Treatment of nervous system disorders using combinations of pxr agonists and thyroid hormones 机翻标题: 暂无翻译,请尝试点击翻译按钮。

公开号/公开日
WO2017075607 A1 2017-05-04 [WO201775607] / 2017-05-04
申请号/申请日
2016WO-US59770 / 2016-10-31
发明人
CHANDRARATNA ROSHANTHA A;SANDERS MARTIN E;
申请人
IO THERAPEUTICS;
主分类号
IPC分类号
A61K-045/06A61P-025/28C07C-057/03C07C-057/30C07C-057/50
摘要
(WO201775607) Disclosed herein are methods of treating disease with a combination of a RXR agonist and a thyroid hormone.
机翻摘要
暂无翻译结果,您可以尝试点击头部的翻译按钮。
地址
代理人
代理机构
;
优先权号
2015US-62249216 2015-10-31
主权利要求
(WO201775607) CLAIMS    1.  A method of treating a nervous system disorder, the method comprising administering to an individual in need thereof a therapeutically effective amount of a RXR agonist and a thyroid hormone, wherein administration of the combination of the RXR agonist and the thyroid hormone treats the nervous system disorder in the individual, wherein the selective RXR agonist is 3,7-dimethyl-6(S),7(S)-methano,7-[1 , 1 ,4,4-tetramethyl- 1 ,2,3,4-tetrahydronaphth-7-yl]2(E),4(E) heptadienoic acid, and has the structure of formula III:     (III), bexarotene, or l_G268;    and wherein the combination of RXR agonist and thyroid hormone causes a greater improvement in the nervous system disorder than the selective RXR agonist or thyroid hormone alone.    2.  The method according to Claim 1 , wherein the RXR agonist is a selective RXR agonist and comprises 3,7-dimethyl-6(S),7(S)-methano,7-[1 , 1 ,4,4-tetramethyl-1 ,2,3,4- tetrahydronaphth-7-yl]2(E),4(E) heptadienoic acid.    3.  The method according to Claim 1 , wherein the RXR agonist is bexarotene.  4. The method according to Claim 1 , wherein the RXR agonist is LG268.    5.  The method according to Claim 1 wherein the combination of RXR agonist and thyroxine treats the nervous system disorder in the individual by both promoting remyelination and neuroprotection of neurons and modulating the individual's immune system.    6.  The method according to Claim 1 , wherein the nervous system disorder is a central nervous system (CNS) disorder.    7.  The method according to Claim 1 , wherein the nervous system disorder is relapsing/remitting, primary progressive, and secondary progressive forms of multiple sclerosis (MS), diffuse white matter injury in pre-term infants, neuromyelitis optica, acute disseminated encephalomyelitis, Marburg multiple sclerosis, diffuse myelinoclastic sclerosis (Schilder's disease), Balo concentric sclerosis, solitary sclerosis, optic neuritis, transverse    myelitis, amyotrophic lateral sclerosis (ALS), leukodystrophy (multiple variants, e.g.   adrenoleukodystrophy, adrenomyeloneuropathy), Parkinson's disease, Alzheimer's disease, progressive supranuclear palsy, stroke, CNS trauma including traumatic brain injury and traumatic spinal cord injury, radiation induced neuroinflammation, radiation somnolence syndrome, Devic's disease, inflammatory demyelinating diseases, CNS neuropathies, central pontine myelinolysis, Tabes dorsalis (syphilitic myelopathy), progressive multifocal leukoencephalopathy, leukodystrophy, depression, schizophrenia, epilepsy, or dementia.    8.  The method according to claim 1 , wherein the nervous system disorder is Parkinson's Disease.    9.  The method according to claim 1 , wherein the nervous system disorder is Alzheimer's Disease.    10.  The method according to claim 1 , wherein the nervous system disorder is a demyelination-related disorder.    1 1 .  The method according to Claim 1 1 , wherein the demyelination-related disorder is multiple sclerosis.    12.  The method according to Claim 1 1 , wherein the demyelination-related disorder is radiation-induced central nervous system inflammation.    13.  The method according to Claim 1 , wherein the nervous system disorder is a peripheral nervous system disorder.    