrate, colloidal silicon
dioxide, sucralose; zinc gluconate; ethyl maltitol; glycine;
acesulfame-K; aspartame; saccharin; acesulfam K, neohesperidin DC,
thaumatin, stevioside, fructose; xylitol; honey; honey extracts;
corn syrup, golden syrup, misri, spray dried licorice root;
glycerrhizine; dextrose; sodium gluconate; stevia powder; glucono
delta-lactone; ethyl vanillin; vanillin; normal and high-potency
sweeteners or syrups or salts thereof and mixtures thereof. Other
examples of appropriate flavoring agents include coffee extract,
mint; lamiacea extracts; citrus extracts; almond oil; babassu oil;
borage oil; blackcurrant seed oil; canola oil; castor oil; coconut
oil; corn oil; cottonseed oil; evening primrose oil; grape seed
oil; groundnut oil; mustard seed oil; olive oil; palm oil; palm
kernel oil; peanut oil; grapeseed oil; sunflower oil; sesame oil;
shark liver oil; soybean oil; hydrogenated castor oil; hydrogenated
coconut oil; hydrogenated palm oil; hydrogenated soybean oil;
hydrogenated vegetable oil; hydrogenated cottonseed and castor oil;
partially hydrogenated soybean oil; soy oil; glyceryl tricaproate;
glyceryl tricaprylate; glyceryl tricaprate; glyceryl
triundecanoate; glyceryl trilaurate; glyceryl trioleate; glyceryl
trilinoleate; glyceryl trilinolenate; glyceryl
tricaprylate/caprate; glyceryl tricaprylate/caprate/laurate;
glyceryl tricaprylate/caprate/linoleate; glyceryl
tricaprylate/caprate/stearate; saturated polyglycolized glycerides;
linoleic glycerides; caprylic/capric glycerides; modified
triglycerides; fractionated triglycerides; safrole, citric acid,
d-limonene, malic acid, and phosphoric acid or salts and/or
mixtures thereof.
[0120] Enhancers are the agents that increase membrane permeability
and/or increase the solubility of a particular active compound.
Both issues can be pivotal to the properties of the formulation. An
enhancer may be a chelator, a surfactant, a membrane-disrupting
compound, a fatty or other acid; a non-surfactant, such as an
unsaturated cyclic urea. A chelator may be, e.g., EDTA, citric
acid, sodium salicylate, or a methoxysalicylate. A surfactant may
be, e.g., sodium lauryl sulphate, polyoxyethylene,
POE-9-laurylether, POE-20-cetylether, benzalkonium chloride,
23-lauryl ether, cetylpyridinium chloride, cetyltrimethyl ammonium
bromide, or an amphoteric or a cationic surfactant. A
membrane-disrupting compound may be, e.g., a powdered alcohol (such
as, menthol) or a compound used as lipophilic enhancer. Fatty and
other acids include, e.g., oleic acid, capric acid, lauric acid,
lauric acid/propylene glycol, methyloleate,
yso-phosphatidylcholine, and phosphatidylcholine. Other enhancers
that may be used in buccal, sublingual, and sublabial formulations
of the present disclosure include, e.g., lysalbinic acid,
glycosaminoglycans, aprotinin, azone, cyclodextrin, dextran
sulfate, curcumin, menthol, polysorbate 80, sulfoxides, various
alkyl glycosides,
chitosan-4-thiobutylamide,chitosan-4-thiobutylamide/GSH,
chitosan-cysteine, chitosan-(85% degree N-deacetylation),
poly(acrylic acid)-homocysteine, polycarbophil-cysteine,
polycarbophil-cysteine/GSH, chitosan-4-thioethylamide/GSH,
chitosan-4-thioglycholic acid, hyaluronic acid, propanolol
hydrochloride, bile salts, sodium glycocholate, sodium
deoxycholate, sodium taurocholate, sodium glycodeoxycholate, and
sodium taurodeoxycholate.
