Treatment of nervous system disorders with a combination of RXR agonists and thyroid hormones

Abstract

Pharmaceutical compositions are provided for treating nervous system disorders by inducing remyelination, neuroprotection, and immunomodulation. [Solution] A pharmaceutical composition comprising a therapeutically effective amount of an RXR agonist for use in combination with thyroid hormone in the treatment of demyelination or neuroinflammation associated with a central nervous system disorder, 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, and the RXR agonist, when used in combination with thyroid hormone, brings about greater improvement of the central nervous system disorder than either the RXR agonist or the thyroid hormone alone.

Description

[Technical Field]

[0001] (Related Applications) This application claims priority to U.S. Provisional Patent Application No. 62 / 249,216, filed October 31, 2015, the entire contents of which are incorporated herein by reference.

[0002] (Technical field) The present disclosure relates to methods of treating nervous system disorders by inducing remyelination, neuroprotection, and immunomodulation using retinoid X receptor (RXR) agonists in combination with thyroid hormone. [Background technology]

[0003] The current standard of care for neurological disorders involves several anti-inflammatory and immunomodulatory drugs that promote clinical benefit by modulating the patient's inflammatory / immune response. While these therapies slow disease progression, they cannot reverse pathology or restore neurological function. One way to achieve significant progress in the current standard of care for patients with neurological disorders is to promote remyelination or neuroprotection, or both, thereby regenerating or maintaining healthy axons and neurons. Summary of the Invention [Means for solving the problem]

[0004] Disclosed herein are methods of treating nervous system disorders by inducing remyelination, neuroprotection, and immunomodulation using retinoid X receptor (RXR) agonists in combination with thyroid hormone.

[0005] Specifically, disclosed herein are methods for treating a nervous system disorder, comprising administering to an individual in need thereof a therapeutically effective amount of an RXR agonist and a therapeutically effective amount of thyroid hormone, wherein administration of the combination of the RXR agonist and thyroid hormone treats the nervous system disorder in the individual more effectively than treatment with either the RXR agonist or thyroid hormone alone. In some embodiments, the combination of the RXR agonist and thyroxine treats the nervous system disorder in the individual by both promoting neuronal remyelination and neuroprotection and modulating the individual's immune system.

[0006] In some embodiments, 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 and has Formula III: [ka] It has the following structure.

[0007] In other embodiments, the RXR agonist is bexarotene or LG268.

[0008] In certain embodiments, the nervous system disorder is a central nervous system (CNS) disorder. In certain embodiments, the nervous system disorder is relapsing / remitting primary progressive and secondary progressive forms of multiple sclerosis (MS), diffuse white matter lesions of early childhood, neuritis, acute disseminated encephalomyelitis, Marburg multiple sclerosis, diffuse myelosclerotic sclerosis (Scheder's disease), baroconcentric sclerosis, isolated 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 syndrome, Devick's disease, inflammatory demyelinating diseases, CNS neuropathies, central pontine myelinolysis, dorsal funiculus (syphilitic myelopathy), progressive multifocal leukoencephalopathy, leukodystrophy, depression, schizophrenia, epilepsy, migraine, and dementia.

[0009] In certain embodiments, the nervous system disorder is a demyelination-related disorder such as multiple sclerosis or radiation-induced nervous system inflammation.

[0010] In some embodiments, the demyelination-related disorder is a peripheral nervous system disorder such as Guillain-Barré syndrome, acute inflammatory demyelinating polyneuropathy, chronic inflammatory demyelinating polyneuropathy, demyelinating diabetic neuropathy, progressive inflammatory neuropathy, drug-induced or toxin-induced neuropathy such as chemotherapy-induced neuropathy or organophosphate-induced neuropathy, anti-MAG peripheral neuropathy, Charcot-Marie-Tooth disease, or copper deficiency.

[0011] In some embodiments, the therapeutically effective amount of the RXR agonist is about 0.001 mg / day to about 100 mg / day. In other embodiments, the therapeutically effective amount of the RXR agonist is about 1 mg / day to about 20 mg / day. In some embodiments, the thyroid hormone is thyroxine. In certain embodiments, the therapeutically effective amount of thyroxine is about 12.5 μg / day to about 250 μg / day. In some embodiments, the RXR agonist is administered intranasally. In some embodiments, both the RXR agonist and thyroxine are administered intranasally. In some embodiments, the RXR agonist is administered orally. In some embodiments, the RXR agonist and thyroxine are administered substantially simultaneously. In some embodiments, the RXR agonist and thyroxine are administered on different schedules. In some embodiments, the thyroid hormone is administered orally or subcutaneously.

[0012] In certain embodiments, the combination of RXR agonist and thyroxine treatment reduces at least one symptom of nervous system disorder, and the at least one symptom that is reduced is inflammation, fatigue, dizziness, headache, malaise, high fever and hyperthermia, extreme sensitivity to cold in hands and feet, muscle and joint weakness and stiffness, weight change, digestive or gastrointestinal problems, low or high blood pressure, irritability, anxiety or depression, blurred or double vision, ataxia, clonus, dysarthria, fatigue, poor speech, hand numbness, migraine, genital anesthesia, incoordination, paresthesia, eye numbness, muscle coordination disorder, weakness (muscle), loss of sensation, visual impairment, neurological symptoms, unsteady gait, spastic paresis, incontinence, hearing impairment or speech problems.In other embodiments, the combination of RXR agonist and thyroxine treatment reduces at least two symptoms of nervous system disorder. In other embodiments, treatment with the combination of an RXR agonist and thyroxine reduces at least five symptoms of a nervous system disorder.

[0013] In some embodiments, the method further comprises measuring free serum thyroxine and adjusting the dose of thyroxine to keep the concentration of thyroxine in the euthyroid range.

[0014] In some embodiments, the method further comprises administering a neurotrophic factor or a neurotrophic factor mimic in combination with an RXR agonist and a thyroid hormone for the treatment of nervous system diseases. In some embodiments, the neurotrophic factor is BDNF, GDNF, NGF, NT-3, bFGF, CNTF, NT-4 / 5, IGF, or insulin, or a mimic thereof.

[0015] In certain embodiments, the disease of the nervous system is Parkinson's disease, Alzheimer's disease, multiple sclerosis, optic neuritis, stroke, CNS trauma, amyotrophic lateral sclerosis, neuropathy, nervous system hypoxia, CNS toxicity, dementia, retinopathy, Huntington's disease, synucleinopathy, epilepsy, autism, schizophrenia, depression, or age-related CNS degeneration.

[0016] In some embodiments, the neurotrophic factor is GDNF or a GDNF mimetic, and the nervous system disease is Parkinson's disease. In some embodiments, the neurotrophic factor is GDNF or a GDNF mimetic, and the nervous system disease is amyotrophic lateral sclerosis. In some embodiments, the neurotrophic factor is BDNF, and the nervous system disease is Alzheimer's disease. In some embodiments, the neurotrophic factor is insulin or an insulin-like growth factor, and the nervous system disease is Alzheimer's disease. In some embodiments, the neurotrophic factor is BDNF, and the nervous system disease is multiple sclerosis. In some embodiments, the neurotrophic factor is BDNF, and the nervous system disease is stroke, nervous system trauma, aging, or dementia. In some embodiments, the neurotrophic factor is BDNF, GDNF, or insulin, and the nervous system disease is aging-related nervous system neurodegeneration. In certain embodiments, the neurotrophic factor or mimetic is administered orally, parenterally, nasally, or topically, or by controlled release.

[0017] Also disclosed herein is the use of a combination of an RXR agonist, thyroid hormone, and a neurotrophic factor or neurotrophic factor mimetic to promote the survival or growth of neurons or glial cells in vitro for subsequent transplantation into the nervous system of a patient with a nervous system disorder.

[0018] Also disclosed herein is a method for promoting neuronal or glial cell survival or repair in an individual suffering from a nervous system disorder, comprising administering to an individual in need of such treatment a therapeutically effective amount of an RXR agonist described herein and a therapeutically effective amount of a thyroid hormone described herein, wherein administering the combination of the RXR agonist and the thyroid hormone is a method of treating the nervous system disorder in the individual.

[0019] In certain embodiments, the method of promoting neuronal or glial cell survival or repair further comprises administering a neurotrophic factor or neurotrophic factor mimetic to promote neuronal or glial cell survival or repair in a patient with a nervous system disorder. In some embodiments, the neurotrophic factor is BDNF, GDNF, NGF, NT-3, bFGF, CNTF, NT-4 / 5, IGF, or insulin, or a mimetic thereof.

[0020] In some embodiments, the neurotrophic factor is GDNF or a GDNF mimetic, and the nervous system disease is Parkinson's disease. In some embodiments, the neurotrophic factor is GDNF or a GDNF mimetic, and the nervous system disease is amyotrophic lateral sclerosis. In some embodiments, the neurotrophic factor is BDNF, and the nervous system disease is Alzheimer's disease. In some embodiments, the neurotrophic factor is insulin or an insulin-like growth factor, and the nervous system disease is Alzheimer's disease. In some embodiments, the neurotrophic factor is BDNF, and the nervous system disease is multiple sclerosis. In some embodiments, the neurotrophic factor is BDNF, and the nervous system disease is stroke, nervous system trauma, aging, or dementia. In some embodiments, the neurotrophic factor is BDNF, GDNF, or insulin, and the nervous system disease is aging-related nervous system neurodegeneration. In certain embodiments, the neurotrophic factor or mimetic is administered orally, parenterally, nasally, or topically, or by controlled release.

[0021] Also disclosed herein is 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 (a compound of Formula III) and a therapeutically effective amount of thyroxine, wherein administration of the combination treats multiple sclerosis in the individual more effectively than treatment with either 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 thyroid hormone alone.

[0022] Also disclosed herein are methods of treating a nervous system 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 a therapeutically effective amount of thyroxine, wherein administration of the combination treats the nervous system disorder 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 thyroid hormone alone, and wherein the RXR agonist is delivered directly to the individual's nervous system by intrathecal administration, epidural administration, intracranial injection or implantation, or intranasal administration.

[0023] Also disclosed herein is 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),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl]2(E),4(E)heptadienoic acid and a therapeutically effective amount of thyroxine, wherein administration of the combination treats Parkinson's disease in the individual more effectively than treatment with either 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 thyroid hormone alone.

[0024] Also disclosed herein is 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),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl]2(E),4(E)heptadienoic acid and a therapeutically effective amount of thyroxine, wherein administration of the combination more effectively treats Alzheimer's disease in the individual than treatment with either 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 thyroid hormone alone. [Brief explanation of the drawings]

[0025] [Figure 1] A transactivation assay is used to demonstrate RXR agonist activation of transcription from RXRα, RXRβ, RXRγ, RARα, RARβ, and RARγ. [Figure 2] We show that an RXR agonist in combination with thyroid hormone attenuates experimental autoimmune encephalomyelitis (EAE) in C57BL / 6 mice. [Figure 3A] Figure 3A shows the number of CD4+ cells, indicating that RXR agonists reduce leukocyte infiltration into the central nervous system. [Figure 3B] Figure 3B shows that RXR agonists reduce leukocyte infiltration into the central nervous system. Figure 3B shows the number of CD11c+CD11b+ cells (myeloid DCs) in mice treated with the selective RXR agonist IRX4204 (4204) versus vehicle control. [Figure 4] 1 shows that RXR agonists attenuate EAE in SJL mice. [Figure 5A] Figure 1 shows that IRX4204 selectively activates the RXR-Nurr1 heterodimer.Transactivation assay of IRX4204 (194204, Formula III) on the farnesoid X receptor FXR. [Figure 5B]Figure 1 shows that IRX4204 selectively activates the RXR-Nurr1 heterodimer. Transactivation assay of IRX4204 (194204, Formula III) on liver X receptors LXRα and LXRβ. [Figure 5C] Figure 1 shows that IRX4204 selectively activates the RXR-Nurr1 heterodimer.Transactivation assay of IRX4204 (194204, Formula III) for the peroxisome proliferator-activated receptor PPARγ. [Figure 5D] Figure 1 shows that IRX4204 selectively activates the RXR-Nurr1 heterodimer.Transactivation assay of IRX4204 (194204, Formula III) on the Nurr1 receptor in the presence or absence of RXR. [Figure 6] 1 shows the percentage of green fluorescent protein (EGFP) positive oligodendrocytes after culture of oligodendrocyte precursor cells derived from embryonic mouse brain with IRX4204 and thyroid hormone. [Figure 7] 1 shows the effect of the selective RXR agonist IRX4204 on EAE in mice. [Figure 8A] CCR6 expression on splenocytes from EAE mice treated with 200 μg / day IRX4204 or control is shown. [Figure 8B] CD49d expression on splenocytes from EAE mice treated with 200 μg / day IRX4204 or control is shown. [Figure 9A] Quantification of CD4+CD25hi cells in splenocytes from EAE mice treated with 200 μg / day IRX4204 or control is shown. [Figure 9B] 1 shows the frequency of CD4+CD25hi cells in splenocytes from EAE mice treated with 200 μg / day IRX4204 or control. [Figure 9C] The total number of effector and memory CD4 T cells in splenocytes from EAE mice treated with 200 μg / day of IRX4204 or control is shown. [Figure 9D]The total number of activated CD4 T cells in splenocytes from EAE mice treated with 200 μg / day IRX4204 or control is shown. [Figure 10] Shown are the total numbers of infiltrating CD4 T cells in the CNS of EAE mice treated with 200 μg / day IRX4204 or control. [Figure 11A] FIG. 10 shows restimulation of infiltrating lymphocytes to determine expression of interferon gamma (IFNγ). [Figure 11B] FIG. 10 shows restimulation of infiltrating lymphocytes to determine expression of IL-17A. [Figure 11C] FIG. 10 shows restimulation of infiltrating lymphocytes to determine tumor necrosis factor (TNF) expression. [Figure 11D] FIG. 10 shows restimulation of infiltrating lymphocytes to determine L-4 expression. [Figure 12A] Quantification of co-expression of IFNγ and IL-17A by the CD4 T cells of FIG. 10 expresses IL-17A and, but not IFNγ (FIG. 12A). [Figure 12B] Quantification of co-expression of IFNγ and IL-17A by CD4 T cells from FIG. 10 expressing IL-17A and IFNγ (FIG. 12B) is shown. [Figure 12C] Quantification of co-expression of IFNγ and IL-17A by the CD4 T cells in FIG. 10 expresses IFNγ and IL-17A, but not IL-17A (FIG. 12C). [Figure 13] Figure 1 shows changes in paw-placing behavior in the rat 6-OHDA-induced model of Parkinson's disease by treatment with compounds and combinations described herein (*P<0.05 vs. vehicle using Dunnett's test after one-way ANOVA). [Figure 14] The percentage and fold change of EGFP+ oligodendrocytes after treatment of oligodendrocytes with IRX4204, thyroid hormone and vitamin D are shown (*: P<0.05, Student's t-test vs. DMSO control; error bars, SD). [Figure 15A]The change in percentage of EGFP+ oligodendrocytes after treating oligodendrocytes with IRX4204 and thyroid hormone is shown (FIG. 15A: 10nMIRX4204). ***P<0.0001; **P<0.01. [Figure 15B] The change in percentage of EGFP+ oligodendrocytes after treating oligodendrocytes with IRX4204 and thyroid hormone is shown (FIG. 15B: 1nMIRX4204). ***P<0.0001; **P<0.01. [Figure 15C] The change in percentage of EGFP+ oligodendrocytes after treating dendrocytes with IRX4204 and thyroid hormone is shown (FIG. 15C: 0.1nM IRX4204). ***P<0.0001; **P<0.01. [Figure 16A] Figure 16 shows the effect of IRX4204 on remyelination in a cuprizone-induced demyelination model. Figure 16A shows remyelination in the hippocampus. [Figure 16B] Figure 16B shows the effect of IRX4204 on remyelination in a cuprizone-induced demyelination model. Figure 16B shows remyelination in the cortex. [Figure 17A] Quantification of myelinated axon size. Myelinated axon size after 6 weeks of treatment was quantified using Image J. The histogram of axon size distribution shows a shift in distribution toward larger axon diameters in IRX4204-treated axons. [Figure 17B] Quantification of myelinated axon size. Myelinated axon size after 6 weeks of treatment was quantified using Image J. Examination of the third quartile of axon size, approximately 0.7 μm, shows a significant increase (P<0.0001) in axon size in the upper quartile. [Figure 18] Shown are peripheral circulating serum T4 concentrations in animals receiving vehicle, IRX4204, or IRX4204 and T4 (**P<0.005 vs. vehicle and naive controls). [Figure 19] Quantification of SMI32-positive ovaries within the corpus callosum in animals treated with vehicle, IRX4204, or IRX4204 and T4 for 6 weeks is shown (*P<0.05 vs. Veh+Veh control). [Figure 20A]Quantification of myelination of the corpus callosum after in vivo treatment with the combinations described herein and separation of the data into potential responders and non-responders are shown (one-way ANOVA with Tukey's multiple comparisons, *P<0.05 **P<0.01, ****P<0.001). Figure 20A shows myelinated axons per CC unit. [Figure 20B] Quantification of myelination of the corpus callosum after in vivo treatment with the described combinations and separation of the data into potential responders and non-responders are shown (one-way ANOVA with Tukey's multiple comparisons, *P<0.05 **P<0.01, ****P<0.001). Figure 20B shows the density of myelinated axons (per 10,000 μm2). [Figure 20C] Quantification of myelination of the corpus callosum after in vivo treatment with the described combinations and separation of the data into potential responders and non-responders are shown (one-way ANOVA with Tukey's multiple comparisons, *P<0.05 **P<0.01, ****P<0.001). Figure 20C shows the density of SM132+ ovaries (per 250,000 μm). DETAILED DESCRIPTION OF THE INVENTION

