Methods of using s1p receptor modulators

Abstract

Among other things, the present disclosure provides methods for treating or preventing achromotrichia. The present disclosure provides methods for treating, preventing, protecting from, or mitigating a radiation induced disease, disorder, or condition. The present disclosure provides methods for decreasing or preventing senescence. The present disclosure provides methods comprising administering to a subject a therapeutically effective amount of an S1P receptor modulator.

Description

96SB-705021-WO / 25-008-02PCTMETHODS OF USING SIP RECEPTOR MODULATORSRELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 748,743, filed January 23, 2025. The content of this related application is incorporated herein by reference in its entirety for all purposes.GOVERNMENT SUPPORT

[0002] This invention was made with government support under R01 HL141880 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND

[0003] Exposure to radiation can significantly impact individuals, leading to health problems, aesthetic changes such as achromotrichia, work capacity reduction, and even life span shortening. Diseases, disorders, or conditions related to radiation include radiation sickness, radiation poisoning, cancer, genetic damage, cardiovascular disease, cataracts, and skin conditions. Notably, exposure to radiation is not limited to extraordinary circumstance but is relatively common. Among other things, medical procedures such as X-rays, CT scans, and radiation therapies for cancer are sources of radiation exposure. In addition, individuals employed in certain industries such as nuclear power plants, hospitals, and fields involving drilling, fracking, mining, or research institutions face higher levels of exposure and thus higher risk of radiation induced diseases, disorders, or conditions. Additionally, achromotrichia is common even amongst individuals that have not been exposed to high levels of radiation. Both age and stress are known to contribute to achromotrichia. However, no known treatments to address achromotrichia exist; rather, individuals either leave it untreated or dye their hair to cover up the achromotrichia. Given the prevalence of radiation exposure and the consequential health impacts, there is an unmet need for treating, preventing, or mitigating radiation induced diseases, disorders, and conditions. Additionally, given the prevalence of achromotrichi in the population and the lack of available treatments, there is a need for treating and / or reversing achromotrichia.SUMMARY

[0004] Among other things, the present disclosure provides an insight that a sphingosine- 1-phosphate (SIP) receptor modulator can be used to treat, reverse, and / or preventachromotrichia. In some embodiments, achromotrichia is associated with or caused by age and / or stress. In some embodiments, achromotrichia is induced by radiation. In some embodiments, achromotrichia is not associated with or induced by radiation. The present disclosure recognizes that an SIP receptor modulator can be used to decrease or treat senescence. In some embodiments, the senescence is age or stress related senescence. In some embodiments, senescence is induced by radiation. In some embodiments, the senescence is not associated with or induced by radiation. In some embodiments, the senescence is replicative senescence. Furthermore, the present disclosure recognizes that an SIP receptor modulator can be used to treat and / or prevent various radiation induced diseases, disorders, and conditions, e.g., radiation induced achromotrichia, radiation induced senescence, acute radiation syndrome (ARS), nausea, vomiting, loss of appetite, skin conditions, bleeding, delayed effects of acute radiation exposure (DEARE), gastrointestinal conditions, etc. The present disclosure recognizes that a method provided herein can address various diseases, disorders, and conditions, including health impacts related to radiation exposure. In some embodiments, a provided method can decrease or prevent senescence (e.g., radiation induced senescence), thereby treating, preventing, or mitigation various health impacts related to senescence, e.g., achromotrichia, life-span shortening effect of radiation, etc. In some embodiments, a provided method can treat or prevent radiation induced aesthetic changes such as achromotrichia.

[0005] An aspect of the in vention described herei n is a method of treating or preventing a radiation induced disease, disorder, or condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of an SIP receptor modulator.

[0006] Another aspect of the invention described herein is a method of mitigating a radiation induced disease, disorder, or condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of an SI receptor modulator.

[0007] Another aspect of the invention described herein is a method of protecting from a radiation induced disease, disorder, or condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of an SIP receptor modulator.

[0008] Another aspect of the invention described herein is a method of decreasing or preventing senescence, the method comprising administering to a subject in need thereof a therapeutically effective amount of an SIP receptor modulator.

[0009] Another aspect of the invention described herein is a method of treating or prevent achromotrichia, the method comprising administering to a subject in need thereof a therapeutically effective amount of an SI receptor modulator.INCORPORATION BY REFERENCE

[0010] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0012] F IG. 1A depicts the level of achromotrichia in control mice 101 and experimental mice 102 at 30 days post 850 cGy of gamma irradiation.

[0013] FIG. IB depicts the level of achromotrichia in control mice 103 and experimental mice 104 at 60 days post 750 cGy of gamma irradiation.

[0014] FIG. 2 depicts the level of achromotrichia in control mice 201 and experimental mice 202 at 31 days post 693 cGy of X-ray irradiation.

[0015] FIG. 3 illustrates that Fingolimod administered starting 28h post-exposure to X-ray radiation can mitigate achromotrichia 320 days post-radiation.

[0016] FIG. 4 illustrates that Fingolimod can mitigate DEARE bone marrow architecture damage caused by gamma irradiation exposure.

