Treatment of diseases by concurrently eliciting remyelination effects and immunomodulatory effects using selective rxr agonists

Abstract

The present specification provides RXR agonists with both remyelination promotion and immunomodulatory activities, compositions comprising such RXR agonists, and methods using such compounds and compositions to treat a demyelination-related disorder by both promoting remyelination of neurons and modulating the immune system.

What is claimed is: 
     
         1 . A method of treating a demyelination-related disorder, the method comprising the step of administering to an individual in need thereof a therapeutically effective amount of a composition comprising RXR agonist means for activating permissive heterodimer Nurr1/RXR, and an excipient or carrier, wherein administration of the composition treats the demyelination-related disorder in the individual by both promoting remyelination of neurons and modulating the individual's immune system. 
     
     
         2 . The method according to  claim 1 , wherein the said means activates the permissive heterodimers PPAR/RXR, FXR/RXR, or LXR/RXR by 10% or less relative to bexarotene. 
     
     
         3 . The method according to  claim 1 , wherein the immunomodulatory activity comprises increasing the number of Treg cells in the individual. 
     
     
         4 . The method according to  claim 1 , wherein the immunomodulatory activity comprises decreasing the number of Th17 cells in the individual. 
     
     
         5 . The method according to  claim 1 , wherein the immunomodulatory activity comprises increasing the number of Treg cells and decreasing the number of Th17 cells in the individual. 
     
     
         6 . The method according to  claim 2 , wherein said means 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, which has the structure of formula XXIX: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The method according to  claim 1 , wherein the demyelination-related disorder is a central nervous system disorder. 
     
     
         8 . The method according to  claim 7 , wherein the central nervous system disorder is multiple sclerosis, 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, leukodystrophy, Parkinson's disease, Alzheimer's disease, progressive supranuclear palsy, stroke, traumatic brain injury, radiation induced neuroinflammation, radiation somnolence syndrome, Devic's disease, an inflammatory demyelinating disease, a CNS neuropathy, a myelopathy, a leukoencephalopathy, or a leukodystrophies. 
     
     
         9 . The method according to  claim 1 , wherein the demyelination-related disorder is multiple sclerosis. 
     
     
         10 . The method according to  claim 1 , wherein the demyelination-related disorder is a peripheral nervous system disorder. 
     
     
         11 . The method according to any  claim 1 , wherein the peripheral nervous system disorder is Guillain-Barré Syndrome, acute inflammatory demyelinating polyneuropathy, chronic inflammatory demyelinating polyneuropathy, demyelinating diabetic neuropathy, progressive inflammatory neuropathy, drug- or toxin-induced neuropathy, chemotherapy-induced neuropathy, organophosphate-induced neuropathy, anti-MAG peripheral neuropathy, Charcot-Marie-Tooth Disease, or copper deficiency. 
     
     
         12 . The method according to  claim 1 , wherein the therapeutically effective amount of said means is about 0.001 mg/kg/day to about 100 mg/kg/day. 
     
     
         13 . The method according to  claim 12 , wherein the therapeutically effective amount of said means is about 0.1 mg/kg/day to about 10 mg/kg/day. 
     
     
         14 . The method according to  claim 1 , wherein the therapeutically effective amount of said means is about 0.01 mg/m 2 /day to about 100 mg/m 2 /day. 
     
     
         15 . The method according to  claim 14 , wherein the therapeutically effective amount of said means is about 15 mg/m 2 /day to about 60 mg/m 2 /day. 
     
     
         16 . The method according to  claim 1 , wherein the composition is administered by nasal administration. 
     
     
         17 . The method according to  claim 1 , wherein treatment with the selective RXR agonist reduces at least one symptom of the demyelination-related 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 blood pressure, high blood pressure, irritability, anxiety, depression, blurred vision, double vision, ataxia, clonus, dysarthria, fatigue, clumsiness, hand paralysis, hemiparesis, genital anesthesia, incoordination, paresthesias, ocular paralysis, impaired muscle coordination, loss of sensation, impaired vision, neurological symptoms, unsteady gait, spastic paraparesis, incontinence, hearing problems, or speech problems. 
     
     
         18 . The method of  claim 2 , wherein said means does not activate permissive heterodimers PPAR/RXR, FXR/RXR, and LXR/RXR to any appreciable degree. 
     
     
         19 . A method of  claim 7  wherein the composition is delivered directly to the CNS of the individual by intrathecal administration, epidural administration, cranial injection or implant, or nasal administration. 
     
     
         20 . The method of  claim 19 , wherein the composition is delivered directly to the CNS of the individual by intrathecal administration, epidural administration, cranial injection or cranial implant.