[0121] Buffering materials can be both used to increase solubility
and enhance adsorption of active compounds. Examples of suitable
buffering materials or antacids suitable for use herein comprise
any relatively water soluble antacid acceptable to the Food &
Drug Administration, such as aluminum carbonate, aluminum hydroxide
(or as aluminum hydroxide-hexitol stabilized polymer, aluminum
hydroxide-magnesium hydroxide co-dried gel, aluminum
hydroxide-magnesium trisilicate codried gel, aluminum
hydroxide-sucrose powder hydrated), aluminum phosphate, aluminum
hydroxyl carbonate, dihydroxyaluminum sodium carbonate, aluminum
magnesium glycinate, dihydroxyaluminum aminoacetate,
dihydroxyaluminum aminoacetic acid, bismuth aluminate, bismuth
carbonate, bismuth subcarbonate, bismuth subgallate, bismuth
subnitrate, calcium carbonate, calcium phosphate, hydrated
magnesium aluminate activated sulfate, magnesium aluminate,
magnesium aluminosilicates, magnesium carbonate, magnesium
glycinate, magnesium hydroxide, magnesium oxide, and magnesium
trisilicate, and/or mixtures thereof. Preferred buffering materials
or antacids include aluminum hydroxide, calcium carbonate,
magnesium carbonate and mixtures thereof, as well as magnesium
hydroxide. Many of these compounds have the advantage of also being
taste masking agents particularly useful for addressing throat
catch.
[0122] The selection of the other excipients, such as permeation
enhancers, disintegrants, masking agents, binders, flavors,
sweeteners and taste-masking agents, is specifically matched to the
active depending on the predetermined pharmacokinetic profile
and/or organoleptic outcome.
[0123] Liquid drug formulations suitable for use with nebulizers
and liquid spray devices and electrohydrodynamic (EHD) aerosol
devices will typically include sobetirome or a pharmaceutically
acceptable salt thereof with a pharmaceutically acceptable carrier.
Preferably, the pharmaceutically acceptable carrier is a liquid,
e.g., alcohol, water, polyethylene glycol, or a perfluorocarbon.
Optionally, another material may be added to alter the aerosol
properties of the solution or suspension. Desirably, this material
is liquid, e.g., an alcohol, glycol, polyglycol, or a fatty acid.
Other methods of formulating liquid drug solutions or suspension
suitable for use in aerosol devices are known to those of skill in
the art (see, e.g., U.S. Pat. Nos. 5,112,598 and 5,556,611, each of
which is herein incorporated by reference).
[0124] The dose and dosing schedule for administration of
sobetirome (or a pharmaceutically acceptable salt thereof) can vary
and is determined in part by the severity of the disease, and the
age, weight and general health of the patient. In some embodiments,
the composition is administered daily. In other embodiments the
composition is administered more than once a day, such as twice a
day, three time a day or four times a day. In yet other
embodiments, the composition is administered less than once a day,
such as every other day, every three days or once a week.
[0125] In some embodiments, the dose of sobetirome (or a
pharmaceutically acceptable salt thereof) is about 1 .mu.g to about
500 .mu.g (e.g., twice daily, once daily, twice weekly, or once
weekly), such as about 5 .mu.g to about 250 .mu.g (e.g., twice
daily, once daily, twice weekly, or once weekly), about 10 .mu.g to
about 100 .mu.g (e.g., twice daily, once daily, twice weekly, or
once weekly), about 25 .mu.g to about 75 .mu.g (e.g., twice daily,
once daily, twice weekly, or once weekly), or about 50 .mu.g to
about 100 .mu.g (e.g., twice daily, once daily, twice weekly, or
once weekly). In particular examples, the dose of sobetirome (or a
pharmaceutically acceptable salt thereof) is about 1, 5, 10, 15,
20, 25, 30, 40, 50, 60, 70, 75, 100, 125, 150, 200, 250, 300, 350,
400, 450 or 500 .mu.g (e.g., twice daily, once daily, twice weekly,
or once weekly).
[0126] The following examples are provided to illustrate certain
particular features and/or embodiments. These examples should not
be construed to limit the disclosure to the particular features or
embodiments described.
EXAMPLES
Example 1: Use of Sobetirome for the Treatment of Multiple
Sclerosis (MS)
[0127] This example describes the finding that treatment with
sobetirome decreased demyelination in two different animal models
of MS.