[0026] Many nervous system diseases are associated with demyelination of axons and neurons. Such demyelination disorders can be autoimmune or of other etiologies. Multiple sclerosis (MS) is an example of an autoimmune disease that is also associated with demyelination. Therefore, the optimal drug or drug combination for the treatment of MS would address the autoimmune aspects of the disease while simultaneously preventing demyelination, thereby enhancing remyelination and providing neuroprotection. MS is currently treated with several immunomodulatory drugs that provide clinical benefit by modulating the patient's immune response and producing anti-inflammatory effects. These drugs slow disease progression but do not reverse disease pathology or restore neuronal function by restoring myelination of damaged neurons. When used in combination with thyroid hormone, IRX4204 (194204, Formula III), a retinoid X receptor (RXR) ligand with a unique mechanism of action—it is a selective activator of RXR homodimers and RXR-Nurr1 heterodimers—provides immunomodulatory activity and also promotes remyelination and neuroprotection. IRX4204 promotes the differentiation of suppressive Treg cells while inhibiting the differentiation of pro-inflammatory Th17 cells, thereby favorably affecting the abnormally skewed Th17 / Treg cell ratio underlying human autoimmune diseases such as MS (see co-pending U.S. Patent Application Publication No. 2015 / 0038585, which is incorporated by reference for all that it discloses regarding RXR agonists). Therefore, due to its effect on the Th17 / Treg cell ratio, IRX4204 may have clinical benefits similar to the current level of care in MS. Furthermore, IRX4204 promotes remyelination and neuroprotection of demyelinated neurons by preventing demyelination. IRX4204 in combination with thyroid hormone may further enhance further remyelination of demyelinated neurons and provide greater neuroprotection by more effectively preventing demyelination.Therefore, the combination of thyroid hormone and IRX4204, as well as other RXR ligands with the same receptor activation profile, compounds that provide immunomodulatory activity and promote remyelination and neuroprotection (and regeneration), will not only slow disease progression in MS, but also result in neuronal maintenance and recovery by protecting and regenerating healthy axons and neurons. IRX4204, together with thyroid hormone, is expected to be an optimal drug combination for the treatment of MS and other autoimmune diseases that are also associated with demyelination.

[0027] Retinoic acid receptors (RARs) and RXRs and their cognate ligands function by different mechanisms. RARs always form heterodimers with RXRs, and these RAR / RXR heterodimers bind to specific response elements in the promoter regions of target genes. Binding of RAR agonists to the heterodimers of RAR receptors results in transcriptional activation of target genes, resulting in the retinoid effect. On the other hand, RXR agonists do not activate RAR / RXR heterodimers. RXR heterodimer complexes, such as RAR / RXR, can be called non-permissive RXR heterodimers because transcriptional activation upon ligand binding occurs only with non-RXR proteins (e.g., RARs); transcriptional activation upon ligand binding does not occur with RXRs. RXRs also interact with nuclear receptors other than RARs, and RXR agonists can exert some of their biological effects by binding to such RXR / receptor complexes. These RXR / receptor complexes can be called permissive RXR heterodimers because transcriptional activation resulting from ligand binding can occur via RXR, other receptors, or both receptors. Examples of permissive RXR heterodimers include, but are not limited to, peroxisome proliferator-activated receptor / RXR (PPAR / RXR), farnesyl X receptor / RXR (FXR / RXR), nuclear receptor-associated protein 1 (Nurr1 / RXR), and liver X receptor / RXR (LXR / RXR). Alternatively, RXR can form RXR / RXR homodimers that can be activated by RXR agonists to produce rexinoid effects. RXR also interacts with proteins other than nuclear receptors, and ligands binding to RXR within such protein complexes can also produce rexinoid effects. Due to these differences in their mechanisms of action, RXR agonists and RAR agonists can produce different biological outcomes, and even when they mediate similar biological effects, they do so via different mechanisms. Furthermore, undesirable side effects of retinoids, such as proinflammatory responses or mucocutaneous toxicity, are mediated by activation of one or more RAR receptor subtypes. In other words, biological effects mediated through the RXR pathway do not induce proinflammatory responses and therefore do not result in undesirable side effects.

[0028] Therefore, the present embodiment partially provides RXR agonist.As used herein, the term " RXR agonist " refers to the compound that binds to one or more RXR receptors, such as RXRα, RXRβ or RXRγ, and causes gene transcription through RXR response element.When used, the term " selective RXR agonist " refers to the differential activation of the heterodimer partner for RXR (for example, PPAR or LXR) when RXR agonist binds to one type of RXR heterodimer, and does not bind to another type.

[0029] In one embodiment, the selective RXR agonist does not activate the permissive heterodimers PPAR / RXR, FXR / RXR, and LXR / RXR to any appreciable extent. In another embodiment, the RXR agonist activates the permissive heterodimer Nurr1 / RXR, but not other permissive RXR heterodimers. One example of such a 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 (IRX4204, 194204), disclosed herein, and has the structure shown in Formula III. In other aspects of this embodiment, the RXR agonist activates the permissive heterodimers PPAR / RXR, FXR / RXR, or LXR / RXR by no more than 1%, no more than 2%, no more than 3%, no more than 4%, no more than 5%, no more than 6%, no more than 7%, no more than 8%, no more than 9%, or no more than 10% compared to the ability of an activating RXR agonist to activate the same permissive heterodimer. Examples of RXR agonists that activate one or more of PPAR / RXR, FXR / RXR, or LXR / RXR include, for example, LGD1069 (bexarotene) and LGD268.

[0030] Like some other RXR ligands, IRX4204 does not activate non-permissive heterodimers such as RAR / RXR. However, IRX4204 is unique in that it specifically activates the Nurr1 / RXR heterodimer and does not activate other permissive RXR heterodimers such as PPAR / RXR, FXR / RXR, and LXR / RXR. Other RXR ligands generally activate these permissive RXR heterodimers. Therefore, all RXR ligands cannot be classified as belonging to a single class. IRX4204 belongs to a unique class of RXR ligands that specifically and selectively activates only one of the RXR homodimers and permissive RXR heterodimers, namely the Nurr1 / RXR heterodimer. This unique receptor profile allows IRX4204 to have both immunomodulatory and neurorestorative properties.

[0031] RXR agonists are known to suppress thyroid function. Treatment of human subjects with the specific RXR agonist IRX4204 first reduces plasma TSH levels, followed by a decrease in blood thyroxine levels. If patients on IRX4204 develop adverse clinical symptoms due to functional hypothyroidism, such symptoms can be resolved by treating the patient with pharmacological doses of thyroxine. However, supplementation of RXR agonist treatment with thyroid hormone has not been utilized therapeutically. Surprisingly, the combination of an RXR agonist and thyroid hormone unexpectedly provided superior efficacy compared with the use of the RXR agonist alone, demonstrating synergistic effects between RXR agonists and thyroid hormone in the treatment of nervous system disorders independent of the regulation of plasma thyroid hormone levels.

[0032] Thus, the combination of a selective RXR homodimer, Nurr1 / RXR activator such as IRX4204, with thyroid hormone provides a uniquely effective method for treating nervous system disorders.

[0033] Binding specificity is the ability of an RXR agonist to distinguish between RXR receptors and receptors that do not contain their binding site (e.g., RAR receptors). Certain RXR agonists can activate RXR homodimers as well as most permissive RXR heterodimers (e.g., RXR / PPAR, RXR / LXR, RXR / Nurr1); such RXR agonists are known as non-selective RXR agonists. Certain other RXR agonists activate RXR homodimers and, unexpectedly, only activate one or a few RXR heterodimers. Such RXR agonists (e.g., IRX4204) are known as selective RXR agonists.

[0034] Thus, disclosed herein are selective RXR agonists having the structure of Formula I: [ka] In the formula, R 4 is a lower alkyl of 1 to 6 carbons; B is -COOH or -COOR 8 where R 8 is a lower alkyl of 1 to 6 carbons, the cyclopropane ring is cis in configuration, and the double bonds of the pentadienoic acid or ester chain attached to the cyclopropane ring are trans in configuration at each double bond, or a pharmaceutically acceptable salt of the compound.

[0035] In an exemplary embodiment, the selective RXR agonist is a compound having the structure of Formula II: [ka] where R is H or lower alkyl of 1 to 6 carbons.

[0036] In a further exemplary embodiment, 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 (IRX4204) and has Formula III: [ka] It has the following structure.

[0037] In certain embodiments, the ester form 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 is not within the scope of the present disclosure.

[0038] In certain embodiments, the non-selective RXR agonist is bexarotene (TARGRETIN®, 4-[1-(3,5,5,8,8-pentamethyl-6,7-dihydronaphthalen-2-yl)ethenyl]benzoic acid, Mylan Pharmaceuticals, Inc.). [ka]

[0039] In other embodiments, the RXR agonist is LG268 (LG100268, 2-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)cyclopropyl]pyridine-5-carboxylic acid). [ka]

[0040] As used herein, the term "thyroid hormone" refers to thyroxine and triiodothyronine. Thyroxine (thyroid hormone T4, levothyroxine sodium) is a tyrosine-based hormone produced by the thyroid gland and is primarily involved in regulating metabolism. Thyroxine is a prohormone of triiodothyronine (T3). RXR agonists are known to suppress thyroid function. Clinical symptoms associated with this hypothyroidism can be treated with thyroid hormones. However, supplementing RXR agonist therapy with thyroid hormones to enhance the effectiveness of RXR agonists has not been utilized therapeutically.

[0041] As disclosed herein, the combination of an RXR agonist and thyroid hormone may increase myelination levels by at least about 10% to at least about 25%, at least about 10% to at least about 50%, at least about 10% to at least about 75%, at least about 10% to at least about 100%, at least about 10% to at least about 200%, at least about 10% to at least about 300%, at least about 10% to at least about 400%, at least about 10% to at least about 500%, at least about 25% to at least about 50%, at least about 25% compared to myelination levels in the absence of treatment with an RXR agonist and thyroid hormone. Provides neuroprotection by increasing myelination or preventing demyelination in the central or peripheral nervous system by at least about 75%, at least about 25% to at least about 100%, at least about 25% to at least about 200%, at least about 25% to at least about 300%, at least about 25% to at least about 400%, at least about 25% to at least about 500%, at least about 50% to at least about 100%, at least about 50% to at least about 200%, at least about 50% to at least about 300%, at least about 50% to at least about 400%, or at least about 50% to at least about 500%.

[0042] In yet another aspect of this embodiment, the combination of an RXR agonist and a thyroid hormone increases differentiation levels by at least about 10% to at least about 25%, at least about 10% to at least about 50%, at least about 10% to at least about 75%, at least about 10% to at least about 100%, at least about 10% to at least about 200%, at least about 10% to at least about 300%, at least about 10% to at least about 400%, at least about 10% to at least about 500%, at least about 25% to at least about 50%, at least about Increase differentiation of oligodendrocyte precursor cells into functional oligodendrocytes in the central or peripheral nervous system by 25% to at least about 75%, at least about 25% to at least about 100%, at least about 25% to at least about 200%, at least about 25% to at least about 300%, at least about 25% to at least about 400%, at least about 25% to at least about 500%, at least about 50% to at least about 100%, at least about 50% to at least about 200%, at least about 50% to at least about 300%, at least about 50% to at least about 400%, or at least about 50% to at least about 500%.

[0043] In yet another embodiment of the present disclosure, the combination of an RXR agonist and a thyroid hormone may be effective to improve myelin recovery by at least about 10% to at least about 25%, at least about 10% to at least about 50%, at least about 10% to at least about 75%, at least about 10% to at least about 100%, at least about 10% to at least about 200%, at least about 10% to at least about 300%, at least about 10% to at least about 400%, at least about 10% to at least about 500%, at least about 25% to at least about 300% compared to the rate of myelin recovery in the absence of treatment with an RXR agonist and a thyroid hormone. In some embodiments, the myelin recovery rate is increased by at least about 50%, at least about 25% to at least about 75%, at least about 25% to at least about 100%, at least about 25% to at least about 200%, at least about 25% to at least about 300%, at least about 25% to at least about 400%, at least about 25% to at least about 500%, at least about 50% to at least about 100%, at least about 50% to at least about 200%, at least about 50% to at least about 300%, at least about 50% to at least about 400%, or at least about 50% to at least about 500%.

[0044] In some embodiments, the present disclosure provides a composition comprising an RXR agonist and a thyroid hormone. Exemplary RXR agonists include IRX4204, bexarotene, and LG268. Also provided is a method for treating nervous system disorders using a combination of IRX4204 and thyroxine.

[0045] Aspects of the present disclosure provide, in part, treatment for nervous system disorders, such as demyelination-related disorders. A demyelination-related disorder is any disease or disorder of the nervous system in which the myelin sheath of neurons is damaged. This damage impairs the transmission of signals in the affected nerves. The reduced conduction capacity then causes sensory, motor, cognitive, or other functional deficits, depending on which nerves are involved. Both the central and peripheral nervous systems can be involved.

[0046] Some demyelination-related disorders are due to genetic causes, infectious agents or toxins, autoimmune reactions, radiation damage, or unknown factors. Neuroleptic drugs can cause demyelination. Although the exact mechanism of demyelination is unclear, there is significant evidence that the body's immune system is at least partially responsible, causing demyelination-related disorders to be considered autoimmune disorders.

[0047] Autoimmune disorders, including some nervous system and demyelinating disorders, arise from the body's excessive immune response to substances and tissues normally present in the body, leading to a breakdown of tolerance to self-antigens. In other words, the immune system mistakes a part of the body for a pathogen and attacks it, causing the body to actually attack its own cells. Characterized by the development of pathogenic T cell populations that infiltrate target organs or tissues, autoimmune diseases may be limited to specific organs or may involve specific tissues in different locations.

[0048] Nervous system disorders can be broadly divided into central nervous system disorders and peripheral nervous system disorders, depending on the organ most affected. Central nervous system disorders include, but are not limited to, relapsing / remitting primary progressive and secondary progressive forms of multiple sclerosis (MS), diffuse white matter injury of early childhood, neuritis, acute disseminated encephalomyelitis, Marburg multiple sclerosis, diffuse myelosclerotic sclerosis (Schöder's disease), baroconcentric sclerosis, isolated sclerosis, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS), leukodystrophy (multiple variants, e.g., adrenoleukodystrophy, adrenomyeloneuropathy), and pulmonary tuberculosis. Traumatic CNS injuries, including Parkinson's disease, Alzheimer's disease, progressive supranuclear palsy, stroke, brain and spinal cord trauma, radiation-induced neuroinflammation, radiation syndrome, Devick's disease, inflammatory demyelinating diseases, CNS neuropathies similar to those produced by vitamin B12 deficiency, myelopathies such as central pontine myelinolysis, dorsal funiculus (syphilitic myelopathy), leukoencephalopathy such as progressive multifocal leukoencephalopathy, radiation-induced central nervous system inflammation, and leukodystrophies. Peripheral nervous system disorders include, but are not limited to, Guillain-Barré syndrome, acute inflammatory demyelinating polyneuropathy, chronic inflammatory demyelinating polyneuropathy, demyelinating diabetic neuropathy, progressive inflammatory neuropathy, drug- or toxin-induced neuropathies such as chemotherapy-induced neuropathy or radiation-induced neuropathy or organophosphate-induced neuropathy, anti-MAG peripheral neuropathy, Charcot-Marie-Tooth disease, radiation-induced neuropathy, copper deficiency, depression, schizophrenia, epilepsy, migraine, and dementia.