[0017] FIG. 5 shows Fingolimod administration initiated 24h post 750 cGy gamma radiation mitigated mortality in C57BL / 6 mice.

[0018] FIG. 6 shows Fingolimod can mitigate mortality caused by X-ray radiation and confer significant protection from ARS and DEARE.DETAILED DESCRIPTION

[0019] Provided herein are methods for treating, preventing, and / or reducing the amount of achromotrichia. In some embodiments, achromotrichia is the loss of hair pigment caused by a decline or absence of melanin production in the hair follicle. Without being bound by theory, achromotrichia can be caused by a range of factors such as aging, genetic factors, oxidative stress, nutritional deficiencies, chronic stress, pollutants, smoking, and / or radiation. Withoutbeing bound by theory, achromotrichia may happen when melanocyte stem cells within a hair follicle are gradually depleted and / or lose their function, which may lead to reduced melanin synthesis. Achromotrichia may include hair that has reduced or no melanin compared to the amount of melanin in surrounding hairs or was previously produced in the hair.

[0020] In some embodiments, administration of an SIP receptor modulator may prevent achromotrichia (e.g. prevent hair from graying). Mice were exposed to different doses and types of radiation as a model of hair graying. After the mice were exposed to radiation, they were administered an exemplary S IP receptor modulator (e.g. fmgolimod). The mice were monitored at various time points after the irradiation and treatment. Mice that were treated with the SIP receptor modulator did not have achromotrichia at the time points observed, indicating that SIP receptor modulators can treat and / or reduce achromotrichia and that SIP receptor modulators can treat and / or reduce radiation associated illnesses.Methods

[0021] In some embodiments, a method provided herein comprises treating or preventing achromotrichia. In some embodiments, provided herein is a method of reducing the amount of achromotrichia, or reducing the development of achromotrichia in a subject, the method comprising administering a therapeutically effective amount of an SIP receptor modulator to the subject. In some embodiments, provided herein is a method of reversing achromotrichia in a subject, the method comprising administering a therapeutically effective amount of an SIP receptor modulator to the subject. In some embodiments, the SIP receptor modulator is fmgolimod. In some embodiments, a method provided herein comprises treating or preventing a radiation induced disease, disorder, or condition. In some embodiments, a method provided herein comprises mitigating a radiation induced disease, disorder, or condition. In some embodiments, a method provided herein comprises protecting from a radiation induced disease, disorder, or condition. In some embodiments, a method provided herein comprises decreasing or preventing senescence. In some embodiments, a method of treating or preventing a radiation induced disease, disorder, or condition comprises administering to a subject in need thereof a therapeutically effective amount of an SIP receptor modulator. In some embodiments, a method of mitigating a radiation induced disease, disorder, or condition comprises administering to a subject in need thereof a therapeutically effective amount of an SIP receptor modulator. In some embodiments, a method of protecting from a radiation induced disease, disorder, or condition comprises administering to a subject in need thereof a therapeutically effective amount of an SIPreceptor modulator. In some embodiments, a method of decreasing or preventing senescence comprises administering to a subject in need thereof a therapeutically effective amount of an S IP receptor modulator. In some embodiments, a method of treating or preventing achromotrichia comprises administering to a subject in need thereof a therapeutically effective amount of an SIP receptor modulator. In some embodiments, an SIP receptor modulator can be used as a radiomitigator according to the present disclosure. In some embodiments, an SIP receptor modulator can be used as a radioprotector according to the present disclosure. In some embodiments, the subject does not have multiple sclerosis or has not been diagnosed with multiple sclerosis. In some embodiments, the subject does not have ulcerative colitis.

[0022] In some embodiments, preventing achromotrichia includes slowing down the rate at which hair is graying in a subject. In some embodiments, the methods disclosed herein reduce the rate of rate that hair is graying in a subject. For instance, if a subject experiences a 5% increase in hair graying every year, then preventing and / or slowing achromotrichia can include reducing to 3% increase in hair graying every' year.Radiation Induced Disease Disorder or Condition