14.  The method according to Claim 13, wherein the peripheral nervous system disorder is Guillain-Barre Syndrome, acute inflammatory demyelinating polyneuropathy, chronic inflammatory demyelinating polyneuropathy, demyelinating diabetic neuropathy, progressive inflammatory neuropathy, drug- or toxin-induced neuropathy, such as chemotherapy-induced neuropathy or organophosphate-induced neuropathy, anti-MAG peripheral neuropathy, Charcot-Marie-Tooth Disease, or copper deficiency.    15.  The method according to Claim 1 , wherein the therapeutically effective amount of the RXR agonist is about 0.001 mg/day to about 100 mg/day.    16.  The method according to Claim 1 , wherein the therapeutically effective amount of the RXR agonist is about 1 mg/day to about 20 mg/day.    17.  The method according to Claim 1 , wherein the thyroid hormone is thyroxine.  18. The method according to Claim 17, wherein the dose of thyroxine is about 12.5 .mu.g/day to about 250 .mu.g/day.    19. The method according to Claim 1 , wherein the RXR agonist is administered by nasal administration.    20.  The method according to Claim 19, wherein both the RXR agonist and thyroxine are administered by nasal administration.    21 .  The method according to Claim 1 , wherein the RXR agonist is administered orally.    22.  The method according to Claim 1 , wherein the RXR agonist and the thyroxine are administered substantially simultaneously.    23.  The method according to Claim 1 , wherein the RXR agonist and thyroxine are administered on different schedules.    24.  The method according to Claim 1 , wherein the thyroid hormone is   administered orally or subcutaneously.    25.  The method according to Claim 1 , wherein treatment with the combination of RXR agonist and thyroxine reduces at least one symptom of the CNS disorder, wherein the at least one symptom reduced is inflammation, fatigue, dizziness, malaise, elevated fever and high body temperature, extreme sensitivity to cold in the hands and feet, weakness and stiffness in muscles and joints, weight changes, digestive or gastrointestinal problems, low or high blood pressure, irritability, anxiety, or depression, blurred or double vision, ataxia, clonus, dysarthria, fatigue, clumsiness, hand paralysis, hemiparesis, genital anesthesia, incoordination, paresthesias, ocular paralysis, impaired muscle coordination, weakness (muscle), loss of sensation, impaired vision, neurological symptoms, unsteady gait, spastic paraparesis, incontinence, hearing problems, or speech problems.    26.  The method according to Claim 25, wherein treatment with the combination of RXR agonist and thyroxine reduces at least two symptoms of the CNS disorder.    27.  The method according to Claim 25, wherein treatment with the combination of RXR agonist and thyroxine reduces at least five symptoms of the CNS disorder.    28.  A method of treating multiple sclerosis, the method comprising administering to an individual in need thereof a therapeutically effective amount of 3,7-dimethyl-6(S),7(S)- methano,7-[1 , 1 ,4,4-tetramethyl-1 ,2,3,4-tetrahydronaphth-7-yl]2(E),4(E) heptadienoic acid and thyroxine; and wherein administration of the combination treats the multiple sclerosis in the individual more effectively than treatment with 3,7-dimethyl-6(S),7(S)-methano,7- [1 , 1 ,4,4-tetramethyl-1 ,2,3,4-tetrahydronaphth-7-yl]2(E),4(E) heptadienoic acid or thyroxine alone .    29. A method of treating a CNS disorder, the method comprising administering to an individual in need thereof a therapeutically effective amount of 3,7-dimethyl-6(S),7(S)- methano,7-[1 ,1 ,4,4-tetramethyl-1 ,2,3,4-tetrahydronaphth-7-yl]2(E),4(E) heptadienoic acid and thyroxine; and wherein administration of the combination treats the CNS disorder in the individual and wherein the RXR agonist is delivered directly to the CNS of the individual by intrathecal administration, epidural administration, cranial injection or implant, or nasal administration more effectively than treatment with 3,7-dimethyl-6(S)J(S)-methano,7- [1 ,1 ,4,4-tetramethyl-1 ,2,3,4-tetrahydronaphth-7-yl]2(E),4(E) heptadienoic acid or thyroxine alone.    