[0049] In some embodiments, the disorder is not cachexia.

[0050] In certain embodiments, the nervous system disorder is Alzheimer's disease. In other embodiments, the disorder is not Alzheimer's disease.

[0051] In one embodiment, the demyelination-related disorder is MS. Multiple sclerosis is currently treated with several immunomodulatory drugs that provide clinical benefit by modulating a patient's immune response and producing anti-inflammatory effects. These drugs slow disease progression but do not prevent disease progression by preventing demyelination and providing neuroprotection, or reverse disease pathology by restoring myelination of damaged neurons, or restore neurological function. The selective RXR agonist IRX4204 has a unique mechanism of action in that it is a specific activator of RXR homodimers and RXR / Nurr1 heterodimers and simultaneously provides immunomodulatory activity, promotes remyelination, and prevents demyelination, particularly when used in combination with thyroid hormone. IRX4204 promotes the differentiation of suppressive Treg cells while inhibiting the differentiation of pro-inflammatory Th17 cells, thereby favorably affecting the abnormally skewed Th17 / Treg cell ratio that underlies human autoimmune diseases such as MS. Therefore, due to its effect on the Th17 / Treg cell ratio, the combination of IRX4204 and thyroid hormone is expected to have clinical benefits similar to or better than those of current standard-of-care treatments in MS. Furthermore, IRX4204 combined with thyroid hormone is more effective in providing neuroprotection by promoting remyelination of demyelinated neurons and preventing demyelination. Therefore, the combination of IRX4204 and thyroid hormone not only slows disease progression in MS, but also affects neurorecovery by regenerating healthy axons and neurons.

[0052] Aspects of the present disclosure include, in part, reducing at least one symptom associated with a nervous system disorder. The actual symptoms associated with the nervous system disorders disclosed herein are well known and can be determined by one of skill in the art, taking into consideration factors including, but not limited to, the location of the nervous system disorder, the cause of the nervous system disorder, the severity of the nervous system disorder, the tissue or organ affected by the nervous system, and nervous system related inflammation. Non-limiting examples of the symptoms that can be reduced by the method of treating nervous system disorders disclosed herein include inflammation, fatigue, dizziness, headache, malaise, high fever and hyperthermia, extreme sensitivity to cold in the extremities, muscle and joint weakness and stiffness, weight changes, digestive or gastrointestinal problems, low or high blood pressure, irritability, anxiety, depression, blurred or double vision, ataxia, clonus, dysarthria, poor speech, hand numbness, migraine, genital anesthesia, incoordination, paresthesia, eye numbness, muscle coordination disorder, muscle weakness, loss of sensation, visual impairment, neurological symptoms, unsteady gait, spastic paresis, incontinence, hearing impairment and speech problems.In certain embodiments, treatment with the combination of RXR agonist and thyroid hormone reduces at least one symptom, at least two symptoms, at least three symptoms, at least four symptoms, or at least five symptoms of nervous system disorders.

[0053] In certain embodiments, the RXR agonist treats MS and reduces one or more symptoms of MS, including, but not limited to, back or eye pain, tremors, muscle spasms, difficulty walking, decreased ability to change movements quickly, involuntary movements, muscle paralysis, muscle stiffness, muscle weakness, coordination problems, muscle stiffness, clumsiness, muscle spasms, overactive reflexes, fatigue, dizziness, heat intolerance, poor balance, spatial disorientation, weakness, excessive urination at night, urinary incontinence, persistent urgency to urinate, urinary retention, numbness and tingling sensations, abnormal taste, unpleasant tingling and burning, blurred vision, double vision, vision loss, erectile dysfunction, sexual dysfunction, anxiety, mood swings, slurred speech, voice disorders, seizures, constipation, depression, difficulty swallowing, difficulty thinking and understanding, headaches, heavy legs, numbness, numbness in the face, involuntary rapid eye movements, poor sleep, numbness in the tongue, and difficulty lifting one's feet.

[0054] The efficacy of the compounds or combinations disclosed herein in MS may be determined by improvement in one or more recognized scales of MS, including, but not limited to, the Expanded Disability Status Scale (EDSS; Kurtzke scale), Functional System Score (FSS), MS Progression:Disease Steps (DS), and MS Progression:Multiple Sclerosis Functional Composite (MSFC).

[0055] In certain embodiments, RXR agonists may treat Parkinson's disease and reduce one or more symptoms of Parkinson's disease such as tremors (which may occur at rest, in the hands, feet, limbs, or may be postural), stiff muscles, difficulty standing, difficulty walking, difficulty with body movements, involuntary movements, muscle stiffness, problems with coordination (of muscle movements), rhythmic muscle contractions, slow body movements, slow shuffling gait, daytime sleepiness, early waking, nightmares, restless sleep, fatigue, dizziness, poor balance, restlessness, amnesia, evening confusion, dementia, difficulty thinking and understanding, voice disorder, soft speech, voice box spasms, anxiety, apathy, distorted sense of smell, loss of smell, dribbling urine, urinary incontinence, stiff jaw, reduced facial expression, blank face, constipation, depression, difficulty swallowing, drooling, depression, fear of depression, loss of contrast sensitivity, neck tension, small handwriting, tremors, or unintentional suffering.

[0056] The efficacy of the compounds or combinations disclosed herein in Parkinson's disease can be determined, for example, by improvement in one or more recognized scales of Parkinson's disease, including, but not limited to, the Multiple Sclerosis Functional Composite (MSFC), the Unified Parkinson's Disease Rating Scale (UPDRS), the Hoehn and Yahr scale, and the Schwab and England Activities of Daily Living scale.

[0057] In certain embodiments, the RXR agonist treats Alzheimer's disease and reduces one or more symptoms of Alzheimer's disease, including, but not limited to, mental decline, difficulty thinking and understanding, evening confusion, delusions, confusion, being unable to forget, making up stories, mental confusion, difficulty concentrating, inability to create new memories, inability to do simple calculations, inability to recognize mundane objects, aggression, agitation, difficulty with self-care, irritability, repeating oneself meaninglessly, personality changes, lack of self-control, wandering and getting lost, anger, apathy, general dissatisfaction, loneliness, mood swings, depression, hallucinations, paranoia, decreased appetite, restlessness, inability to combine muscle movements, and disorganized speech.

[0058] The effectiveness of the compounds or combinations disclosed herein in treating Alzheimer's disease can be determined by the improvement of one or more recognized scales of Alzheimer's disease, including but not limited to the Dementia Severity Rating Scale (DSRS), Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale (ADAS) including ADAS-cog, Neuropsychological Test Battery (NTB), Severe Impairment Battery (SIB), Activities of Daily Living Scale, Clinical Global Impression (CGI) scale, BEHAVE-AD, Brief Psychiatric Rating Scale (BPRS), Alzheimer's Disease Related Quality of Life (ADRQL), Dementia Quality of Life Instrument (DQoL), Quality of Life-Alzheimer's Disease (QoL-AD), and Quality of Life in Late-Stage Dementia Scale (QUALID).The treatment of other disorders with the combination of RXR agonists and thyroid hormones is also within the scope of this disclosure. Such disorders include, but are not limited to, cancer types, autoimmune diseases, and muscle diseases.

[0059] Method aspects of the present disclosure include, in part, treating a mammal. The mammal includes a human, and the human can be a patient. Other aspects of the present disclosure provide, in part, an individual. The individual includes a mammal and a human, and the human can be a patient.

[0060] The combination of an RXR agonist and a thyroid hormone disclosed herein is generally administered to an individual as a pharmaceutical composition. The pharmaceutical composition can be prepared by combining a therapeutically effective amount of at least one RXR agonist and one thyroid hormone, or a pharmaceutically acceptable acid addition salt thereof, as active ingredients with conventional acceptable pharmaceutical excipients and preparing a unit dosage form suitable for therapeutic use. As used herein, the term "pharmaceutical composition" refers to a therapeutically effective concentration of an active compound, such as any compound disclosed herein. Preferably, the pharmaceutical composition does not produce adverse, allergic, or other harmful or undesirable reactions when administered to an individual. The pharmaceutical compositions disclosed herein are useful for medical and veterinary applications. The pharmaceutical composition can be administered to an individual alone or in combination with other co-active compounds, agents, drugs, or hormones. The pharmaceutical composition can be prepared using any of a variety of methods, including, but not limited to, conventional mixing, dissolving, granulating, dragee-making, gelling, emulsifying, encapsulating, entrapping, and lyophilizing. Pharmaceutical compositions may take any of a variety of forms, including but not limited to, sterile solutions, suspensions, emulsions, lyophilisates, tablets, pills, pellets, capsules, powders, syrups, elixirs, or other dosage forms suitable for administration.

[0061] The pharmaceutical compositions produced using the methods disclosed herein can be liquid, semi-solid, or solid formulations.The formulations disclosed herein can be produced in a manner that forms one phase, such as an oil or a solid.Alternatively, the formulations disclosed herein can be produced to form two phases, such as an emulsion.The pharmaceutical compositions disclosed herein intended for such administration can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions.

[0062] Liquid formulations suitable for parenteral injection or nasal spray may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.Formulations suitable for nasal administration may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions.Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol (PEG), glycerol, etc.), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by using coating agents such as lecithin, maintaining the required particle size in the case of dispersions, and using surfactants.

[0063] Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists, which may be generated by various types of metered, dose pressurized aerosols, nebulizers, or insufflators.

[0064] The semi-solid preparation suitable for topical administration includes but is not limited to ointment, cream, salve and gel.In such solid preparation, active compound can be mixed with at least one common inert excipient (or carrier) such as lipid and / or polyethylene glycol.

[0065] Solid dosage forms suitable for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, such as glycerol; (d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, sodium carbonate; (e) solution retardants, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, such as kaolin and bentonite; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise a buffer.

[0066] In liquid and semi-solid formulations, the concentration of the RXR agonist can typically be between about 50 mg / mL and about 1,000 mg / mL. In aspects of this embodiment, a therapeutically effective amount of a therapeutic compound disclosed herein can be, for example, about 50 mg / mL to about 100 mg / mL, about 50 mg / mL to about 200 mg / mL, about 50 mg / mL to about 300 mg / mL, about 50 mg / mL to about 400 mg / mL, about 50 mg / mL to about 500 mg / mL, about 50 mg / mL to about 600 mg / mL, about 50 mg / mL to about 700 mg / mL, about 50 mg / mL to about 800 mg / mL, about 50 mg / mL to about 900 mg / mL, about 50 mg / mL to about 1,000 mg / mL, or about 1 00mg / mL~about 200mg / mL, about 100mg / mL~about 300mg / mL, about 100mg / mL~about 400mg / mL, about 100mg / mL~about 500mg / mL, about 100mg / mL~about 600mg / mL, about 100mg / mL~about 700mg / m L, about 100 mg / mL to about 800 mg / mL, about 100 mg / mL to about 900 mg / mL, about 100 mg / mL to about 1,000 mg / mL, about 200 mg / mL to about 300 mg / mL, about 200 mg / mL to about 400 mg / mL, about 200 mg / mL to about 50 0mg / mL, about 200mg / mL to about 600mg / mL, about 200mg / mL to about 700mg / mL, about 200mg / mL to about 800mg / mL, about 200mg / mL to about 900mg / mL, about 200mg / mL to about 1,000mg / mL, about 300mg / mL mL~about 400mg / mL, about 300mg / mL~about 500mg / mL, about 300mg / mL~about 600mg / mL, about 300mg / mL~about 700mg / mL, about 300mg / mL~about 800mg / mL, about 300mg / mL~about 900mg / mL, about 300 mg / mL~about 1,000mg / mL, about 400mg / mL~about 500mg / mL, about 400mg / mL~about 600mg / mL, about 400mg / mL~about 700mg / mL, about 400mg / mL~about 800mg / mL, about 400mg / mL~about 900mg / m L, about 400mg / mL to about 1,000mg / mL, about 500mg / mL to about 600mg / mL, about 500mg / mL to about 700mg / mL, about 500mg / mL to about 800mg / mL, about 500mg / mL to about 900mg / mL, about 500mg / mL to about 1,The concentration may be about 600 mg / mL to about 700 mg / mL, about 600 mg / mL to about 800 mg / mL, about 600 mg / mL to about 900 mg / mL, or about 600 mg / mL to about 1,000 mg / mL.

[0067] In semi-solid and solid formulations, the amount of RXR agonist can typically be between about 0.01% and about 45% by weight. In aspects of this embodiment, the amount of a therapeutic compound disclosed herein can be, for example, between about 0.1% and about 45% by weight, between about 0.1% and about 40% by weight, between about 0.1% and about 35% by weight, between about 0.1% and about 30% by weight, between about 0.1% and about 25% by weight, between about 0.1% and about 20% by weight, between about 0.1% and about 15% by weight, between about 0.1% and about 10% by weight, between about 0.1% and about 5% by weight, or between about 1% and about 45% by weight. Amount%, about 1% to about 40% by weight, about 1% to about 35% by weight, about 1% to about 30% by weight, about 1% to about 25% by weight, about 1% to about 20% by weight, about 1% to about 15% by weight, about 1% by weight About 10% by weight, about 1% to about 5% by weight, about 5% to about 45% by weight, about 5% to about 40% by weight, about 5% to about 35% by weight, about 5% to about 30% by weight, about 5% to about 25% by weight, about 5% by weight %~about 20 weight%, about 5 weight%~about 15 weight%, about 5 weight%~about 10 weight%, about 10 weight%~about 45 weight%, about 10 weight%~about 40 weight%, about 10 weight%~about 35 weight%, about 10 weight%~about 30 Weight%, about 10% to about 25% by weight, about 10% to about 20% by weight, about 10% to about 15% by weight, about 15% to about 45% by weight, about 15% to about 40% by weight, about 15% to about 35% by weight, It can be about 15% to about 30% by weight, about 15% to about 25% by weight, about 15% to about 20% by weight, about 20% to about 45% by weight, about 20% to about 40% by weight, about 20% to about 35% by weight, about 20% to about 30% by weight, about 20% to about 25% by weight, about 25% to about 45% by weight, about 25% to about 40% by weight, about 25% to about 35% by weight, or about 25% to about 30% by weight.

[0068] The pharmaceutical compositions disclosed herein may optionally contain a pharmaceutically acceptable carrier that facilitates processing of the active compound into a pharmaceutically acceptable composition. As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reaction, or other problem complications commensurate with a reasonable benefit / risk ratio. As used herein, the term "pharmacologically acceptable carrier" is synonymous with "pharmacological carrier" and encompasses terms such as "pharmacologically acceptable vehicle, stabilizer, diluent, additive, adjuvant, or excipient" that have substantially no long-term or permanent adverse effects when administered. Such carriers generally are mixed with the active compound or allow the active compound to be diluted or encapsulated, and may be solid, semi-solid, or liquid agents. It is understood that the active compound may be soluble or may be delivered as a suspension in the desired carrier or diluent. Any of a variety of pharmaceutically acceptable carriers may be used, including, but not limited to, aqueous vehicles such as water, saline, glycine, hyaluronic acid, and the like; solid carriers such as starch, magnesium stearate, mannitol, sodium saccharin, talcum, cellulose, glucose, sucrose, lactose, trehalose, magnesium carbonate, and the like; solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotonic and absorption delaying agents, or other inactive ingredients. The choice of pharmaceutically acceptable carrier may depend on the mode of administration. Except insofar as any pharmaceutically acceptable carrier is incompatible with the active compound, its use in a pharmaceutically acceptable composition is contemplated. Non-limiting examples of specific uses of such pharmaceutical carriers are found in Pharmaceutical Dosage Forms and Drug Delivery Systems (Howard C. Ansel et al., eds., Lippincott Williams & Wilkins Publishers, 2007). thed. 1999); Remington: The Science and Practice of Pharmacy(Alfonso R. Gennaro ed., Lippincott, Williams & Wilkins, 20 th ed. 2000); Goodman & Gilman's The Pharmacological Basis of Therapeutics(Joel G. Hardman et al., eds., McGraw-Hill Professional, 10 th ed. 2001); and Handbook of Pharmaceutical Excipients(Raymond C. Rowe et al.,APhA Publications, 4 th These protocols are routine and any modifications are possible within the skill of the art and given the teachings herein.