[0023] In some embodiments, a radiation induced disease, disorder, or condition comprises achromotrichia. In some embodiments, a radiation induced disease, disorder, or condition comprises acute radiation syndrome (ARS). In some embodiments, a radiation induced disease, disorder, or condition is or comprises nausea. In some embodiments, a radiation induced disease, disorder, or condition is or comprises vomiting. In some embodiments, a radiation induced disease, disorder, or condition is or comprises loss of appetite. In some embodiments, a radiation induced disease, disorder, or condition is or comprises skin conditions. In some embodiments, a radiation induced disease, disorder, or condition is or comprises bleeding. In some embodiments, a radiation induced disease, disorder, or condition is or comprises delayed effects of acute radiation exposure (DEARE). In some embodiments, a radiation induced disease, disorder, or condition is or comprises gastrointestinal condition. In some embodiments, a radiation induced disease, disorder, or condition is or comprises cardiovascular disease. In some embodiments, a radiation induced disease, disorder, or condition is or comprises pulmonary condition. In some embodiments, a radiation induced disease, disorder, or condition is or comprises thyroid disorder. In some embodiments, a radiation induced disease, disorder, or condition is or comprises hematopoietic syndrome. In some embodiments, a radiation induced disease, disorder, or condition is or comprisesimmune disorder. In some embodiments, a radiation induced disease, disorder, or condition is or comprises cataracts. In some embodiments, a radiation induced disease, disorder, or condition is or comprises kidney disease. In some embodiments, kidney disease is or comprises kidney stones, kidney infections, polycystic kidney disease, or chronic kidney disease. In some embodiments, a radiation induced disease, disorder, or condition is or comprises neurological disease. In some embodiments, a radiation induced disease, disorder, or condition is or comprises cognitive disease. In some embodiments, a radiation induced disease, disorder, or condition is or comprises dementia. In some embodiments, a radiation induced disease, disorder, or condition is or comprises Alzheimer’s disease. In some embodiments, a radiation induced disease, disorder, or condition is or comprises vascular dementia. In some embodiments, a radiation induced disease, disorder, or condition is or comprises Lewy body dementia. In some embodiments, a radiation induced disease, disorder, or condition is or comprises Frontotemporal Dementia. In some embodiments, a radiation induced disease, disorder, or condition is or comprises mixed dementia. In some embodiments, a radiation induced disease, disorder, or condition is or comprises Parkinson’s disease. In some embodiments, a radiation induced disease, disorder, or condition is or comprises Huntington’s disease. In some embodiments, a radiation induced disease, disorder, or condition is or comprises Creutzfeldt- Jakob disease. In some embodiments, a radiation induced disease, disorder, or condition is or comprises normal pressure hydrocephalus. In some embodiments, a radiation induced disease, disorder, or condition is or comprises Wernicke-Korsakoff Syndrome. In some embodiments, a radiation induced disease, disorder, or condition is or comprises achromotrichia, acute radiation syndrome (ARS), nausea, vomiting, loss of appetite, skin conditions, bleeding, delayed effects of acute radiation exposure (DEARE), gastrointestinal conditions, cardiovascular disease, pulmonary conditions, thyroid disorders, hematopoietic syndrome, immune disorders, or cataracts, or some combination thereof.

[0024] In some embodiments, a radiation induced disease, disorder, or condition is achromotrichia. In some embodiments, a radiation induced disease, disorder, or condition is acute radiation syndrome (ARS). In some embodiments, a radiation induced disease, disorder, or condition is nausea. In some embodiments, a radiation induced disease, disorder, or condition is vomiting. In some embodiments, a radiation induced disease, disorder, or condition is a loss of appetite. In some embodiments, a radiation induced disease, disorder, or condition is skin conditions. In some embodiments, a radiation induced disease, disorder, or condition is bleeding. In some embodiments, a radiation induced disease, disorder, orcondition is the delayed effects of acute radiation exposure (DEARE). In some embodiments, a radiation induced disease, disorder, or condition is gastrointestinal conditions. In some embodiments, a radiation induced disease, disorder, or condition is cardiovascular disease. In some embodiments, a radiation induced disease, disorder, or condition is pulmonary conditions. In some embodiments, a radiation induced disease, disorder, or condition is thyroid disorders. In some embodiments, a radiation induced disease, disorder, or condition is hematopoietic syndrome. In some embodiments, a radiation induced disease, disorder, or condition is an immune disorder. In some embodiments, a radiation induced disease, disorder, or condition is cataracts. In some embodiments, a radiation induced disease, disorder, or condition is achromotrichia, acute radiation syndrome (ARS), nausea, vomiting, loss of appetite, skin conditions, bleeding, delayed effects of acute radiation exposure (DEARE), gastrointestinal conditions, cardiovascular disease, pulmonary conditions, thyroid disorders, hematopoietic syndrome, immune disorders, cataracts, or some combination thereof.Senescence

[0025] In some embodiments, senescence is radiation induced senescence. In some embodiments, senescence is replicative senescence. In some embodiments, senescence is oxidative stress-induced senescence. In some embodiments, senescence is oncogene-indued senescence. In some embodiments, senescence is DNA damage-induced senescence. In some embodiments, senescence is lipid damage-induced senescence. In some embodiments, senescence is protein modification-induced senescence. In some embodiments, senescence is drug-induced senescence. In some embodiments, senescence is cellular senescence.

[0026] In some embodiments, senescence is when cell growth cycles are arrested. In some embodiments, senescence is determined based on gene expression. In some embodiments, senescence is senescence-associated secretory phenotype (SASP). In some embodiments, SASP is determined or associated with senescent cells which secrete inflammatory cytokine, immune modulators, growth factors, and proteases.

[0027] In some embodiments, senescence is caused by telomere shortening. In some embodiments, senescence is caused by DNA damage, oxidative stress, or chemotherapeutic drugs. In some embodiments, the methods disclosed herein protect bone marrow stem cells from chemotherapeutic induced cell death.