Chronic Demyelination Contributes to Disability and Progressive
Impairment in MS
[0128] In MS, inflammatory cells induce multifocal demyelination
and variable axonal degeneration in the CNS, referred to as MS
plaques. Consequently, people with MS develop a variety of
neurologic deficits, including paralysis, gait impairment,
cognitive dysfunction, loss of sensation, and impaired vision.
While remyelination occurs spontaneously as part of the natural
repair process in MS, it is incomplete and tends to become
ineffective as the disease progresses. Failure of remyelination
leads to chronically demyelinated axons that lose their ability to
conduct axon potentials normally resulting in neurologic
dysfunction. Importantly, chronic demyelination may contribute to
the pathogenesis of progressive axonal degeneration, which is a
major cause of permanent disability.
Remyelination Occurs Early in MS but Fails as the Disease
Progresses
[0129] Spontaneous remyelination occurs in MS and can be quite
extensive. More commonly, remyelination occurs at the edges of
typical demyelinated plaques and tends to become less robust with
longer disease duration. Why remyelination fails is uncertain. OPC
are present near or in demyelinated plaques but for uncertain
reasons do not differentiate into OL and form myelin. It is
possible that the demyelinated axons fail to signal OPC properly.
Another theory is that the astrocytic "scar" that develops in
chronic MS plaques inhibits OPC migration and differentiation,
possibly through the presence of high molecular weight hyaluronic
acid. It is also possible that activated microglia and macrophages
within and near the MS plaques release soluble factors that inhibit
OPC differentiation.
Animal Models for Studying Remyelination
[0130] Several animal models are in use to assess the effectiveness
of therapies to promote remyelination, including models that use a
toxin (lysolecithin, ethidium bromide, or cuprizone) to induce
demyelination; EAE; and Theiler's murine encephalomyelitis. In both
the EAE and Theiler's models, demyelination is immune mediated. In
this example, one toxin model (lysolecithin) and one
immune-mediated model (EAE) are used to evaluate sobetirome.
Sobetirome Reduces Demyelination in the Lysolecithin Toxin Model of
Focal Demyelination
[0131] This study revealed that sobetirome can alter demyelination
in this focal demyelination model (FIG. 1). Lysolecithin was
injected into the corpus callosum using stereotactic equipment at
the x, y, z coordinates of +1.000, +1.050, and +2.000 mm from the
Bregma point using a beveled needle with the bevel facing caudally.
To minimize trauma, 2 .mu.L of 2% lysolecithin or 2 .mu.L of PBS
was injected over four minutes using a micropump injector and the
beveled needle was held in place for five minutes before
withdrawal. Brains were harvested 8 days later and fixed in
paraformaldehyde. Free-floating slices of 30 .mu.m were sectioned
with a vibratome and stained with BlackGold.RTM. to detect myelin.
In lysolecithin-injected (but not PBS-injected) C57BL/6 mice,
demyelination was observed in 6-8 serial sections in the corpus
callosum (FIG. 1).
[0132] The initial experiment sought to determine how
hypothyroidism, hyperthyroidism induced with high doses of T3, and
administration of sobetirome initiated before lysolecithin
injection affected the extent of demyelination 8 days after
lysolecithin injection. To induce hypothyroidism, mice were given
0.1% methimazole and 0.2% potassium perchlorate in the drinking
water for two weeks before lysolecithin injection; oral
administration of these reagents inhibits the production of thyroid
hormone and induces hypothyroidism. Both T3 (0.4 mg/kg/day) and
sobetirome (1.0 mg/kg/day) were administered daily by i.p.
injection starting 7 days before and for 8 days after lysolecithin
injection. Euthyroid control mice and hypothyroid mice received
daily i.p. injections of vehicle for 7 days prior and 8 days after
lysolecithin injection. Eight days after administration of
lysolecithin (FIG. 1), mice receiving sobetirome and T3 had much
smaller areas of demyelination than those receiving vehicle.
Hypothyroid mice had much larger areas of demyelination that
euthyroid mice. These initial experiments show that thyroid status
affects demyelination in the lysolecithin model, which has not been
previously demonstrated, and that sobetirome decreases
demyelination in this model.
Sobetirome Decreases Demyelination in EAE
[0133] This study was performed to assess the effects of sobetirome
on EAE in C57BL/6 female mice immunized with MOG 35-55 peptide.