[0069] The pharmaceutical compositions disclosed herein may optionally contain other pharmaceutically acceptable ingredients (or pharmaceutical components), including, but not limited to, buffers, preservatives, tonicity adjusting agents, salts, antioxidants, osmolality adjusting agents, physiological substances, pharmacological substances, bulking agents, emulsifiers, humectants, sweeteners, or flavoring agents. Various buffers and pH adjusting means may be used to prepare the pharmaceutical compositions disclosed herein, provided that the resulting preparation is pharmaceutically acceptable. Such buffers include, but are not limited to, acetate buffer, borate buffer, citrate buffer, phosphate buffer, neutral buffered saline, and phosphate buffered saline. It is understood that acids or bases may be used to adjust the pH of the composition as needed. Pharmaceutically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene. Useful preservatives include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, stable oxychloro compositions such as sodium chlorite, and chelating agents such as DTPA or DTPA-bisamide, calcium DTPA, and CaNaDTPA-bisamide. Tonicity modifiers useful in pharmaceutical compositions include, but are not limited to, salts of sodium chloride, potassium chloride, mannitol, or glycerin, and other pharmaceutically acceptable tonicity modifiers. Pharmaceutical compositions can be provided as salts, which can be formed with many acids, including, but not limited to, hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. Salts tend to be more soluble in aqueous or other protic solvents than the corresponding free base forms. It is understood that these and other substances known in the art of pharmacology can be included in the pharmaceutical compositions useful in the present invention.

[0070] The combination of an RXR agonist and a thyroid hormone can also be incorporated into a drug delivery platform to achieve a controlled release profile over time. Such a drug delivery platform includes the combination disclosed herein dispersed in a polymer matrix, typically a biodegradable, bioerodible, and / or bioabsorbable polymer matrix. As used herein, the term "polymer" refers to synthetic homo- or copolymers, natural homo- or copolymers, and synthetic modifications or derivatives thereof having linear, branched, or star structures. Copolymers can be arranged in any configuration, such as random, block, segmented, tapered block, graft, or triblock. Polymers are generally condensation polymers. Polymers can be further modified to enhance their mechanical or degradation properties by introducing crosslinkers or changing the hydrophobicity of side residues. When crosslinked, polymers are typically less than 5% crosslinked, typically less than 1% crosslinked.

[0071] Suitable polymers include, but are not limited to, alginates, aliphatic polyesters, polyalkylene oxalates, polyamides, polyamide esters, polyanhydrides, polycarbonates, polyesters, polyethylene glycols, polyhydroxyaliphatic carboxylic acids, polyorthoesters, polyoxaesters, polypeptides, polyphosphazene polysaccharides, and polyurethanes. The polymer typically comprises at least about 10% (w / w), at least about 20% (w / w), at least about 30% (w / w), at least about 40% (w / w), at least about 50% (w / w), at least about 60% (w / w), at least about 70% (w / w), at least about 80% (w / w), or at least about 90% (w / w) of the drug delivery platform. Examples of biodegradable, biodegradable and / or bioabsorbable polymers and methods useful for making drug delivery platforms are described, for example, in U.S. Pat. No. 4,756,911, U.S. Pat. No. 5,378,475, U.S. Pat. No. 7,048,946, U.S. Patent Application Publication No. 2005 / 0181017, U.S. Patent Application Publication No. 2005 / 0244464, U.S. Patent Application Publication No. 2011 / 0008437, each of which is incorporated by reference in its entirety.

[0072] In aspects of this embodiment, the polymer comprising the matrix is ​​a polypeptide, such as silk fibroin, keratin, or collagen. In other aspects of this embodiment, the polymer comprising the matrix is ​​a polysaccharide, such as cellulose, agarose, elastin, chitosan, chitin, or the glycosaminoglycans chondroitin sulfate, dermatan sulfate, keratan sulfate, or hyaluronic acid. In yet other aspects of this embodiment, the polymer comprising the matrix is ​​a polyester, such as D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid, caprolactone, and combinations thereof.

[0073] Those skilled in the art will understand that the selection of a suitable polymer for forming a suitable disclosed drug delivery platform depends on several factors. The more relevant factors in selecting a suitable polymer(s) include, but are not limited to, the compatibility of the polymer with the drug, the desired release kinetics of the drug, the desired biodegradation kinetics of the platform at the implantation site, the desired bioerosion kinetics of the platform at the implantation site, the desired bioresorption kinetics of the platform at the implantation site, the mechanical performance of the platform in vivo, the processing temperature, the biocompatibility of the platform, and the patient's tolerance. Other relevant factors that determine the in vitro and in vivo behavior of a polymer include the chemical composition, the spatial distribution of the components, the molecular weight and crystallinity of the polymer.

[0074] Drug delivery platform includes both sustained release drug delivery platform and sustained release drug delivery platform.As used herein, the term "sustained release" refers to the release of the compound or combination disclosed herein for about 7 days or more.As used herein, the term "sustained release" refers to the release of the compound or combination disclosed herein for less than about 7 days.

[0075] In aspects of this embodiment, the sustained release drug delivery platform releases the RXR agonist and thyroid hormone combination with substantially first order release kinetics, e.g., over a period of about 7 days after administration, about 15 days after administration, about 30 days after administration, about 45 days after administration, about 60 days after administration, about 75 days after administration, or about 90 days after administration. In other aspects of this embodiment, the sustained release drug delivery platform releases the combination disclosed herein with substantially first order release kinetics, e.g., over a period of at least about 7 days after administration, at least about 15 days after administration, at least about 30 days after administration, at least about 45 days after administration, at least about 60 days after administration, at least about 75 days after administration, or at least about 90 days after administration.

[0076] In aspects of this embodiment, the drug delivery platform releases the combination disclosed herein with substantially first order release kinetics, e.g., over a period of about 1 day after administration, about 2 days after administration, about 3 days after administration, about 4 days after administration, about 5 days after administration, or about 6 days after administration. In other aspects of this embodiment, the drug delivery platform releases the combination disclosed herein with substantially first order release kinetics, e.g., over a period of about 1 day after the longest administration, about 2 days after the longest administration, about 3 days after the longest administration, about 4 days after the longest administration, about 5 days after the longest administration, or about 6 days after the longest administration.

[0077] Aspects of the present disclosure include, in part, administering a combination of an RXR agonist and a thyroid hormone. As used herein, the term "administering" refers to any delivery mechanism that provides a compound or combination disclosed herein to an individual that may result in a clinical, therapeutic, or experimental beneficial outcome.

[0078] Administration of the combinations disclosed herein may include, but is not limited to, oral administration in any acceptable form, such as, for example, tablets, liquids, capsules, powders, and the like; topical administration in any acceptable form, such as, for example, drops, sprays, creams, gels, or ointments; buccal, nasal, and / or inhalation administration in any acceptable form; rectal administration in any acceptable form; vaginal administration in any acceptable form, such as, for example, intravenous bolus injection, intravenous infusion, intra-arterial bolus injection, intra-arterial infusion, and catheter infusion into the vascular system. Intravascular administration; any acceptable form of peri- and intra-tissue administration, such as intraperitoneal injection, intramuscular injection, subcutaneous injection, subcutaneous infusion, intraocular injection, retinal injection, or subretinal or epidural injection; any acceptable form of intravesical administration, such as catheter infusion; various enteral or parenteral approaches, including those using placement devices such as implants, stents, patches, pellets, catheters, osmotic pumps, suppositories, bioerodible delivery systems, non-bioerodible delivery systems, or implanted slow-release or sustained-release systems. An exemplary list of biodegradable polymers and methods of use can be found, for example, in Handbook of Biodegradable Polymers (Abraham J. Domb et al., eds., Overseas Publishers Association, 1997).

[0079] The combinations disclosed herein can be administered to mammals via various routes. Suitable administration routes for the treatment of demyelination-related disorders disclosed herein include both local and systemic administration. Local administration results in significantly more delivery of the combination to a specific location compared to administration to the entire body of a mammal, while systemic administration essentially results in delivery of the combination to the entire body of an individual. Suitable administration routes for the treatment of nervous system disorders disclosed herein include both central and peripheral administration. Central administration essentially results in delivery of the combination to the central nervous system of an individual, including, for example, intranasal administration, intrathecal administration, epidural administration, and intracranial injection or implantation. Peripheral administration results in delivery of the compound or combination to essentially any region of an individual other than the central nervous system, and includes any administration route other than direct administration to the spine or brain. The actual route of administration of a compound or combination disclosed herein to be used can be determined by one of skill in the art taking into consideration factors including, but not limited to, the type of nervous system disorder, the location of the nervous system disorder, the cause of the nervous system disorder, the severity of the nervous system disorder, the desired duration of treatment, the desired degree of relief, the desired duration of relief, the particular compound or combination used, the rate of excretion of the compound or combination used, the pharmacodynamics of the compound or combination used, the nature of the other compounds included in the combination, the particular route of administration, the specific characteristics, the individual's medical history and risk factors, e.g., age, weight, general health, etc., the individual's response to treatment, or any combination thereof. Thus, an effective dosage of a compound or combination disclosed herein can be readily determined by one of skill in the art taking all criteria into consideration and utilizing the artisan's best judgment on behalf of the individual.

[0080] In one embodiment, the combinations disclosed herein are administered systemically to the mammal. In another embodiment, the combinations disclosed herein are administered locally to the mammal. In one aspect of this embodiment, the combinations disclosed herein are administered to the mammal at the site of a nervous system disorder. In another aspect of this embodiment, the combinations disclosed herein are administered to the mammal in the region of a nervous system disorder.

[0081] In other embodiments, the combination is administered directly to the nervous system by intrathecal administration, epidural administration, intracranial injection or implantation, or intranasal administration.

[0082] In other embodiments, the RXR agonist is administered orally, buccally, nasally, and / or by inhalation, intravenously, intraperitoneally, intramuscularly, subcutaneously, intraocularly, epidurally, or intravesically, and the thyroid hormone is administered orally. The RXR agonist and thyroid hormone need not be administered by the same route or on the same dosing schedule.

[0083] Aspects of the present specification provide, in part, administering a therapeutically effective amount of a combination of an RXR agonist and a thyroid hormone.As used herein, the term "therapeutically effective amount" is synonymous with "therapeutically effective dose", and when used in relation to the treatment of nervous system disorders, refers to the minimum dose of the combination required to achieve the desired therapeutic effect, including a dose sufficient to alleviate at least one symptom associated with nervous system disorders.In aspects of this embodiment, a therapeutically effective amount of the combination reduces at least one symptom associated with nervous system disorders by, for example, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%. In other aspects of this embodiment, a therapeutically effective amount of a compound or combination disclosed herein reduces at least one symptom associated with a nervous system disorder, e.g., by up to 10%, up to 20%, up to 30%, up to 40%, up to 50%, up to 60%, up to 70%, up to 80%, up to 90%, or up to 100%. In still other aspects of this embodiment, a therapeutically effective amount of a compound or combination disclosed herein reduces at least one symptom associated with a nervous system disorder by, e.g., about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%. In yet other aspects of this embodiment, the therapeutically effective amount of the combination is sufficient to alleviate at least one symptom associated with a nervous system disorder, e.g., for at least 1 week, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months.

[0084] In further embodiments, the combination treatment reduces at least one symptom, at least two symptoms, at least three symptoms, at least four symptoms, or at least five symptoms of a nervous system disorder.

[0085] The amounts of active ingredients in the combinations disclosed herein for treating nervous system disorders can be varied to obtain an appropriate dosage. The actual therapeutically effective amounts of the combinations disclosed herein to be administered to a mammal can be determined by one of ordinary skill in the art, taking into account factors including, but not limited to, the type of demyelination-related disorder, the location of the nervous system disorder, the cause of the nervous system disorder, the severity of the nervous system disorder, the desired duration of treatment, the desired degree of relief, the desired duration of relief, the particular combination used, the excretion rate of the combination, the pharmacodynamics of the combination, the nature of other compounds included in the combination, the particular route of administration, the specific characteristics of the individual, their medical history and risk factors, such as age, weight, general health, and the individual's response to treatment, or any combination thereof. Thus, the effective dosage of the compounds or combinations disclosed herein can be readily determined by one of ordinary skill in the art, taking into account all criteria and utilizing the artisan's best judgment on behalf of the individual.

[0086] Furthermore, when repeated administration of the combinations disclosed herein is used, the actual effective amount of the compounds, compositions, or combinations disclosed herein will further depend on factors including, but not limited to, the frequency of administration of the compounds, compositions, or combinations disclosed herein, the half-life, or any combination thereof. Those skilled in the art will know that the effective amount of the compounds or combinations disclosed herein can be extrapolated from in vitro assays using animal models and in vivo administration tests before administration to humans. Considering the different efficiencies of various administration routes, a wide variation in the required effective amount is expected. For example, oral administration will generally be expected to require higher dosage concentrations than administration by intravenous or intravitreal injection. Variations in these dosage concentrations can be adjusted using standard empirical routines of optimization well known to those skilled in the art. The exact therapeutically effective dosage concentration and pattern are preferably determined by a physician, taking into account the above factors.

[0087] As a non-limiting example, when administering the RXR agonists disclosed herein to a mammal, a therapeutically effective amount generally ranges from about 0.001 mg / kg / day to about 100.0 mg / kg / day. In aspects of this embodiment, an effective amount of a compound disclosed herein can be, for example, from about 0.01 mg / kg / day to about 0.1 mg / kg / day, from about 0.03 mg / kg / day to about 3.0 mg / kg / day, from about 0.1 mg / kg / day to about 3.0 mg / kg / day, or from about 0.3 mg / kg / day to about 3.0 mg / kg / day. In yet another aspect of this embodiment, a therapeutically effective amount of a compound described herein can be, for example, at least 0.001 mg / kg / day, at least 0.01 mg / kg / day, at least 0.1 mg / kg / day, at least 1.0 mg / kg / day, at least 10 mg / kg / day, or at least 100 mg / kg / day. In yet another aspect of this embodiment, a therapeutically effective amount of a compound described herein can be, for example, up to 0.001 mg / kg / day, up to 0.01 mg / kg / day, up to 0.1 mg / kg / day, up to 1.0 mg / kg / day, up to 10 mg / kg / day, or up to 100 mg / kg / day.

[0088] In other embodiments, the RXR agonist is generally administered to the mammal in a therapeutically effective amount ranging from about 0.001 mg / day to about 100 mg / day, from about 0.1 mg / day to about 50 mg / day, from about 0.5 mg / day to about 40 mg / day, from about 1 mg / day to about 30 mg / day, or from about 1 mg / day to about 20 mg / day.

[0089] Suitable thyroxine doses are generally about 5 μg / day to about 250 μg / day orally initially, increasing every 2 to 4 weeks as needed. In other embodiments, suitable thyroxine doses are about 5 μg / day to about 225 μg / day, about 7.5 μg / day to about 200 μg / day, about 10 μg / day to about 175 μg / day, about 12.5 μg / day to about 150 μg / day, about 15 μg / day to about 125 μg / day, about 17.5 μg / day to about 100 μg / day, or about 20 μg / day to about 100 μg / day. The dose is typically about 22.5 μg / day to about 100 μg / day, about 25 μg / day to about 100 μg / day, about 5 μg / day to about 200 μg / day, about 5 μg / day to about 100 μg / day, about 7.5 μg / day to about 90 μg / day, about 10 μg / day to about 80 μg / day, about 12.5 μg / day to about 60 μg / day, or about 15 μg / day to about 50 μg / day. Dose increases are generally made in increments of about 5 μg / day, about 7.5 μg / day, about 10 μg / day, about 12.5 μg / day, about 15 μg / day, about 20 μg / day, or about 25 μg / day. In certain embodiments, an appropriate thyroid hormone dose is one that produces a serum T4 concentration in the upper 50%, upper 60%, upper 70%, upper 80%, or upper 90% of the normal range for a laboratory. Because different laboratories may have different normal ranges for T4 concentrations, the target T4 concentration is based on the normal range established for a particular laboratory.