[0028] In some embodiments, senescence is determined by observing a decline in tissue regeneration. In some embodiments, senescence is quantified using Senescence- Associated P-Galactosidase (SA-P-Gal). In some embodiments, SA-P-Gal is measured using fluorometricsubstrate. In some embodiments, SA-P-Gal is measured using a commercially available kit. In some embodiments, SA-p-Gal is measured using a technique known in the art such as that described in Idelfonso-Garcia et al., “Protocol to detect senescence-associated P-galactosidase and immunoperoxidase activity in fresh-frozen murine tissues.” Star Protocols; 5(2) 2024. In some embodiments, senescence is measured by measuring expression or levels of p!6 INK4a, p21, p53, and / or H2AX. In some embodiments, senescence is measured by telomere length. In some embodiments, senescence is measured by proinflammatory cytokines (e.g. IL-6, IL-8, and / or TNFa).Achromotrichia

[0029] As used herein, achromotrichia refers to loss of hair pigmentation that results in a change of color in hair, e.g., grey or white hair. Achromotrichia can also be referred to as gray hair. In some embodiments, achromotrichia is radiation-induced achromotrichia. In some embodiments, achromotrichia is stress related achromotrichia. In some embodiments, achromotrichia is age related achromotrichia. In some embodiments, achromotrichia is disease-related achromotrichia. In some embodiments, achromotrichia is associated with or caused by nutritional deficiencies. In some embodiments, the nutritional deficiencies are a vitamin B12, iron, copper, and / or zinc deficiency. In some embodiments, achromotrichia is associated with or caused by an autoimmune disease. In some embodiments, the autoimmune disease is vitiligo and / or a thyroid disease. In some embodiments, achromotrichia is associated with or caused by smoking. In some embodiments, achromotrichia is associated with or caused by pollutants. In some embodiments, achromotrichia is associated with or caused by chronic stress. In some embodiments, achromotrichia is radiation-induced achromotrichia, stress-related achromotrichia, age-related achromotrichia, disease-related achromotrichia, or any combination thereof.

[0030] In some embodiments, disclosed herein is a method of reducing the amount of achromotrichia or reducing the development of achromotrichia in a subject (including preventing achromotrichia). In some embodiments, disclosed herein is a method of reversing achromotrichia in a subject. In some embodiments, the method includes administering a therapeutically effective amount of an SIP receptor modulator to the subject.

[0031] In some embodiments, achromotrichia is a reduction in melanocytes in individual hair follicles. In some embodiments, achromotrichia is a reduction of melanin in hair. In some embodiments, achromotrichia is caused by a reduction in melanocyte activity.Radiation

[0032] In some embodiments, radiation is ionizing radiation. In some embodiments, radiation is alpha-particle irradiation. In some embodiments, radiation is beta-particle irradiation. In some embodiments, radiation is gamma ray irradiation. In some embodiments, radiation is X-ray irradiation. In some embodiments, radiation is positron irradiation. In some embodiments, radiation is ultraviolet irradiation. In some embodiments, radiation is neutron irradiation. In some embodiments, radiation is proton irradiation. In some embodiments, radiation is heavy charged particle irradiation. In some embodiments, radiation is Bremsstrahlung radiation. In some embodiments, radiation is cosmic ray irradiation. In some embodiments, radiation is neutrino irradiation. In some embodiments, radiation is alpha-particle irradiation, beta- particle irradiation, gamma ray irradiation, X-ray irradiation, positron irradiation, ultraviolet irradiation, neutron irradiation, proton irradiation, heavy charged particle irradiation, Bremsstrahlung radiation, cosmic ray irradiation, neutrino irradiation, or some combination thereof. In some embodiments, radiation is non-ionizing radiation. In some embodiments, radiation is long- wavelength ultraviolet irradiation. In some embodiments, radiation is infrared irradiation. In some embodiments, radiation is microwave irradiation. In some embodiments, radiation is radio frequency irradiation. In some embodiments, radiation is vety low frequency irradiation. In some embodiments, radiation is extremely low frequency irradiation. In some embodiments, radiation is thermal irradiation. In some embodiments, radiation is ultrasonic wave irradiation. In some embodiments, radiation is long-wavelength ultraviolet irradiation, infrared irradiation, microwave irradiation, radio frequency irradiation, ver}' low frequency irradiation, extremely low frequency irradiation, thermal irradiation, ultrasonic wave irradiation, or some combination thereof.Radiation Exposure

[0033] In some embodiments, a subject as described herein has been exposed to acute radiation. In some embodiments, a subject as described herein has been exposed to a one-time dose of acute radiation. In some embodiments, a subject as described herein has been exposed to chronic radiation .Dose of Radiation