Seventeen days after immunization, at peak of clinical disease,
mice were randomized to receive daily injections of sobetirome (1
mg/kg/day) or vehicle. After 11 days of treatment, mice were
euthanized and processed for histologic examination. EAE clinical
scores for the two groups did not differ significantly. This is
because the degree of inflammation within the spinal cords was
similar between the two groups (Table 1) and much of the short term
paralysis that occurs in EAE is secondary to effects of
inflammation on neural function. However, the lateral columns of
the lumbosacral cord had significantly less demyelination in the
mice receiving sobetirome compared with those receiving vehicle
(p<0.01; FIG. 2). Much of the effect appears related to
protection of axons and myelin from damage (FIG. 3). Thus,
sobetirome has a neuroprotective effect that decreases axonal
damage and demyelination.
TABLE-US-00001 TABLE 1 Immunofluorescent staining of lumbosacral
spinal cord sections stained for a macrophage marker (CD11b) and a
T cell marker (CD4) ID Group # % CD11b Staining % CD4 Staining 1339
and 1340 Sobetirome 8 5.76 1.24 1342 Vehicle 4 3.89 1.01
Summary of Animal Model Data
[0134] Sobetirome decreased demyelination in the lysolecithin focal
demyelination model. This model is widely used to study mechanisms
of myelin repair and to assess the therapeutic potential of drugs
and other therapies to promote remyelination in multiple sclerosis.
Sobetirome also decreased demyelination and axonal injury in
experimental autoimmune encephalomyelitis (EAE), the classic model
of multiple sclerosis. These studies demonstrate that Sobetirome is
effective in promoting remyelination and serves as a
neuroprotectant in multiple sclerosis.
Example 2: Sobetirome in an Animal Mode of Neonatal Hypoxia
[0135] Chronic neonatal hypoxia is a clinically relevant model of
premature brain injury caused by insufficient gas exchange from
poor lung development. This hypoxic state is a significant
contributor to diffuse white matter injury (DWMI), which is common
in infants born prematurely. Chronic hypoxia can cause myelination
abnormalities. A mouse model of chronic hypoxia has been previously
described (Scafidi et al., Nature doi: 10.1038/nature12880 [Epub
ahead of print], Dec. 25, 2013). This model can be used to evaluate
the effect of sobetirome on oligodendrocyte regeneration and
remyelination following hypoxia.
[0136] Mice are randomly selected to undergo hypoxic rearing or to
serve as normoxic controls. Hypoxic mice are placed in a sealed
chamber maintaining O.sub.2 concentration at 10.5% by displacement
with N.sub.2 as described previously (Raymond et al., J Neurosci
31:17864-17871, 2011; Bi et al., J Neurosci 31:9205-9221, 2011;
Jablonska et al., J Neurosci 32:14775-14793, 2012). Hypoxia is
initiated at post-natal day (P)3 and continues for 8 days until
P11. This time frame in rodent white matter oligodendrocyte
development reproduces changes that occur at 23-40 weeks of
gestation in the human brain (Back et al., J Neurosci 21:1302-1312,
2001). Age- and strain-matched mice serve as normoxic controls.
[0137] Hypoxic mice and normoxic control mice are randomized to
receive daily injections of sobetirome (1 mg/kg/day) or vehicle. In
some examples, administration of sobetirome (or vehicle) is
initiated at P11. In other examples, treatment is initiated at P3
or any time between P3 and P11. Multiple daily doses of sobetirome
(and vehicle) can be administered. Following the desired course of
treatment, mice are sacrificed and brain sections are prepared and
processed to evaluate myelin thickness and the number of
oligodendrocyte precursor cells in the white matter as described
(Scafidi et al., Nature doi: 10.1038/nature12880 [Epub ahead of
print], Dec. 25, 2013).
[0138] All publications, patents, and patent applications mentioned
in the above specification are hereby incorporated by reference.
Various modifications and variations of the described device and
methods of use of the invention will be apparent to those skilled
in the art without departing from the scope and spirit of the
invention. Although the invention has been described in connection
with specific embodiments, it should be understood that the
invention as claimed should not be unduly limited to such specific
embodiments. Indeed, various modifications of the described modes
for carrying out the invention that are obvious to those skilled in
the art are intended to be within the scope of the invention.
* * * * *