[0090] The dose may be a single dose or a cumulative dose (sequential administration) and can be easily determined by one skilled in the art. For example, treatment of a nervous system disorder may involve a single administration of an effective dose of the combination disclosed herein. As a non-limiting example, an effective amount of the combination disclosed herein may be administered to a mammal once, for example, as a single injection or attachment at or near the site of symptoms of a nervous system disorder, or as a single oral administration of the combination. Alternatively, treatment of a nervous system disorder may involve multiple administrations of an effective dose of the combination disclosed herein, administered over a range of time periods, such as daily, once every few days, weekly, monthly, or yearly. As a non-limiting example, the combination disclosed herein may be administered to a mammal once or twice a week. The timing of administration may vary from mammal to mammal, depending on factors such as the severity of the mammal's symptoms. For example, an effective dose of the combination disclosed herein may be administered to a mammal once a month, irregularly, or until the mammal no longer requires treatment. Those skilled in the art will recognize that the condition of a mammal can be monitored throughout the course of treatment, and the effective amount of the combination disclosed herein that is administered can be adjusted accordingly.Furthermore, each element of the combination, for example, RXR agonist and thyroid hormone, can be administered by different routes and different schedules, and optionally administered separately to an individual, but both compositions (RXR agonist and thyroid hormone) are administered to an individual so that the plasma concentration of both compounds can be detected simultaneously.

[0091] The combinations disclosed herein as disclosed herein can also be administered to a mammal in combination with other therapeutic compounds to increase the overall therapeutic effect of the treatment. The use of multiple compounds to treat an indication can increase the beneficial effects while reducing the presence of side effects.

[0092] Also disclosed herein is a combination of an RXR agonist and a thyroid hormone co-administered with one or more neurotrophic factors, including, but not limited to, brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), fibroblast growth factor, basic (bFGF), ciliary neurotrophic factor (CNTF), neurotrophic factor-4 / 5 (NT-4 / 5), insulin-like growth factor (IGF), insulin; or another neurotrophic factor; or a synthetic mimetic molecule that provides similar biological activity as BDNF, GDNF, NGF, NT-3, bFGF, CNTF, NT-4 / 5, IGF, insulin, or another neurotrophic factor.

[0093] The administration of a combination of an RXR agonist and thyroid hormone with a neurotrophic factor or neurotrophic factor mimetic can be used to effect neuroprotection, i.e., enhancing the survival of various types of nervous system cells, including neurons and glial cells.

[0094] Furthermore, administration of a combination of RXR agonists and thyroid hormone with neurotrophic factors or neurotrophic factor mimetics can be used to effect recovery of damaged nervous system cells (including neurons and glial cells), as evidenced by promotion of neurite outgrowth, resulting in the formation and / or restoration of neural connections; or the formation or restoration of neuroglial structures such as the myelin sheath around neurons, which are essential for supporting optimal neural signaling and nervous system function.

[0095] Specific examples of the use of a combination of an RXR agonist and thyroid hormone with a neurotrophic factor or neurotrophic factor mimetic include, but are not limited to, co-administration of a combination of thyroid hormone and an RXR agonist, such as IRX4204 or bexarotene, with GDNF or a GDNF mimetic to enhance dopaminergic neuron survival or promote dopaminergic neuron recovery or restoration in patients with Parkinson's disease or a disease of dopaminergic neurons; co-administration of GDNF or a GDNF mimetic to enhance motor neuron survival or promote motor neuron recovery or restoration in patients with amyotrophic lateral sclerosis; co-administration of BDNF or a BDNF mimetic, or with insulin or insulin-like growth factor, to enhance cortical or hippocampal neuron survival or promote cortical or hippocampal neuron recovery or restoration in Alzheimer's disease; or co-administration of NGF to enhance sensory neuron survival or promote sensory neuron recovery or restoration in patients with peripheral neuropathy. Other combinations of RXR agonists and thyroid hormones with other neurotrophic factors or neurotrophic factor mimetics may be used to enhance neuronal or glial cell survival or promote repair or recovery in additional diseases of the central or peripheral nervous system, including, but not limited to, various forms of multiple sclerosis, including relapsing-remitting or progressive multiple sclerosis; optic neuritis; stroke of various etiologies; various types of nervous system trauma; neuropathies of various etiologies; nervous system hypoxia; various types of nervous system toxic insults; dementia of various etiologies; retinopathies of various etiologies; various synucleinopathies, such as Huntington's disease, progressive supranuclear palsy; epilepsy; autism; schizophrenia; depression, or age-related nervous system deterioration.

[0096] In the above embodiments, the neurotrophic factor or neurotrophic factor mimetic may be delivered to the patient orally, or by a parenteral route, or by a topical route such as intranasally, or as an inhaled agent, or may be delivered using an implantable or wearable sustained release formulation or slow delivery device.

[0097] Combinations of RXR agonists and thyroid hormones, as well as neurotrophic factors or neurotrophic factor mimetics, may also be used to promote the survival or growth of various types of neurons or glial cells in vitro, for subsequent transplantation into the nervous system of patients with neurological diseases.

[0098] The present invention can also be described as follows.

[0099] (Example) The following non-limiting examples are provided for illustrative purposes only to facilitate a more complete understanding of the presently contemplated representative embodiments, and should not be construed as limiting any of the embodiments described herein, including those relating to methods of treating autoimmune disorders, neuropathy, and / or demyelination-related disorders using RXR agonists in combination with thyroid hormones disclosed herein, or those relating to the use of RXR agonists and thyroid hormones disclosed herein for the manufacture of medicaments and / or for treating autoimmune disorders, nervous system disorders, and / or demyelination-related disorders.

[0100] Example 1 A selective RXR agonist, IRX4204, exerts its biological effects through RXR signaling To determine whether RXR agonists could mediate their effects through RXRα, RXRβ, or RXRγ receptor homodimers, or any combination thereof, or the corresponding RAR / RXR heterodimers, we performed receptor-mediated transactivation assays. For transactivation assays assessing RXR homodimer signaling, CV-1 cells were transfected with 1) expression constructs containing full-length RXRα, RXRβ, or RXRγ; and 2) the rCRBPII / RXRE-tk-Luc reporter construct, which contains the RXR homodimer-specific RXRE / DR1 response element linked to the luciferase gene. For transactivation assays assessing RAR / RXR heterodimer signaling, CV-1 cells were transfected with 1) an expression construct containing a fusion protein containing the estrogen receptor (ER) DNA-binding domain linked to the ligand-binding domain of RARα, RARβ, or RARγ, and 2) an ERE-tk-Luc reporter construct containing an estrogen receptor response element linked to a luciferase gene. The ER-RAR fusion protein provided an accurate readout of only the transfected ER-RAR. After transfection, CV-1 cells were treated with increasing concentrations of the RXR agonist IRX4204 for 20 hours before measuring luciferase activity. Luciferase activity is expressed as a percentage of the maximal activity obtained with 1 μM of the RXR agonist IRX4204 for RXR and 1 μM of all-trans-retinoic acid (ATRA) for RAR (Table 1). Data are means ± SE from five independent experiments. [Table 1]

[0101] These results demonstrate that the RXR agonist IRX4204 has very high potency (EC 50 The EC values ​​of RXR agonists for RAR were <0.5 nM (Table 1). 50The activity was >1000 nM, with minimal activity detected at ≥1 μM. This difference represents a >2000-fold selectivity for RXR over RAR in functional transactivation assays. Furthermore, these data demonstrate that the RXR agonist IRX4204 is >1000-fold more potent at activating RXR receptors but not RAR receptors. These results indicate that Treg differentiation was mediated through the RXR signaling pathway, not through the RAR signaling pathway. Furthermore, using appropriate receptor and reporter constructs, we demonstrated that the RXR agonist IRX4204 does not transactivate the so-called "permissive RXR heterodimers" PPAR / RXR, FXR / RXR, and LXR / RXR (Figure 1A-C). In this regard, the RXR agonist IRX4204 differs from other RXR agonists. Furthermore, IRX4204 selectively activates the Nurr1 / RXR permissive heterodimer (Figure 1D). Thus, the RXR agonist IRX4204 has a unique profile in that it selectively activates only RXR homodimers and Nurr1 / RXR heterodimers.

[0102] Example 2 Binding affinity of RXR agonists To determine the binding affinity of RXR agonists, a competitive displacement assay was performed. RXRα, RXRβ, RXRγ, RARα, RARβ, or RARγ were expressed in SF21 cells using a baculovirus expression system, and the resulting proteins were purified. To determine the binding affinity of RXR agonists to RXR, purified RXRα, RXRβ, and RXRγ were incubated with 10 nM [ 3 H]-9CRA to determine the binding affinity of the RXR agonist IRX4204 by incubating with [ 3 To determine the binding affinity of RXR agonists to RARs, purified RARα, RARβ, and RARγ were separately incubated with 5 nM [H]-9CRA. 3 H]-ATRA, and the binding affinity of the RXR agonist IRX4204 was assessed by incubating it with [ 3Ki values ​​were determined by competitive displacement of [H]-ATRA. Ki values ​​are the mean values ​​of at least two independent experiments (Table 2). The standard error (±) between independent experiments is shown.

[0103] As shown in Table 2, the RXR agonist IRX4204 exhibited high affinity for RXRα, RXRβ, and RXRγ, with Ki values ​​of 1.7, 16, and 43 nM, respectively. In contrast, the RXR agonist IRX4204 bound to each RAR with very low affinity (Ki values ​​>1000 nM). These data indicate that IRX4204 has high selectivity for RXR over RAR. [Table 2]

[0104] Example 3 RXR agonists attenuate EAE in B6 mice To determine whether RXR agonists can attenuate multiple sclerosis, experimental autoimmune encephalomyelitis (EAE) was induced by immunizing C57BL / 6 (B6) mice (day 0) with 200 μL of adjuvant containing 125 μg of myelin oligodendrocyte glycoprotein peptide (35-55) (MOG peptide; Peptides International, Louisville, KY) and 400 μg of nonviable M. tuberculosis H37 dry matter emulsified in a mixture of incomplete Freund's adjuvant and phosphate-buffered saline (PBS) by subcutaneous (sc) injection at the base of the spine. Mice also received 200 ng of pertussis toxin in PBS administered by intraperitoneal (ip) injection on the same day as the MOG emulsion injection (day 0) and two days later (day 2). Starting on day 7 after immunization, mice were administered the RXR agonist IRX4204 (50 μg), vehicle control (ip), thyroxine (T4), or IRX4204 plus thyroxine every other day for the duration of the experiment (n = 6–7 mice per group). Statistics are presented using the Mann-Whitney test (analysis from the start of treatment to the end of the experiment). Mice were scored using the following scale: 0 - no disease, 1 - the mouse had a terminally weak tail or weakness (paralysis) of one hind leg, 1.5 - the mouse had a terminally weak tail and weakness of one hind leg, 2 - the mouse had a generalized weak tail and weakness of one hind leg, 2.5 - the mouse had a generalized weak tail and weakness in both hind legs, 3 - the mouse had a generalized weak tail and paralysis in both hind legs, and 3.5 - the mouse had a generalized weak tail, paralysis in both hind legs, and weakness in the forelimbs. Mice receiving a score of 3.5 were immediately euthanized.

[0105] Figure 2 shows the disease severity score over time. The results show that administration of the RXR agonist IRX4204 at 50 μg significantly reduced EAE symptoms in mice. The efficacy of the RXR agonist was observed after the first administration (day 7) and was maintained throughout the course of the study (day 20). However, the combination of IRX4204 and thyroxine further reduced EAE symptoms in mice (Figure 2).

[0106] Dose titration experiments were also performed in EAE mice. EAE was induced in 28 B6 mice with MOG / CFA and PT as described above. Mice were scored on day 7 as described above and divided into groups based on scores to ensure that averages were as similar as possible. Starting on day 8, mice were scored daily and injected with vehicle control or IRX4204 (50 μg, 100 μg, or 200 μg).

[0107] Mice were weighed at the start of the experiment, and if they had a score of 2.5 or higher, they were weighed daily. If they lost more than 15% of their body weight, they were euthanized. All mice treated with IRX4204 had significantly lower overall disease (Figure 7). At the end of the experiment, the vehicle control and 200 μg / day groups were euthanized, and spleen and CNS samples were obtained.

[0108] Spleen samples were evaluated for CD49d (Figure 8A) and CCR6 (Figure 8B). IRX4204 treatment reduced CCR6 expression on CD4 T cells, but not CD49d expression. Furthermore, CD4+CD25hi cells (generally consisting of Tregs) were reduced, although their frequency remained unchanged (Figures 9A and 9B). The total number of effector and memory CD4 T cells, as indicated by CD44 expression, was reduced with IRX4204 treatment (Figure 12C). The total number of recently activated CD4 T cells, as indicated by the expression of both CD69 and CD44, was also reduced with IRX4204 treatment (Figure 9D).

[0109] In the CNS, IRX4204 treatment reduced the total number of infiltrating CD4 T cells (Figure 10). Cytokine production was detected using restimulation with PMA / ionomycin. Both IFNγ (Figures 11A and 11B) and TNF (Figures 11C and 11D) were significantly reduced by treatment. Co-expression of IFNγ and IL-17A by CD4 T cells in the CNS was quantified, but there was no significant difference between the groups (Figures 12A-12C).

[0110] Example 4 RXR agonist-treated mice had reduced CNS-infiltrating cells To determine whether RXR agonists can reduce central nervous system (CNS)-infiltrating cells, C57BL / 6 (B6) mice were treated as described in Example 6. Twenty days after immunization, mice were sacrificed and perfused with phosphate-buffered saline (PBS). Brain and spinal cord tissues were isolated, digested with DNase and LIBERASE DL® (Roche Diagnostics, Indianapolis, IN) for 30 minutes, and homogenized through a 70-micron nylon mesh filter. The resulting cells were placed on a Percoll gradient to remove myelin. The remaining cells (microglia and CNS-infiltrating cells) were counted, stained for molecules of interest, and analyzed by flow cytometry. Based on the frequencies of these cell populations obtained by FACS, CD4 + T cells and CD11c + CD11b + The total cell count of CNS-infiltrating leukocytes expressing CD45, including myeloid dendritic cells (DCs), was calculated.

[0111] Figure 3 shows CD4 in mice treated with the RXR agonist IRX4204 versus vehicle control. + cells (Figure 3A) or CD11c + CD11b + Figure 3B shows the number of CD4 cells (bone marrow DCs; Figure 3B) entering the CNS in animals treated with RXR agonists compared to controls. + Cells and CD11c + CD11b + There was a significant reduction in the infiltration of both cells. Treatment of mice with a combination of IRX4204 and thyroxine is expected to further reduce the infiltration of these cells into the CNS. + CD11b + CD4 reactivated by cells + Since the disease spreads to the CNS via cells, this suggests that part of the mechanism of action in this model is restricting the presence of cells within the CNS.

[0112] Example 5 RXR agonists attenuate EAE in SJL mice To determine whether RXR agonists can attenuate multiple sclerosis, SJL mice were immunized to induce EAE by sc injection at the base of the spine with 200 μg of adjuvant containing 200 μg of proteolipid protein (139-151) (PLP peptide; Peptides International, Louisville, KY) and 400 μg of nonviable M. tuberculosis H37 dry matter emulsified in a mixture of incomplete Freund's adjuvant and PBS. Mice also received 150 ng of pertussis toxin in PBS i.p. on the same day as the PLP emulsion injection and two days later. Starting on day 7 post-immunization, mice were administered the RXR agonist IRX4204 (50 μg) or vehicle control i.p. every other day for the duration of the experiment (n = 6 mice / group). Mice were scored using the scale described in Example 3.