[0034] In some embodiments, a subject as described herein has been exposed to a dose of radiation of at least about 0.1 cGy, at least about 0.5 cGy, at least about 1 cGy, at least about 5 cGy, at least about 10 cGy, at least about 30 cGy, at least about 50 cGy, at least about 100cGy, at least about 200 cGy, at least about 300 cGy, at least about 500 cGy, at least about 600 cGy, at least about 650 cGy, at least about 700 cGy, at least about 750 cGy, at least about 800 cGy, at least about 850 cGy, at least about 900 cGy, at least about 1000 cGy, at least about 1500 cGy, at least about 2000 cGy, at least about 3000 cGy, at least about 4000 cGy, or at least about 5000 cGy. In some embodiments, a subject has been exposed to a dose of radiation of at least about 0.1 cGy. In some embodiments, a subject has been exposed to a dose of radiation of at least about 0.5 cGy. In some embodiments, a subject has been exposed to a dose of radiation of at least about 1 cGy. In some embodiments, a subject has been exposed to a dose of radiation of at least about 5 cGy. In some embodiments, a subject has been exposed to a dose of radiation of at least about 10 cGy. In some embodiments, a subject has been exposed to a dose of radiation of at least about 30 cGy. In some embodiments, a subject has been exposed to a dose of radiation of at least about 50 cGy. In some embodiments, a subject has been exposed to a dose of radiation of at least about 100 cGy. In some embodiments, a subject has been exposed to a dose of radiation of at least about 200 cGy. In some embodiments, a subject has been exposed to a dose of radiation of at least about 300 cGy. In some embodiments, a subject has been exposed to a dose of radiation of at least about 500 cGy. In some embodiments, a subject has been exposed to a dose of radiation of at least about 600 cGy. In some embodiments, a subject has been exposed to a dose of radiation of at least about 650 cGy. In some embodiments, a subject has been exposed to a dose of radiation of at least about 700 cGy. In some embodiments, a subject has been exposed to a dose of radiation of at least about 750 cGy. In some embodiments, a subject has been exposed to a dose of radiation of at least about 800 cGy. In some embodiments, a subject has been exposed to a dose of radiation of at least about 850 cGy. In some embodiments, a subject has been exposed to a dose of radiation of at least about 900 cGy. In some embodiments, a subject has been exposed to a dose of radiation of at least about 1000 cGy. In some embodiments, a subject has been exposed to a dose of radiation of at least about 1500 cGy. In some embodiments, a subject has been exposed to a dose of radiation of at least about 2000 cGy. In some embodiments, a subject has been exposed to a dose of radiation of at least about 3000 cGy. In some embodiments, a subject has been exposed to a dose of radiation of at least about 4000 cGy. In some embodiments, a subject has been exposed to a dose of radiation of at least about 5000 cGy.

[0035] In some embodiments, a subject has been exposed to a dose of radiation of about 50 cGy to about 500 cGy. In some embodiments, a subject has been exposed to a dose of radiation of about 100 cGy to about 600 cGy. In some embodiments, a subject has beenexposed to a dose of radiation of about 200 cGy to about 700 cGy. In some embodiments, a subject has been exposed to a dose of radiation of about 300 cGy to about 800 cGy. In some embodiments, a subject has been exposed to a dose of radiation of about 500 cGy to about 900 cGy. In some embodiments, a subject has been exposed to a dose of radiation of about 600 cGy to about 1000 cGy. In some embodiments, a subject has been exposed to a dose of radiation of about 700 cGy to about 1500 cGy. In some embodiments, a subject has been exposed to a dose of radiation of about 800 cGy to about 2000 cGy. In some embodiments, a subject has been exposed to a dose of radiation of about 900 cGy to about 3000 cGy. In some embodiments, a subject has been exposed to a dose of radiation of about 1000 cGy to about 4000 cGy. In some embodiments, a subject has been exposed to a dose of radiation of about 2000 cGy to about 5000 cGy. In some embodiments, a subject has been exposed to a dose of radiation of about 0.1 cGy to about 5000 cGy. In some embodiments, a subject has been exposed to a dose of radiation of about 30 cGy to about 5000 cGy. In some embodiments, a subject has been exposed to a dose of radiation of about 50 cGy to about 5000 cGy. In some embodiments, a subject has been exposed to a dose of radiation of about 50 cGy to about 3000 cGy. In some embodiments, a subject has been exposed to a dose of radiation of about 50 cGy to about 1000 cGy. In some embodiments, a subject has been exposed to a dose of radiation of about 50 cGy to about 100 cGy. In some embodiments, a subject has been exposed to a dose of radiation of about 50 cGy to about 200 cGy. In some embodiments, a subject has been exposed to a dose of radiation of about 50 cGy to about 300 cGy. In some embodiments, a subject has been exposed to a dose of radiation of about 0.1 cGy to about 50 cGy. In some embodiments, a subject has been exposed to a dose of radiation of about 0.1 cGy to about 30 cGy.

[0036] In some embodiments, a subject has been exposed to a dose of acute one-time radiation of at least about 0.1 cGy, at least about 0.5 cGy, at least about 1 cGy, at least about 5 cGy, at least about 10 cGy, at least about 30 cGy, at least about 50 cGy, at least about 100 cGy, at least about 200 cGy, at least about 300 cGy, at least about 500 cGy, at least about 600 cGy, at least about 650 cGy, at least about 700 cGy, at least about 750 cGy, at least about 800 cGy, at least about 850 cGy, at least about 900 cGy, at least about 1000 cGy, at least about 1500 cGy, at least about 2000 cGy, at least about 3000 cGy, at least about 4000 cGy, or at least about 5000 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of at least about 0.1 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of at least about 0.5 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of at leastabout 1 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of at least about 5 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of at least about 10 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of at least about 30 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of at least about 50 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of at least about 100 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of at least about 200 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of at least about 300 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of at least about 500 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of at least about 600 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of at least about 650 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of at least about 700 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of at least about 750 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of at least about 800 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of at least about 850 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of at least about 900 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of at least about 1000 cGy. In some embodiments, a subject has been exposed to a dose of acute one¬ time radiation of at least about 1500 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of at least about 2000 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of at least about 3000 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of at least about 4000 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of at least about 5000 cGy.