30.  A method of treating Parkinson's Disease, the method comprising administering to an individual in need thereof a therapeutically effective amount of 3,7- dimethyl-6(S)J(S)-methano,7-[1 ,1 ,4,4-tetramethyl-1 ,2,3,4-tetrahydronaphth-7-yl]2(E),4(E) heptadienoic acid and thyroxine; and wherein administration of the combination treats the Parkinson's Disease in the individual more effectively than treatment with 3,7-dimethyl- 6(S),7(S)-methanoJ-[1 ,1 ,4,4-tetramethyl-1 ,2,3,4-tetrahydronaphth-7-yl]2(E),4(E) heptadienoic acid or thyroxine alone.    31.  A method of treating Alzheimer's Disease, the method comprising administering to an individual in need thereof a therapeutically effective amount of 3,7- dimethyl-6(S)J(S)-methano,7-[1 ,1 ,4,4-tetramethyl-1 ,2,3,4-tetrahydronaphth-7-yl]2(E),4(E) heptadienoic acid and thyroxine; and wherein administration of the combination treats the Alzheimer's Disease in the individual more effectively than treatment with 3,7-dimethyl- 6(S),7(S)-methanoJ-[1 ,1 ,4,4-tetramethyl-1 ,2,3,4-tetrahydronaphth-7-yl]2(E),4(E) heptadienoic acid or thyroxine alone.    32.  The method according to any of Claims 1 , 28, 28, 30, or 31 , further comprising:    determining free serum thyroxine; and    adjusting the dose of thyroxine to keep thyroxine levels in a euthyroid range.    33.  The method of any one of claims 1 , 28, 28, 30, or 31 , comprising further administration of a neurotrophic factor, or neurotrophic factor mimetic.    34.  The method of claim 33, wherein the neurotrophic factor is BDNF, GDNF, NGF, NT-3, bFGF, CNTF, NT-4/5, IGF, or insulin, or a mimetic thereof.    35.  The method of claim 31 , wherein the disease of the central nervous system is Parkinson's disease, Alzheimer's disease, a multiple sclerosis, an optic neuritis, a stroke, a nervous system trauma, amyotrophic lateral sclerosis, a neuropathy, a nervous system hypoxia, a nervous system toxicity, a dementia, a retinopathy, Huntington's disease, a   56    RECTIFIED (RULE 91) - ISA/US    synucleinopathy, epilepsy, autism, schizophrenia, depression, or and aging-related nervous system degeneration.    36.  The method of claim 35, wherein the neurotrophic factor is GDNF, or a GDNF mimetic, and the nervous system disease is Parkinson's disease or amyotrophic lateral sclerosis.    37.  The method of claim 31 , wherein the neurotrophic factor is BDNF and the nervous system disease is Alzheimer's disease, multiple sclerosis, stroke, nervous system trauma, aging, or dementia.    38.  The method of claim 31 , wherein the neurotrophic factor is insulin or insulinlike growth factor, and the nervous system disease is Alzheimer's disease.    39.  The method of claim 31 , wherein the neurotrophic factor is BDNF, GDNF, or insulin, and the nervous system disease is aging-related CNS neurodegeneration.    40.  The method of claim 31 , wherein the neurotrophic factor or mimetic is administered by oral, parenteral, nasal, or topical routes, or by controlled release formulation with any of these routes of administration.    41.  Use of a combination of a RXR agonist, a thyroid hormone, and a neurotrophic factor, or neurotrophic factor mimetic, for in vitro promotion of survival or growth of neurons or glial cells, for subsequent implantation into the nervous system of a patient with a nervous system disorder.    42.  