[0113] The results show that administration of the RXR agonist IRX4204 significantly reduces EAE symptoms in mice. Table 3 shows the characteristics of RXR agonist IRX4204 treatment in SLJ mice. Figure 4 shows disease severity scores over time. Efficacy of the RXR agonist was observed after the second administration (day 8) and was maintained throughout the course of the study (day 14). When IRX4204 is administered in combination with thyroxine treatment, further reductions in EAE symptoms and disease severity scores are expected. [Table 3]

[0114] Example 6 RXR agonist IRX4204 as a selective activator of Nurr1 / RXR permissive heterodimers To determine which permissive RXR heterodimers were activated by the RXR agonist IRX4204, receptor transactivation assays were performed for PPARγ / RXR, FXR / RXR, LXRα / RXR, LXRβ / RXR, and Nurr1 / RXR as follows: For PPARγ, CV-1 cells were transfected with the 3x(rAOX / DR1)-tk-Luc reporter gene and a PPARγ expression vector. For FXR, CV-1 cells were transfected with the 3x(IBABP / IRI)-tk-Luc reporter gene and vectors for FXR and RXRα. For LXR, CV-1 cells were transfected with the 3x(PLTP / LXRE)-tk-Luc reporter gene together with vectors for LXRα or LXRβ. For Nurr1: COS7 cells were transfected with the 3xNBRE-tk-luc reporter gene and full-length Nurr-1 with or without the full-length RXRα plasmid. Cells were then treated with vehicle or IRX4204 for 20 hours. Luciferase data were normalized to the activity of co-transfected β-gal. Luciferase activity was expressed as a percentage of the maximal activity obtained with specific agonists: rosiglitazone (PPARγ), GW4064 (FXR), and T0901317 (LXR). The data show that IRX4204 does not activate FXR / RXR (Figure 5A), LXRα / RXR or LXRβ / RXR (Figure 5B), or PPARγ / RXR (Figure 5C). In contrast, IRX4204 potently (EC 50 <1 nM), activates the Nurr1 / RXR heterodimer. These data collectively demonstrate that IRX4204 is a unique RXR agonist in that it selectively activates the Nurr1 / RXR heterodimer but not the PPARγ / RXR, FXR / RXR, or LXR / RXR heterodimers.

[0115] Example 7 Effects of RXR agonists on oligodendrocyte precursor cell differentiation The purpose of this study was to evaluate the effect of IRX4204 on the differentiation of oligodendrocyte precursor cells (OPCs) into oligodendrocytes. OPCs were generated from neurosphere cultures of E14.5 PLP-EGFP (on a C57BL / 6J background) mouse brains. To evaluate green fluorescent protein (EGFP) expression, which correlates with OPC differentiation into oligodendrocytes, isolated OPCs were treated with IRX4204 and / or T3. EGFP-expressing cells were quantified with the Cellomics neuronal profiling algorithm. The positive (T3) control demonstrated the expected OPC differentiation. The results show that IRX4204 promotes OPC differentiation into oligodendrocytes, as indicated by an increased number of EGFP-positive cells compared to the negative control (DMSO). The lowest concentration (1 -6 All concentrations tested except for 1 μM (Figure 6) showed a significant increase in OPC differentiation into oligodendrocytes. However, the addition of T3 to IRX4204-treated cultures induced higher concentrations of EGFR+ oligodendrocytes, indicating a significant benefit of the combination of IRX4204 and thyroid hormone.

[0116] EGFP-expressing cells in the control and all compounds were quantified using the Cellomics neuronal profiling algorithm. The experiment was successful, as demonstrated by a significant increase in the %EGFP cells in the positive control (T3; 8.5%) compared to the negative control (DMSO; 2.3%). IRX4204 promotes OPC differentiation into oligodendrocytes, as demonstrated by a dose-dependent increase in the number of EGFP-positive cells compared to the negative control (DMSO). IRX4204 did not show any differences in total cell number or oligodendrocytes compared to the control. The results of this study demonstrate that IRX4204 promotes OPC differentiation. The data show a dose-dependent increase in the percentage of EGFP cells compared to the negative control. These data indicate that IRX4204 promotes the growth of myelinating cells in cell culture.

[0117] Example 8 IRX4204 enhances central nervous system (CNS) remyelination in an in vivo model by directly acting on the remyelination process. To confirm the direct action of IRX4204 on acute demyelination, independent of its immunomodulatory effects, a focal toxin (ethidium bromide)-induced rat model of demyelination is used. Relatively old (1-year-old) rats are used in this experiment because such rats do not undergo efficient remyelination, thereby providing data more relevant to the clinical treatment of human patients with multiple sclerosis or other demyelinating diseases.

[0118] Focal demyelination was induced in 1-year-old rats (approximately 300 g body weight) by stereotactically injecting 5 μl of ethidium bromide solution (0.01% vol / vol in saline) bilaterally into the caudal cerebellar placode (CCP). Starting 7 days after ethidium bromide injection, rats were treated by oral gavage with 10 mg / kg / day IRX4204 (in DMSO and corn oil) for 14 days (days 7–21 after ethidium bromide treatment), or with the same dose of oral IRX4204 plus 20 ng / g subcutaneous thyroxine, or vehicle (DMSO and corn oil plus thyroxine vehicle) for 14 days. Rats were sacrificed 24 days after ethidium bromide treatment for analysis of remyelination by quantitative polymerase chain reaction (qPCR) and microscopy.

[0119] Lesion analysis revealed that Olig2 +The density of oligodendrocyte lineage cells and CC1+ differentiated oligodendrocytes was increased in IRX4204-treated animals compared with vehicle-treated animals, with a further increase in IRX4204 + thyroxine animals. Nkx2.2+ oligodendrocyte progenitor cells (OPCs) were increased in IRX4204-treated lesions compared with vehicle-treated lesions, with the highest levels in IRX4204 + thyroxine-treated lesions. Real-time qPCR analysis of lesion samples also demonstrated increased Mbp and Pdgfra expression, indicating greater levels of remyelination in IRX4204-treated animals, with the highest levels of Mbp and Pdgfra expression observed in IRX4204 and thyroxine-treated animals. Ultrastructural analysis of CCP lesions further demonstrated that IRX4204 + thyroxine treatment resulted in more remyelinated axons in animals than IRX4204 alone, and more remyelinated axons than vehicle treatment. Analysis of the A-G ratio (which is the ratio of axon diameter to myelinated axons) also shows that IRX4204-treated animals have a lower G-ratio than vehicle-treated animals, and this lower ratio is due to the formation of a thicker remyelinated sheath surrounding the axons in IRX4204-treated animals. The G-ratio was further reduced in animals treated with a combination of IRX4204 and thyroxine. All of these findings are consistent with increased CNS remyelination in IRX4204-treated animals and an optimal increase in IRX4204 + thyroxine-treated animals.

[0120] Example 9 IRX4204 in combination with thyroid hormone promotes remyelination in a cuprizone / rapamycin mouse model of toxic demyelination The cuprizone (bis-cyclohexanone oxaldihydrazone) model facilitates reliable, reproducible, and unambiguous analysis of myelin parameters in both white and gray matter. The cuprizone model is a model of toxic demyelination. In this model, young mice are given the copper chelator cuprizone, which leads to oligodendrocyte death and subsequent reversible demyelination. Mice receiving cuprizone along with rapamycin, a drug that blocks mTOR and spontaneous remyelination, allow for better quantification of oligodendrocyte turnover. In the acute cuprizone paradigm, 6-9 week-old male C57BL / 6 mice are fed a diet containing 0.2% cuprizone for 6 weeks. By the third week of cuprizone feeding, consistent demyelination can be observed in the corpus callosum, the largest white matter tract in the mouse brain. Demyelination reaches a maximum at 5 or 6 weeks. Maintaining cuprizone intake in C57BL / 6 mice for 12 weeks can induce chronic demyelination.

[0121] The purpose of this study was to evaluate the remyelination potential of IRX4204 in a mouse model of adverse demyelination. Previous studies have shown the efficacy of IRX4204 in the EAE model of MS. Previous data also indicate that IRX4204 can induce significant oligodendrocyte progenitor cell (OPC) differentiation in vitro. The current study is conducted to further investigate the CNS effects of IRX4204 in the cuprizone model of MS regarding remyelination and neuroprotection.

[0122] Animals (8-week-old male C57BL / 6J mice) were treated with a cuprizone diet plus rapamycin injections (CR, 10 mg / kg) for 12 weeks to induce demyelination in the white matter (CC, corpus callosum). After 12 weeks, CR was discontinued, and a subset of animals was treated daily with either vehicle (oral IRX4204 vehicle) or IRX4204 (10 mg / kg, PO) for 6 weeks. All animals were sacrificed after 12 weeks of CR or an additional 6 weeks of treatment to assess myelin in the white matter (corpus callosum) and gray matter (hippocampus and cortex). Additionally, the size of myelinated axons was quantified, and larger myelinated axons were further evaluated by 3D-electron microscopy (3D-EM).

[0123] Demyelinating diseases, such as MS, are characterized by myelin loss, chronic inflammation, and axonal and oligodendrocyte loss in the CNS. While the etiology of MS remains unknown, the disease generally begins with sporadic acute episodes and, over time, develops into a chronic and progressive condition. Acute and chronic demyelinating lesions of MS can be demonstrated in a cuprizone diet-induced mouse model, the severity of which depends on the duration of cuprizone administration. Cuprizone induces extensive demyelination in the brains of adult mice, and coadministration of rapamycin blocks oligodendrocyte differentiation and prevents spontaneous remyelination during the demyelinating phase. This model also demonstrates hippocampal demyelination in MS. Upon discontinuation of cuprizone plus rapamycin (CR), quantifiable spontaneous remyelination occurs in this model, which can be modified by drug intervention in the remyelination process. The 12-week demyelinating CR model provides an opportunity to evaluate the therapeutic potential of new drugs that promote remyelination in the mouse brain.

[0124] A total of 40 animals were included in the study, and all 40 underwent CR demyelination for 12 weeks. After demyelination, a subset of animals (n = 10) were sacrificed to serve as controls to assess baseline demyelination. The remaining animals were divided into groups (n = 15) and treated daily with oral IRX4204 (10 mg / kg) or oral vehicle for IRX4204 for 6 weeks.

[0125] There were no significant differences in body weight between any of the groups.

[0126] Free-floating brain sections are immunostained with myelin prolipid protein (PLP) to visualize and quantify myelin in the gray matter, hippocampus (Figure 16A), and cortex (Figure 16B). The percentage of area covered by PLP staining in animals treated with vehicle alone after discontinuation of the demyelination regimen is significantly greater than that in animals sacrificed immediately after CR demyelination, indicating the occurrence of spontaneous remyelination.

[0127] In this study, we use a 12-week demyelination model to evaluate the CNS effects of IRX4204 after 6 weeks of treatment, with or without thyroid hormone replacement. Results from this study show that IRX4204 significantly increases the size of myelinated axons in the corpus callosum (Figure 17). Furthermore, these large myelinated fibers are indicative of a healthy phenotype. Therefore, IRX4204 has a neuroprotective effect on myelinated neurons.

[0128] Furthermore, IRX4204 plus thyroxine increases the number and density of myelinated axons in white and gray matter, in addition to increasing the size of myelinated axons in the corpus callosum.

[0129] Example 10 Evaluation of the neuroprotective potential of IRX4204 and IRX4204 plus thyroxine in a mouse model of non-immune-mediated demyelination The modified cuprizone model (cuprizone + rapamycin) facilitates reliable, reproducible, and unambiguous analysis of neurodegeneration caused by demyelination. SMI-32 immunostaining allows visualization and quantification of swelling and severed axons (ovoids) in the corpus callosum, allowing assessment of the degree of axonal degeneration. In this study, there were four groups of mice: cuprizone + rapamycin (CR) only (n = 6), CR + vehicle (n = 12), CR + IRX4204 (n = 12), and CR + IRX4204 + thyroxine (n = 12). The test substances were administered simultaneously with CR for 6 weeks. IRX4204 was administered orally once daily at 10 mg / kg body weight. Thyroxine (T4) treatment was initiated 1 day after the initiation of IRX4204 treatment. T4 was administered subcutaneously (SC) daily at 20 ng / g body weight. The CR + vehicle group received IRX4204 vehicle (oral) and T4 vehicle (sc). All animals underwent terminal blood collection to measure plasma T4 concentrations. After sacrifice, the density of SMI-32-positive ovoids per unit area was determined for each group. The higher the SMI-32-positive ovoid density, the greater the degree of axonal degeneration. Compared with the vehicle group, the IRX4204 group had a 13.3% reduction in SMI-32+ ovoids, indicating some neuroprotection by IRX4204 alone. However, the IRX4204 + thyroxine group had a 37.5% reduction compared with the vehicle group, indicating that the combination of IRX4204 + thyroxine provided a significant degree of neuroprotection from CR-induced neurotoxicity.

[0130] Example 11 Human clinical trials to demonstrate the efficacy of IRX4204 in Parkinson's disease An open-label, single-site clinical trial of patients with early Parkinson's disease treated with IRX4204 was conducted to determine whether the preclinical support for IRX4204 as a disease-modifying drug for PD translates to the clinical setting when treating patients with early PD with IRX4204 as determined by Unified Parkinson's Disease Rating Scale (UPDRS) measurements and safety assessments. Changes in UPDRS scores correlated with blood thyroxine concentrations.

[0131] The objectives of this study were to further characterize the safety and tolerability of IRX4204 in early stage patients, particularly the reduction of T4 concentrations, and to evaluate the effect of treatment with IRX4204 on motor symptoms of PD as measured by UPDRS.

[0132] The study endpoints were (1) the change in exercise test score from the end of treatment (day 17) and (2) the change in T4 concentration.

[0133] (a) Design Overview This was a single-site, open-label study designed to examine the efficacy (reduction in UPDRS scores) and safety of three dose levels of IRX4204 in cohorts of patients with early PD over approximately two weeks. In the three cohorts, each subject reported to the clinical study site on at least three occasions: Screening (Visit 1) - Screening to determine eligibility (up to 30 days prior to the baseline visit) Baseline Period (Visit 2) - Treatment with IRX4204 began on Day 1. Week 2 (Visit 3) - Subjects returned to the clinic approximately 17 days after initiating IRX4204 for safety and efficacy evaluations.

[0134] Safety and tolerability were assessed throughout all study visits, including laboratory tests, ECG, physical examination, neurological examination, and blood and urine samples for evaluation of adverse events.

[0135] To be eligible for study participation, subjects had to meet the following criteria: age 40–80 years, have a clinical diagnosis of PD based on UK Brain Bank criteria; participants had Hoehn and Yahr stage <3; participants had access to PD symptomatic treatment at a stable dose for at least 30 days prior to the screening visit, including a stable dose of PD symptomatic treatment that would remain stable throughout the study; participants had to be willing and able to provide informed consent; and women had to be either non-childbearing or willing to avoid pregnancy using medically acceptable contraception 4 weeks before and 4 weeks after the last dose of study medication.

[0136] Subjects who met any of the following criteria were not included in the study: have any form of parkinsonism other than idiopathic PD; currently experiencing motor fluctuations reflective of the late stages of PD (wearing off or movement disorders at the end of dosing); have evidence of dementia or significant cognitive impairment; have clinically significant abnormal laboratory values ​​and / or clinically significant unstable medical or psychiatric illness; subject has any disorder that may interfere with drug absorption, distribution, metabolism, or excretion; subject has evidence of clinically significant gastrointestinal, cardiovascular, hepatic, pulmonary, or other disorder or disease; pregnant or lactating.

[0137] At the clinical site, study drug was prepared for administration by dispensing the correct dose of IRX4204 (20 mg / day, 10 mg / day, or 5 mg / day) for each subject. On Day 1, subjects received their first dose of IRX4204. After Day 1, IRX4204 drug administration occurred daily at home. Patients took their daily dose of study drug with food at approximately the same time each day, preferably between 8:00 AM and 10:00 AM. On Day 1, subjects received a 15-day supply of IRX4204 at a once-daily dose of 20 mg, 10 mg, or 5 mg. Five subjects were recruited for each of the three dose levels. All 15 subjects completed the 15-day course.

[0138] All subjects (n = 52 total, n = 12-13 per dose concentration) completed 15 days of medication and returned to the clinic at the end of week 2 (days 15-17) for UPDRS score determination and safety assessments, including determination of plasma thyroxine (T4) concentrations. Percentage changes in total motor score, total UPDRS score, and plasma T4 levels were determined as follows: Percentage change = (baseline value - week 2 value) × 100 / baseline value.