[0037] In some embodiments, a subject has been exposed to a dose of acute one-time radiation of about 50 cGy to about 500 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of about 100 cGy to about 600 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of about 200 cGy to about 700 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of about 300 cGy to about 800 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of about 500 cGy to about 900 cGy. Insome embodiments, a subject has been exposed to a dose of acute one-time radiation of about 600 cGy to about 1000 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of about 700 cGy to about 1500 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of about 800 cGy to about 2000 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of about 900 cGy to about 3000 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of about 1000 cGy to about 4000 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of about 2000 cGy to about 5000 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of about 0.1 cGy to about 5000 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of about 30 cGy to about 5000 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of about 50 cGy to about 5000 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of about 50 cGy to about 3000 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of about 50 cGy to about 1000 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of about 50 cGy to about 100 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of about 50 cGy to about 200 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of about 50 cGy to about 300 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of about 0.1 cGy to about 50 cGy. In some embodiments, a subject has been exposed to a dose of acute one-time radiation of about 0.1 cGy to about 30 cGy.

[0038] In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of at least about 0.1 cGy per year, at least about 0.5 cGy per year, at least about 1 cGy per year, at least about 5 cGy per year, at least about 10 cGy per year, at least about 30 cGy per year, at least about 50 cGy per year, at least about 100 cGy per year, at least about 200 cGy per year, at least about 300 cGy per year, at least about 500 cGy per year, at least about 600 cGy per year, at least about 650 cGy per year, at least about 700 cGy per year, at least about 750 cGy per year, at least about 800 cGy per year, at least about 850 cGy per year, at least about 900 cGy per year, at least about 1000 cGy per year, at least about 1500 cGy per year, at least about 2000 cGy per year, at least about 3000 cGy per year, at least about 4000 cGy per year, or at least about 5000 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of at least about 0.1 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of at leastabout 0.5 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of at least about 1 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of at least about 5 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of at least about 10 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of at least about 30 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of at least about 50 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of at least about 100 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of at least about 200 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of at least about 300 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of at least about 500 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of at least about 600 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of at least about 650 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of at least about 700 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of at least about 750 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of at least about 800 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of at least about 850 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of at least about 900 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of at least about 1000 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of at least about 1500 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of at least about 2000 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of at least about 3000 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of at least about 4000 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of at least about 5000 cGy per year.

[0039] In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of about 50 cGy per year to about 500 cGy per year. In some embodiments, asubject has been exposed to a cumulative dose of chronic radiation of about 100 cGy per year to about 600 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of about 200 cGy per year to about 700 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of about 300 cGy per year to about 800 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of about 500 cGy per year to about 900 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of about 600 cGy per year to about 1000 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of about 700 cGy per year to about 1500 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of about 800 cGy per year to about 2000 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of about 900 cGy per year to about 3000 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of about 1000 cGy per year to about 4000 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of about 2000 cGy per year to about 5000 cGy per year. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of about 0.1 cGy to about 5000 cGy. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of about 30 cGy to about 5000 cGy. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of about 50 cGy to about 5000 cGy. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of about 50 cGy to about 3000 cGy. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of about 50 cGy to about 1000 cGy. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of about 50 cGy to about 100 cGy. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of about 50 cGy to about 200 cGy. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of about 50 cGy to about 300 cGy. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of about 0.1 cGy to about 50 cGy. In some embodiments, a subject has been exposed to a cumulative dose of chronic radiation of about 0.1 cGy to about 30 cGy.Timing of Administration

[0040] In some embodiments, an SIP receptor modulator is administered immediately afterexposure to radiation, about 30 min after exposure to radiation, about 1 hour after exposure to radiation, about 2 hours after exposure to radiation, about 3 hours after exposure to radiation, about 6 hours after exposure to radiation, about 10 hours after exposure to radiation, about 12 hours after exposure to radiation, about 18 hours after exposure to radiation, about 24 hours after exposure to radiation, about 36 hours after exposure to radiation, about 48 hours after exposure to radiation, about 3 days after exposure to radiation, about 4 days after exposure to radiation, about 5 days after exposure to radiation, about 7 days after exposure to radiation, about 14 days after exposure to radiation, about 21 days after exposure to radiation, about 1 month after exposure to radiation, about 2 months after exposure to radiation, about 3 months after exposure to radiation, or about 6 months after exposure to radiation. In some embodiments, an SIP receptor modulator is administered immediately after exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 30 min after exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 1 hour after exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 2 hours after exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 3 hours after exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 6 hours after exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 10 hours after exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 12 hours after exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 18 hours after exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 24 hours after exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 36 hours after exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 48 hours after exposure to radiation. In some embodiments, an SI receptor modulator is administered about 3 days after exposure to radiation. In some embodiments, an SIP receptor modulator is administered 4 days after exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 5 days after exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 7 days after exposure to radiation. In some embodiments, an SIP receptor modulator is administered 14 days after exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 21 days after exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 1 month after exposure to radiation. In some embodiments, an S IP receptor modulator is administered about 2 months after exposure to radiation. In some embodiments, an SIPreceptor modulator is administered about 3 months after exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 6 months after exposure to radiation. In some embodiments, an SIP receptor modulator is administered at a time while an exposure to chronic radiation is ongoing. In some embodiments, an SIP receptor modulator is administered from about 30 min to about 48 hours after exposure to radiation. In some embodiments, an SIP receptor modulator is administered from about 30 min to about 24 hours after exposure to radiation. In some embodiments, an SIP receptor modulator is administered from about 30 min to about 12 hours after exposure to radiation. In some embodiments, an SIP receptor modulator is administered from about 30 min to about 6 hours after exposure to radiation. In some embodiments, an SIP receptor modulator is administered from about 24 to about 36 hours after exposure to radiation.