A method of promoting survival or repair of neurons or glial cells in a patient with a nervous system disorder, the method comprising administering to an individual in need thereof a therapeutically effective amount of a RXR agonist and a thyroid hormone, wherein the RXR agonist is 3,7-dimethyl-6(S),7(S)-methano,7-[1 ,1 ,4,4-tetramethyl-1 ,2,3,4- tetrahydronaphth-7-yl]2(E),4(E) heptadienoic acid, bexarotene, or LG268, and administration of the combination of the RXR agonist and the thyroid hormone promotes survival or repair of neurons or glial cells in the individual more effectively that treatment with the RXR agonist or thyroid hormone alone.    43.  The method according to Claim 42, wherein the nervous system disorder is a central nervous system (CNS) disorder, a demyelination-related disorder, or a peripheral nervous system disorder.    44.  The method according to Claim 43, wherein the nervous system disorder is multiple sclerosis (MS), Parkinson's disease, or Alzheimer's disease.   57    RECTIFIED (RULE 91) - ISA/US    45. The method according to Claim 42, wherein the therapeutically effective amount of the RXR agonist is about 0.001 mg/day to about 100 mg/day.    46.  The method according to Claim 42, wherein the therapeutically effective amount of the RXR agonist is about 1 mg/day to about 20 mg/day.    47.  The method according to Claim 42, wherein the thyroid hormone is thyroxine.  48. The method according to Claim 47, wherein the dose of thyroxine is about 12.5 [lg/day to about 250 pg/day.    49.  The method according to Claim 42, wherein treatment with the combination of RXR agonist and thyroxine reduces at least one symptom of the nervous system disorder, wherein the at one symptom reduced is inflammation, fatigue, dizziness, malaise, elevated fever and high body temperature, extreme sensitivity to cold in the hands and feet, weakness and stiffness in muscles and joints, weight changes, digestive or gastrointestinal problems, low or high blood pressure, irritability, anxiety, or depression, blurred or double vision, ataxia, clonus, dysarthria, fatigue, clumsiness, hand paralysis, hemiparesis, genital anesthesia, incoordination, paresthesias, ocular paralysis, impaired muscle coordination, weakness (muscle), loss of sensation, impaired vision, neurological symptoms, unsteady gait, spastic paraparesis, incontinence, hearing problems, or speech problems.    50.  The method according to Claim 49, wherein treatment with the combination of RXR agonist and thyroxine reduces at least two symptoms of the nervous system disorder.    51.  The method according to Claim 49, wherein treatment with the combination of RXR agonist and thyroxine reduces at least five symptoms of the nervous system disorder.   58    RECTIFIED (RULE 91) - ISA/US
法律状态
(WO201775607) LEGAL DETAILS FOR WO2017075607  Actual or expected expiration date=2019-04-30    Legal state=ALIVE    Status=PENDING     Event publication date=2016-10-31  Event code=WO/APP  Event indicator=Pos  Event type=Examination events  Application details  Application country=WO WOUS2016059770  Application date=2016-10-31  Standardized application number=2016WO-US59770     Event publication date=2017-05-04  Event code=WO/A1  Event type=Examination events  Published application with search report  Publication country=WO  Publication number=WO2017075607  Publication stage Code=A1  Publication date=2017-05-04  Standardized publication number=WO201775607  LEGAL DETAILS FOR DESIGNATED STATE EP  Actual or expected expiration date=2035-10-31    Legal state=ALIVE    Status=PENDING   Corresponding cc:  Designated or member state=EP Corresponding appl: EP16861054    Event publication date=2017-06-21  Event code=WO/121  Event type=Designated states  EP: The EPO has been informed by wipo that ep was designated in this application Corresponding cc:  Designated or member state=EP
专利类型码
A1
国别省市代码
若您需要申请原文,请登录。

最新评论

暂无评论。

登录后可以发表评论

意见反馈
返回顶部