[0139] The mean percentage changes in total motor and total UPDRS scores for the three dose concentrations are shown in Table 4. Negative scores indicate disease improvement as measured by the global UPDRS assessment. The greatest therapeutic response to IRX4204 treatment, as measured by total motor score (-31.4%), was achieved with the lowest dose of IRX4204 (5 mg / day). Surprisingly, the higher doses of 10 mg / day (11.7%) and 20 mg / day (-14.5%) were less effective as measured by total motor score. Similar results were obtained when considering total UPDRS score. The best treatment response was achieved in the 5 mg / day cohort (-18.7%). The higher doses of 10 mg / day and 20 mg / day were progressively less effective, with total UPDRS changes of -13.6% and 6.6%, respectively. [Table 4]

[0140] The mean percentage change in plasma T4 concentrations for the three cohorts is shown in Table 5. The relationship between dose concentration and percentage reduction in plasma thyroxine (T4) was direct: the higher the dose of IRX4204, the greater the reduction in T4 concentrations. A dose of 20 mg / day of IRX4204 resulted in almost complete elimination of plasma T4 (98.8% reduction). Interestingly, this high dose of IRX4204 was the least effective (only a 6.6% reduction in total UPDRS score). [Table 5]

[0141] These data from human clinical trials clearly demonstrate that reduced thyroid hormone levels during IRX4204 administration negatively impacts the therapeutic benefit of IRX4204. Clinical trial data demonstrate an inverse relationship between thyroid axis suppression (as indicated by suppression of TSH, thyroid-stimulating hormone) and clinical improvement from baseline in total motor score and UPDRS.

[0142] Example 12 Human clinical trial to demonstrate the effect of the combination of IRX4204 and thyroxine on myelin recovery in patients with relapsing-remitting multiple sclerosis A double-blind, placebo-controlled clinical proof-of-concept trial of IRX4204 in combination with thyroxine will be conducted in patients with multiple sclerosis (MS) to demonstrate the direct effect of IRX4204 on myelin recovery in patients with relapsing-remitting MS. Patients with relapsing-remitting MS will be recruited to participate in the clinical trial and provide informed consent explaining the risks and potential benefits of participation. MS patients will be treated with IRX4204 at one of several dose concentrations ranging from 1 mg / day to 40 mg / day, e.g., 5 mg / day administered orally as a capsule once daily, and thyroxine at 12.5 μg / day to 250 μg / day, e.g., 50 μg / day administered orally. Some patients will be randomized to receive either IRX4204 or a placebo using matching capsules without thyroxine. Patients will be treated for a minimum of 30 days and up to 180 days. Patients are evaluated for the state of myelin damage and the rate of recovery of demyelination in MS lesions occurring in the brain, spinal cord, and / or optic nerve over this period. Quantification of myelin damage and repair is performed at baseline and periodically throughout the course of medication using specialized imaging methods that specifically examine and quantify myelin damage and repair in these parts of the nervous system. Such methods include, but are not limited to, positron emission tomography (PET) using contrast agents such as the thioflavin-T derivative 2-(4'-methylaminophenyl)-6-hydroxybenzothiazole (PIB), which also binds to amyloid plaques. This compound is useful for quantifying myelin repair. Alternatively, magnetic resonance imaging (MRI) using special contrast agents that bind to or enhance the appearance of areas of myelin damage or repair can be used; or specialized MRI analysis algorithms, such as magnetization transfer imaging or diffusion tensor imaging, can be used to quantify myelin damage and repair in IRX4204 and thyroxine-treated patients compared to placebo-treated patients. The dose-response relationship of the IRX4204 / thyroxine combination on myelin protection or restoration is analyzed across cohorts of patients treated with various dose concentrations of IRX4204 and thyroxine.In addition to quantifying myelin damage and recovery using imaging techniques, the clinical status of MS patients' disease progression will be assessed using standard clinical endpoints in MS clinical trials, such as the Expanded Disability Status Scale (EDSS). The EDSS is a 10-point scale that quantifies the level of disability in MS patients by assessing physical activities of daily living, such as walking, swallowing, and bowel and bladder function. Furthermore, visual acuity tests will be performed to quantify the effect of the IRX4204 / thyroxine combination on myelin damage and recovery in the optic nerve. Substantial clinical benefits, as measured by one or more of the above techniques, will be observed in groups treated with the IRX4204 and thyroxine combination compared to the vehicle combination group. A positive, but less substantial, clinical benefit will be observed in groups treated with the IRX4204 + thyroxine vehicle combination.

[0143] Example 13 Human clinical trial to demonstrate the effect of combining IRX4204 with thyroxine treatment on disability progression in multiple sclerosis patients with relapsing-remitting disease A double-blind, placebo-controlled clinical trial will be conducted to demonstrate evidence of the benefit of IRX4204 / thyroxine treatment on disability progression in MS patients with relapsing-remitting MS. Patients with relapsing-remitting MS will be recruited to participate in the clinical trial and provide informed consent, explaining the risks and potential benefits of participation. MS patients will be randomized to receive 24 months of treatment with IRX4204 at dose levels ranging from 1 to 40 mg / day administered orally, and thyroxine at dose levels (12.5 μg / day to 250 μg / day orally) or a matching placebo. The primary clinical efficacy outcome measure will be the EDSS, a 10-point scale that quantifies MS patients' disability level by assessing physical activities of daily living, such as walking, swallowing, and bowel and bladder function. The clinical trial will use a sample size selected to demonstrate a statistically significant difference of at least 1 point in the mean EDSS change over time between the IRX4204 / thyroxine and placebo treatment groups at the end of 24 months of treatment. Additionally, this clinical trial will conduct visual acuity testing to quantify the effects of IRX4204 / thyroxine on myelin damage and recovery in the optic nerve. At the end of 24 months of treatment, a sample size will be selected that demonstrates a statistically significant difference in visual acuity over time of at least one line on a standard visual acuity chart between the IRX4204 / thyroxine-treated group and the placebo-treated group.

[0144] Example 14 Human clinical trial demonstrating the effect of combining IRX4204 and thyroxine treatment on clinical improvement in Parkinson's disease A double-blind, placebo-controlled clinical trial demonstrating evidence of benefit of IRX4204 / thyroxine treatment on disability progression in Parkinson's disease (PD) will be conducted in patients who provided informed consent describing the risks and potential benefits of participation. PD patients will be randomized to receive 24 months of treatment with IRX4204 at dose levels ranging from 1 to 40 mg / day administered orally, and thyroxine at dose levels ranging from 12.5 μg / day to 250 μg / day orally, or a matching placebo. The primary clinical efficacy outcome measure is the Unified Parkinson's Disease Rating Scale (UPDRS). The UPDRS is an assessment tool that follows the longitudinal course of PD. It consists of 1) desire, behavior, and mood, 2) activities of daily living (ADL), and 3) motor sections. These are assessed by interview. Some sections require multiple grades assigned to each limb. A total of 199 points are awarded, with 199 representing the worst (total) impairment and 0 indicating no impairment.

[0145] The clinical trial will use a sample size selected to demonstrate a statistically significant level of difference in the change in mean UPDRS over time between the IRX4204 / thyroxine and placebo treatment groups at the end of 24 months of treatment.

[0146] Example 15 Human clinical trial demonstrating the efficacy of combination therapy with IRX4204 and thyroxine on clinical improvement in Alzheimer's disease A double-blind, placebo-controlled clinical trial demonstrating evidence of benefit of IRX4204 / thyroxine treatment on the progression of cognitive impairment in Alzheimer's disease (AD) will be conducted in patients who provided informed consent describing the risks and potential benefits of participation. Patients will be randomized to receive IRX4204 at dose levels ranging from 1 to 40 mg / day administered orally, and thyroxine at dose levels ranging from 12.5 μg / day to 250 μg / day orally, or a matching placebo for 24 months. The primary clinical efficacy outcome scale will be the Mini-Mental State Examination (MMSE), optionally including one or more of the Functional Assessment Questionnaire (FAQ), Physical Self-Maintenance Scale (PSMS), and Neuropsychiatric Inventory (NPI). The clinical trial will use a sample size selected to demonstrate a statistically significant level of difference in mean MMSE change over time between the IRX4204 / thyroxine and placebo treatment groups at the end of 24 months of treatment.

[0147] Example 16 Effects of IRX4204 in Parkinson's disease models The purpose of this study was to evaluate IRX4204 treatment for ameliorating behavioral deficits in a rat 6-OHDA-induced Parkinson's disease (PD) model. The rat model of PD was generated by unilateral striatal injection of the neurotoxin 6-hydroxydopamine (6-OHDA). This injection results in dopaminergic (DA) neuron loss on the injected side, sparing contralateral DA neurons. The study design is shown in Table 6. [Table 6]

[0148] Injury was assessed using the paw placing (cylinder test), which assesses the rat's independent use of its forelimbs to support its body against the walls of a cylindrical enclosure. This test exploits the animal's natural locomotor activity of exploring a novel environment by standing on its hindlimbs and leaning toward the surrounding wall.

[0149] To perform this test, rats were individually placed in a glass cylinder (21 cm diameter, 34 cm height) and their wall exploration was recorded for 3 min. They were allowed to habituate to the cylinder prior to recording.

[0150] Statistical analysis was performed using the ratio between the intact and injured paws (R / L ratio). This ratio was expressed as the value for the intact right + both forelimbs divided by the value for the injured left + both forelimbs. A lower value of this ratio indicates greater healing of 6-OHDA-induced brain injury.

[0151] All treated animals gained weight throughout the study. The mean body weights of animals treated with the TA2 vehicle (Group 2) or the test article IRX4204 (TA1) in combination with thyroxine and triiodothyronine (TA2; Group 4) were significantly higher than the vehicle-treated group on days 17 and 24 of the study (142.62 ± 2.93% for the vehicle group on day 24; p < 0.05), compared with 157.17 ± 2.93% for Group 2 and 157.61 ± 3.54% for Group 4).

[0152] All animals with an R / L ratio >1.5 were included in the study (the ratio between intact paws (R) and impaired paws (L) was expressed as the value of intact right + both forelimbs divided by the value of impaired left hindlimb + both forelimbs).

[0153] Paw placing was measured before the induction of the lesion (baseline), which was 1 day before IRA4204 treatment, and 3 days after the 6-OHDA injection. Once a week for 3 weeks (test days 10, 17, and 24), animals were retested for their performance on the paw placing test.

[0154] Animals were preselected based on the R / L ratio on test day 3 if the mean ratio between the injured and intact side was increased relative to baseline levels (1.01 ± 0.01 pre-surgery vs. 6.49 ± 0.59 on day 3 post-surgery).

[0155] As shown in Figure 13, compared with the vehicle-treated group (Group 1) on day 10 of the study, treatment with IRX4204 (TA1) in combination with TA2 vehicle (Group 2) or thyroxine and triiodothyronine (TA2; Group 4) significantly reduced the mean calculated R / L ratio (6.33 ± 1.41 in the vehicle group; p < 0.05 vs. 2.76 ± 0.57 in Group 2 and 2.86 ± 0.76 in Group 4).

[0156] The calculated mean ratios were also lower in these groups compared to the vehicle group on test days 17 and 24, but this ratio was not statistically significant.

[0157] The mean ratio was calculated from the four values ​​on days 3, 10, 17, and 24. The calculated values ​​for Group 2 and Group 4 were 3.79 and 3.14, respectively, indicating that Group 4 (the combination of IRX4204 with thyroxine and triiodothyronine) was more effective than Group 2 (IRX4204) alone.

[0158] Example 17 Differentiation of mouse oligodendrocyte precursor cells in the presence of vitamin D The purpose of this study was to evaluate the potential effects of IRX4204 in combination with vitamin D, or vitamin D and triiodothyronine (T3), on the differentiation of mouse oligodendrocyte precursor cells (OPCs) into oligodendrocytes. OPCs were derived from plp-EGFP-expressing mice.

[0159] Therapeutic agents were tested in 96-well plates (6 wells per concentration). Negative and positive controls (DMSO or 10 ng / ml T3 thyroid hormone) were included in each plate. All media contained 0.1% DMSO and 0.1% EtOH. At the end of 5 days of treatment, cells were imaged in two channels on a Cellomics system, and an algorithm was used to count nuclei and EGFP+ oligodendrocytes.

[0160] Surprisingly, it was observed that different doses of vitamin D combined with IRX4204 showed a negative effect on oligodendrocyte production (Figure 14). The production of oligodendrocytes in response to the three regimen treatments (IRX4204, vitamin D, and T3) was slightly higher than that without T3 (IRX4204 and vitamin D). This suggests an additive effect of T3 in the combination of the three regimens.

[0161] Example 18 Differentiation of mouse oligodendrocyte precursor cells The purpose of this study was to evaluate the potential effects of IRX4204 in combination with triiodothyronine (T3) on the differentiation of mouse oligodendrocyte precursor cells (OPCs) into oligodendrocytes. OPCs were derived from plp-EGFP-expressing mice.

[0162] Therapeutic agents were tested in 96-well plates (6 wells per concentration). Negative and positive controls (DMSO or 10 ng / ml T3 thyroid hormone) were included in each plate. All media contained 0.1% DMSO. At the end of 5 days of treatment, cells were imaged in two channels on a Cellomics system, and an algorithm was used to count nuclei and EGFP+ oligodendrocytes.

[0163] Figures 15A-15C show a clear dose-response in oligodendrocyte production in response to different doses of IRX4204 and T3. Oligodendrocyte production in response to combined treatment with IRX4204 and T3 was higher than either treatment alone in all conditions. This suggests an additive, or potentially synergistic, effect between IRX4204 and T3 in promoting oligodendrocyte precursor cell differentiation. Similar results were obtained when cells were stained with MBP antibody and quantified (data not shown). These data suggest that the combination of IRX4204 and T3 (or T4) is optimal for remyelination.

[0164] Example 19 Neuroprotective effects of IRX4204 in a mouse model of demyelination The aim of this study was to evaluate the neuroprotective effects of IRX4204 in a mouse model of non-immune-mediated demyelination.

[0165] In this study, we used a 6-week demyelination model to evaluate the neuroprotective potential of IRX4204 after 6 weeks of co-treatment during demyelination. A subgroup of animals was treated with T4 along with IRX4204. The results of this study demonstrate that IRX4204 promotes neuroprotection without reducing the extent of demyelination in the corpus callosum.

[0166] Animals (8-week-old male C57BL / 6J mice) were treated with a cuprizone diet plus rapamycin injections (CR) for 6 weeks to induce demyelination. During demyelination, animals were treated daily with either vehicle, IRX4204 (10 mg / kg PO), or IRX4204+T4 (10 mg / kg PO and 20 ng / g SQ) throughout the 6 weeks. After 6 weeks of CR, all animals were sacrificed to assess axonal integrity and microglia / macrophage activity in the white matter (corpus callosum, CC). Two groups (vehicle and IRX4204+T4) were further tested for any protective effect on the extent of myelination in the CC.

[0167] There was a significant reduction in axonal transection, as indicated by a decrease in the number of SMI32-positive axonal nuclei in animals treated with IRX4204+T4. However, there was no difference between microglia / macrophage activation and the number of myelinated axons in the CC between the vehicle and IRX4204+T4 groups. These findings support the neuroprotective role of IRX4204, potentially mediated by a direct effect on demyelinated axons.

[0168] A total of 50 animals were included in the study, 43 of which underwent CR demyelination over a 6-week period. During demyelination, a subset of animals (n = 7) was maintained on a normal diet to serve as naive, age-adjusted controls. The remaining animals were simultaneously administered IRX4204 (n = 14), vehicle (n = 14), or IRX4204 + T4 (n = 15) for 6 weeks during CR. No deaths occurred during the survival phase. Furthermore, no health concerns were observed during the treatment phase. All animals were alert and exhibited appropriate grooming behavior. ANOVA analysis comparing multiple groups showed no significant differences in final body weight between the IRX4204 or vehicle groups.

[0169] To assess thyroid hormone levels, terminal blood collection was performed to quantify T4 levels. Animals treated with IRX4204 alone showed an approximately 50% decrease in T4 levels compared to vehicle control animals. Exogenous treatment with T4 corrected thyroid hormone levels, as shown by the increased T4 levels in the IRX4204 + T4 group.