[0041] In some embodiments, an SIP receptor modulator is administered immediately before exposure to radiation, about 30 min before exposure to radiation, about 1 hour before exposure to radiation, about 2 hours before exposure to radiation, about 3 hours before exposure to radiation, about 6 hours before exposure to radiation, about 10 hours before exposure to radiation, about 12 hours before exposure to radiation, about 18 hours before exposure to radiation, about 24 hours before exposure to radiation, about 36 hours before exposure to radiation, about 48 hours before exposure to radiation, about 3 days before exposure to radiation, about 4 days before exposure to radiation, about 5 days before exposure to radiation, about 7 days before exposure to radiation, about 14 days before exposure to radiation, about 21 days before exposure to radiation, about 1 month before exposure to radiation, about 2 months before exposure to radiation, about 3 months before exposure to radiation, or about 6 months before exposure to radiation. In some embodiments, an SIP receptor modulator is administered immediately before exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 30 min before exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 1 hour before exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 2 hours before exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 3 hours before exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 6 hours before exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 10 hours before exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 12 hours before exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 18 hours before exposure to radiation. In someembodiments, an S IP receptor modulator is administered about 24 hours before exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 36 hours before exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 48 hours before exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 3 days before exposure to radiation. In some embodiments, an SIP receptor modulator is administered 4 days before exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 5 days before exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 7 days before exposure to radiation. In some embodiments, an SIP receptor modulator is administered 14 days before exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 21 days before exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 1 month before exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 2 months before exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 3 months before exposure to radiation. In some embodiments, an SIP receptor modulator is administered about 6 months before exposure to radiation. In some embodiments, an SIP receptor modulator is administered from about 30 min to about 48 hours before exposure to radiation. In some embodiments, an SIP receptor modulator is administered from about 30 min to about 24 hours before exposure to radiation. In some embodiments, an SIP receptor modulator is administered from about 30 min to about 12 hours before exposure to radiation. In some embodiments, an SIP receptor modulator is administered from about 30 rain to about 6 hours before exposure to radiation. In some embodiments, an SIP receptor modulator is administered from about 24 to about 36 hours before exposure to radiation.Dosing Regimen

[0042] In some embodiments, an SIP receptor modulator is administered in a dosing regimen.

[0043] In some embodiments, an SIP receptor modulator is administered three times daily, twice daily, once daily, once every other day, once every 3 days, once every week, once every two weeks, once every month, once every two months, once every three months, once every six months, or once every year. In some embodiments, an SIP receptor modulator is administered three times daily. In some embodiments, an SIP receptor modulator is administered twice times daily. In some embodiments, an SIP receptor modulator isadministered once daily. In some embodiments, an SIP receptor modulator is administered once every other day. In some embodiments, an SIP receptor modulator is administered once every 3 days. In some embodiments, an SIP receptor modulator is administered once every week. In some embodiments, an SIP receptor modulator is administered once every two weeks. In some embodiments, an S IP receptor modulator is administered once every month. In some embodiments, an SIP receptor modulator is administered once every two months. In some embodiments, an SIP receptor modulator is administered once every three months. In some embodiments, an S IP receptor modulator is administered once every six months. In some embodiments, an SIP receptor modulator is administered once every year.

[0044] In some embodiments, an S IP receptor modulator is administered in a dosing regimen comprising a loading dose after exposure to radiation and a maintaining dose.

[0045] In some embodiments, an SIP receptor modulator is administered in a dosing regimen comprising a loading dose before exposure to radiation and a maintaining dose.Dosing Duration

[0046] In some embodiments, an SIP receptor modulator is administered for at least 5 days, at least 7 days, at least 10 days, at least 14 days, at least 1 month, at least 2 months, at least 3 months, at least 6 months, or at least 1 year. In some embodiments, an SIP receptor modulator is administered for at least 5 days. In some embodiments, an SIP receptor modulator is administered for at least 7 days. In some embodiments, an SIP receptor modulator is administered for at least 10 days. In some embodiments, an SIP receptor modulator is administered for at least 14 days. In some embodiments, an SIP receptor modulator is administered for at least 1 month. In some embodiments, an SIP receptor modulator is administered for at least 2 months. In some embodiments, an SIP receptor modulator is administered for at least 3 months. In some embodiments, an SIP receptor modulator is administered for at least 6 months. In some embodiments, an S IP receptor modulator is administered for at least 1 year. In some embodiments, an SIP receptor modulator is administered once daily for 5 days and then administered every other day for 10 days.