[0170] Free-floating brain sections were immunostained with SMI-32 to visualize and quantify axonal ovoids in the CC. Compared with naive animals, animals subjected to CR had significantly higher numbers of SMI-32-stained axonal ovoids in the CC. There was a significant decrease in the number of axonal ovoids in animals treated with both IRX4204 and T4 compared with the vehicle group. IRX4204 alone tended to decrease the number of axonal ovoids, but the results were not statistically different from those in the vehicle group.

[0171] Free-floating brain sections were immunostained with Iba-1 to visualize and quantify microglia / macrophages in the CC. Animals subjected to CR and treated with vehicle showed a robust increase in Iba1 staining in the CC compared with naive animals. There was no difference in Iba1 staining density in IRX4204- or IRX4204+T4-treated animals compared with vehicle.

[0172] The number and density of myelinated axons in the CC were visualized and quantified using semithin (1 μm) sections of Epon-embedded CC tissue from animals receiving CR and vehicle or IRX4204+T4. Animals receiving CR and vehicle showed robust demyelination of the CC. There was no significant difference in the number and density of myelinated axons in IRX4204+T4-treated animals compared with vehicle.

[0173] Treatment with IRX4204 alone without T4 showed a trend toward a decrease in axon ovoids, but this was not statistically different from vehicle. However, when exogenous T4 was supplemented to IRX4204-treated animals, the number of axon ovoids was significantly reduced compared to vehicle. This data, along with our previous in vivo findings, supports the neuroprotective effect of IRX4204. Although there was a decrease in axon ovoids, there was no significant difference in microglia / macrophage activation and myelination in the corpus callosum between the vehicle and IRX4204 + T4 groups.

[0174] The finding that IRX4204 showed a neuroprotective effect only in the group with adjunctive T4 suggests an enhanced effect of the combination over IRX4204 alone.

[0175] Quantification of myelinated axons in the corpus callosum indicates potential responders and non-responders. Figures 20A-C show a high correlation between the number of axon ovals and the number of myelinated axons (i.e., animals with very few ovals had very high numbers and densities of myelinated axons in the corpus callosum).

[0176] Finally, while aspects of the present specification have been emphasized by reference to specific embodiments, those skilled in the art will readily appreciate that these disclosed embodiments are merely illustrative of the principles of the subject matter disclosed herein. Therefore, it should be understood that the disclosed subject matter is in no way limited to the specific methodology, protocols, and / or reagents, etc., described herein. Accordingly, various modifications or variations or alternative configurations of the disclosed subject matter can be made in accordance with the teachings herein without departing from the spirit of the specification. Finally, the terminology used herein is for the purpose of describing particular embodiments only and does not limit the scope of the present invention, which is defined solely by the claims. Therefore, the present invention is not limited to that precisely as shown and described.

[0177] Certain embodiments of the present invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those skilled in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as they see fit, and the inventors intend to practice the invention otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Furthermore, this invention includes any combination of the above-described embodiments in all possible variations thereof unless otherwise indicated herein or clearly contradicted by context.

[0178] Groupings of alternative embodiments, elements, or steps of the invention are not to be construed as limiting. Each group member may be referenced and claimed individually or in any combination with other group members disclosed herein. It is anticipated that one or more group members may be included in, or deleted from, a group for reasons of convenience and / or patentability. When such inclusion or deletion occurs, the specification is deemed to include the modified group and, therefore, to satisfy all Markush group descriptions used in the appended claims.

[0179] Unless otherwise indicated, all numbers expressing features, items, quantities, parameters, characteristics, terms, etc. used in the specification and claims should be understood to be modified in all instances by the term "about." As used herein, the term "about" refers to a feature, item, quantity, parameter, characteristic, or term encompassing a range of ±10% of the value of the stated feature, item, quantity, parameter, characteristic, or term. Thus, unless indicated to the contrary, the numerical parameters set forth in this specification and the appended claims are approximations that may vary. At the very least, and not as an attempt to limit the scope of the claims and the application of the doctrine of equivalents, each numerical designation should be construed in accordance with at least the number of reported significant digits and ordinary rounding techniques. Notwithstanding that the numerical ranges and values ​​setting forth the broad scope of the invention are approximations, the numerical ranges and values ​​set forth in the specific examples are reported as precisely as possible. However, numerical ranges or values ​​inherently contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value within that range. Unless otherwise stated herein, each value of a numerical range is incorporated herein as if each individual value were individually recited herein.

[0180] Unless otherwise indicated herein or clearly contradicted by context, the terms "a," "an," "the," and similar referents as used in the context of describing the present invention (particularly in the context of the appended claims) should be construed to encompass both the singular and the plural. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "etc.") provided herein is intended merely to better illustrate the invention and does not limit the scope of the invention as otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0181] Certain embodiments disclosed herein may be further limited in the claims using the language "consisting of" or "consisting essentially of." When used in a claim, whether added at the time of filing or by amendment, the transitional term "consisting of" excludes any element, step, or ingredient not recited in the claim. The transitional term "consisting essentially of" limits the claim to specific materials or steps and those that do not materially affect the basic and novel characteristic(s). Embodiments of the invention so claimed are essentially or explicitly described herein and enabled herein.

[0182] All patents, patent publications, and other publications referenced or identified herein are individually and expressly incorporated herein by reference in their entirety for the purpose of describing and disclosing, for example, the compositions and methodologies described in such publications that may be used in connection with the present invention. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or presentation of the contents of these documents are based on the information available to the applicant and do not constitute an admission as to the accuracy of the dates or contents of these documents.

[0183] (Addendum) (Appendix 1) 1. A method of treating a nervous system disorder, comprising administering to an individual in need thereof a therapeutically effective amount of an RXR agonist and a thyroid hormone, wherein administering the combination of the RXR agonist and the thyroid hormone treats the nervous system disorder in the individual, and 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 having the structure of Formula III. [ka] , bexarotene, or LG268, The method, wherein the combination of an RXR agonist and a thyroid hormone results in greater improvement of the nervous system disorder than either the selective RXR agonist or the thyroid hormone alone.

[0184] (Appendix 2) The method of 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.

[0185] (Appendix 3) 2. The method of claim 1, wherein the RXR agonist is bexarotene.

[0186] (Appendix 4) 2. The method of claim 1, wherein the RXR agonist is LG268.

[0187] (Appendix 5) 2. The method of claim 1, wherein the combination of an RXR agonist and thyroxine treats a nervous system disorder in an individual by both promoting neuronal remyelination and neuroprotection and modulating the individual's immune system.

[0188] (Appendix 6) 2. The method of claim 1, wherein the nervous system disorder is a central nervous system (CNS) disorder.

[0189] (Appendix 7) The nervous system disorders include relapsing / remitting primary progressive and secondary progressive forms of multiple sclerosis (MS), diffuse white matter lesions of early childhood, neuritis, acute disseminated encephalomyelitis, Marburg multiple sclerosis, diffuse myelosclerotic sclerosis (Scheder's disease), baroconcentric sclerosis, isolated sclerosis, optic neuritis, transverse myelitis, amyotrophic lateral sclerosis (ALS), leukodystrophy (multiple variants, e.g., adrenoleukodystrophy, adrenal myeloneuropathy), and leukodystrophy (multiple variants, e.g., adrenoleukodystrophy, adrenal myeloneuropathy). 10. The method of claim 1, wherein the condition is a neurodegenerative disorder, including encephalopathy, 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 syndrome, Devick's disease, inflammatory demyelinating disease, CNS neuropathy, central pontine myelinolysis, dorsal funiculus (syphilitic myelopathy), progressive multifocal leukoencephalopathy, leukodystrophy, depression, schizophrenia, epilepsy, or dementia.

[0190] (Appendix 8) 2. The method of claim 1, wherein the nervous system disorder is Parkinson's disease.

[0191] (Appendix 9) 2. The method of claim 1, wherein the nervous system disorder is Alzheimer's disease.

[0192] (Appendix 10) 2. The method of claim 1, wherein the nervous system disorder is a demyelination-related disorder.

[0193] (Appendix 11) 12. The method of claim 11, wherein the demyelination-related disorder is multiple sclerosis.

[0194] (Appendix 12) 12. The method of claim 11, wherein the demyelination-related disorder is radiation-induced central nervous system inflammation.

[0195] (Appendix 13) 2. The method of claim 1, wherein the nervous system disorder is a peripheral nervous system disorder.

[0196] (Appendix 14) 14. The method of claim 13, 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-induced or toxin-induced neuropathy such as chemotherapy-induced neuropathy or organophosphate-induced neuropathy, anti-MAG peripheral neuropathy, Charcot-Marie-Tooth disease, or copper deficiency.

[0197] (Appendix 15) 2. The method of claim 1, wherein the therapeutically effective amount of the RXR agonist is about 0.001 mg / day to about 100 mg / day.

[0198] (Appendix 16) 2. The method of claim 1, wherein the therapeutically effective amount of the RXR agonist is about 1 mg / day to about 20 mg / day.

[0199] (Appendix 17) 2. The method of claim 1, wherein the thyroid hormone is thyroxine.

[0200] (Appendix 18) 18. The method of claim 17, wherein the dose of thyroxine is about 12.5 μg / day to about 250 μg / day.

[0201] (Appendix 19) 2. The method of claim 1, wherein the RXR agonist is administered by intranasal administration.

[0202] (Appendix 20) 20. The method of claim 19, wherein both the RXR agonist and thyroxine are administered by intranasal administration.

[0203] (Appendix 21) 2. The method of claim 1, wherein the RXR agonist is administered orally.

[0204] (Appendix 22) 2. The method of claim 1, wherein both the RXR agonist and the thyroxine are administered substantially simultaneously.

[0205] (Appendix 23) 2. The method of claim 1, wherein both the RXR agonist and the thyroxine are administered on different schedules.

[0206] (Appendix 24) 2. The method of claim 1, wherein the thyroid hormone is administered orally or subcutaneously.

[0207] (Appendix 25) 2. The method of claim 1, wherein treatment with a combination of an RXR agonist and thyroxine reduces at least one symptom of the CNS disorder, wherein the at least one symptom that is reduced is inflammation, fatigue, dizziness, lethargy, high fever and body temperature, extreme sensitivity to cold in the hands and feet, muscle and joint weakness and stiffness, weight changes, digestive or gastrointestinal problems, low or high blood pressure, irritability, anxiety or depression, blurred or double vision, ataxia, clonus, dysarthria, fatigue, poor speech, hand numbness, migraines, genital anesthesia, incoordination, paresthesia, eye numbness, muscle coordination loss, weakness (muscles), loss of sensation, visual impairment, neurological symptoms, unsteady gait, spastic paresis, incontinence, hearing loss, or speech problems.

[0208] (Appendix 26) 26. The method of claim 25, wherein treatment with a combination of an RXR agonist and thyroxine reduces at least two symptoms of the CNS disorder.

[0209] (Appendix 27) 26. The method of claim 25, wherein treatment with a combination of an RXR agonist and thyroxine reduces at least five symptoms of the CNS disorder.

[0210] (Appendix 28) 1. A method of treating multiple sclerosis, comprising administering to an individual in need thereof therapeutically effective amounts 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, wherein administration of the combination treats said multiple sclerosis in said individual more effectively than treatment with either 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.

[0211] (Appendix 29) 1. A method of treating a CNS disorder, comprising administering to an individual in need thereof therapeutically effective amounts 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, wherein administering 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, intracranial injection or implantation, or intranasal administration 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.

[0212] (Appendix 30) 1. A method of treating Parkinson's disease, comprising administering to an individual in need thereof therapeutically effective amounts 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, wherein administration of the combination treats Parkinson's disease in the individual more effectively than treatment with either 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.

[0213] (Appendix 31) 1. A method of treating Alzheimer's disease, comprising administering to an individual in need thereof therapeutically effective amounts 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, wherein administration of the combination treats the Alzheimer's disease in the individual more effectively than treatment with either 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.

[0214] (Appendix 32) Measuring free serum thyroxine; Adjusting the dose of thyroxine to maintain thyroxine concentrations in the euthyroid range; and 32. The method of any one of appendixes 1, 28, 29, 30, or 31, further comprising:

[0215] (Appendix 33) 32. The method of any one of appendix 1, 28, 29, 30, or 31, further comprising administration of a neurotrophic factor or a neurotrophic factor mimetic.

[0216] (Appendix 34) 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.

[0217] (Appendix 35) 32. The method of claim 31, wherein the disease of the central nervous system is Parkinson's disease, Alzheimer's disease, multiple sclerosis, optic neuritis, stroke, nervous system trauma, amyotrophic lateral sclerosis, neuropathy, nervous system hypoxia, nervous system toxicity, dementia, retinopathy, Huntington's disease, synucleinopathy, epilepsy, autism, schizophrenia, depression, or aging-related nervous system degeneration.

[0218] (Appendix 36) 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.

[0219] (Appendix 37) 32. 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.

[0220] (Appendix 38) 32. The method of claim 31, wherein the neurotrophic factor is insulin or an insulin-like growth factor, and the nervous system disease is Alzheimer's disease.

[0221] (Appendix 39) 32. The method of claim 31, wherein the neurotrophic factor is BDNF, GDNF, or insulin, and the nervous system disease is aging-related CNS neurodegeneration.

[0222] (Appendix 40) 32. The method of claim 31, wherein the neurotrophic factor or mimetic is administered by oral, parenteral, nasal, or topical routes, or by a controlled release formulation using any of these routes of administration.

[0223] (Appendix 41) Use of a combination of an RXR agonist, thyroid hormone, and a neurotrophic factor or neurotrophic factor mimetic to promote the survival or growth of neurons or glial cells in vitro, for subsequent transplantation into the nervous system of a patient with a nervous system disorder.

[0224] (Appendix 42) 1. A method for promoting neuronal or glial cell survival or repair in a patient with a nervous system disorder, comprising administering to an individual in need of such treatment therapeutically effective amounts of an 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 wherein administration of the combination of the RXR agonist and the thyroid hormone promotes neuronal or glial cell survival or repair in the individual more effectively than treatment with either the RXR agonist or the thyroid hormone alone.

[0225] (Appendix 43) 43. The method of claim 42, wherein the nervous system disorder is a central nervous system (CNS) disorder, a demyelination-related disorder, or a peripheral nervous system disorder.

[0226] (Appendix 44) 44. The method of claim 43, wherein the nervous system disorder is multiple sclerosis (MS), Parkinson's disease, or Alzheimer's disease.

[0227] (Appendix 45) 43. The method of claim 42, wherein the therapeutically effective amount of the RXR agonist is about 0.001 mg / day to about 100 mg / day.

[0228] (Appendix 46) 43. The method of claim 42, wherein the therapeutically effective amount of the RXR agonist is about 1 mg / day to about 20 mg / day.

[0229] (Appendix 47) 43. The method of claim 42, wherein the thyroid hormone is thyroxine.

[0230] (Appendix 48) 48. The method of claim 47, wherein the dose of thyroxine is about 12.5 μg / day to about 250 μg / day.

[0231] (Appendix 49) 43. The method of claim 42, wherein treatment with a combination of an RXR agonist and thyroxine reduces at least one symptom of the nervous system disorder, wherein the at least one symptom that is reduced is inflammation, fatigue, dizziness, lethargy, high fever and body temperature, extreme sensitivity to cold in the hands and feet, muscle and joint weakness and stiffness, weight changes, digestive or gastrointestinal problems, low or high blood pressure, irritability, anxiety or depression, blurred or double vision, ataxia, clonus, dysarthria, fatigue, poor speech, hand numbness, migraines, genital anesthesia, incoordination, paresthesia, eye numbness, muscle coordination loss, weakness (muscle), loss of sensation, visual impairment, neurological symptoms, unsteady gait, spastic paresis, incontinence, hearing loss, or speech problems.

[0232] (Appendix 50) 50. The method of claim 49, wherein treatment with a combination of an RXR agonist and thyroxine reduces at least two symptoms of the nervous system disorder.

[0233] (Appendix 51) 50. The method of claim 49, wherein treatment with a combination of an RXR agonist and thyroxine reduces at least five symptoms of the nervous system disorder.

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