[0047] In some embodiments, the SIP receptor modulator is administered for between about 1 month and 10 years. In some embodiments, the SIP receptor modulator is administered for between about 1 month and 5 years. In some embodiments, the SIP receptor modulator is administered for between about 1 month and 2 years. In some embodiments, the SIP receptor modulator is administered for between about 1 month and 1 year. In some embodiments, theSIP receptor modulator is administered for between about 1 month and 6 months. In some embodiments, the SIP receptor modulator is administered for between about 1 week and 6 months. In some embodiments, the SIP receptor modulator is administered for between about 1 week and 3 months. In some embodiments, the SIP receptor modulator is administered for between about 1 week and 2 months. In some embodiments, the SIP receptor modulator is administered for between about 1 week and 1 month.Administration Methods

[0048] In some embodiments, an SIP receptor modulator is administered orally, topically, subcutaneously, or some combination thereof. In some embodiments, an SIP receptor modulator is administered orally. In some embodiments, an SIP receptor modulator is administered topically. In some embodiments, an SIP receptor modulator is administered subcutaneously.SIP Receptor Modulators

[0049] Sphingosine 1 -phosphate (SIP) receptors, a family of G protein-coupled receptors, are implicated in lymphocyte trafficking, brain and cardiac function, vascular permeability, and vascular and bronchial tone. SIP receptors include S IP 1 receptors, S1P2 receptors, S1P3 receptors, S1P4 receptors, and S1P5 receptors. The present disclosure recognizes that SIP receptor modulators provide therapeutic benefits in various diseases, disorders, or conditions, including achromotrichia and radiation induced health impacts. In some embodiments, an SIP receptor modulator described herein is an agonist of an SIP receptor. In some embodiments, an SIP receptor modulator described herein comprises an agonist of an SIP receptor. In some embodiments, an S IP receptor modulator is an antagonist of an SIP receptor. In some embodiments, an SIP receptor modulator comprises an antagonist of an S IP receptor. In some embodiments, an S IP receptor modulator is a functional antagonist of an SIP receptor. In some embodiments, an SIP receptor modulator comprises a functional antagonist of an SIP receptor. In some embodiments, the SIP receptor modulator is a functional antagonist because the SIP receptor modulator binds to or has an affinity to an SIP receptor and upon the SIP receptor modulator binding the SIP receptor, the SIP receptor is internalized. In some embodiments, a functional antagonist to an S IP receptor that can bind to or has an affinity to an SIP receptor but binding of the functional antagonist to the SIP receptor causes the receptor to be internalized and degraded. In some embodiments, a functional antagonist prevents egress of lymphocytes out of lymph nodes. In someembodiments, a functional antagonist reduces egress of lymphocytes from a lymph node by 5%, 10%, 20%, 30%, 40%, 50%, 75%, 85%, 90%, or 95% compared to egress of lymphocytes from a lymph node that has not been treated. In some embodiments, the SIP receptor modulator is a functional antagonist as described in Camm et al., “Cardiac and vascular effects of fingolimod: Mechanistic basis and clinical implications” ri / werzcan Heart Journal 168(5):632-644 (2014); Brinkmann et al., “Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis” Nat Rev Drug Discov 9:883-897 (2010); Matloubin et al., “Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on SIP receptor 1” Nature 427:355-360 (2004); Choi et al., “FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1 -phosphate receptor 1 (SI Pi) modulation” Proc Natl Acad Set 108:751-756 (2011); and Chun et al., “Fingolimod: Lessons Learned and New Opportunities for Treating Multiple Sclerosis and Other Disorders” Annual Review of Pharmacology and Toxicology 59: 149-70 (2019). In some embodiments, the SIP receptor modulator causes internalization of an SIP receptor. In some embodiments, the SIP receptor modulator causes degradation of an SIP receptor. In some embodiments, the SIP receptor modulator causes internalization and / or degradation of an SIP receptor.

[0050] In some embodiments, an SIP receptor modulator described herein comprises an S1P1 receptor modulator. In some embodiments, an S IP receptor modulator described herein comprises an S1P2 receptor modulator. In some embodiments, an SIP receptor modulator described herein comprises an S1P3 receptor modulator. In some embodiments, an SIP receptor modulator described herein comprises an S1P4 receptor modulator. In some embodiments, an SIP receptor modulator described herein comprises an S1P5 receptor modulator. In some embodiments, an SIP receptor modulator described herein comprises an S1P1 receptor modulator, an S1P3 receptor modulator, an S1P4 receptor modulator, an S1P5 receptor modulator, or some combination thereof. In some embodiments, the SIP receptor modulator is an S1P1 receptor modulator, an S1P2 receptor modulator, an S1P3 receptor modulator, an S1P4 receptor modulator, or an S1P5 receptor modulator or any combination thereof. In some embodiments, the SIP receptor modulator is an S1P1 receptor modulator, an S1P3 receptor modulator, an S1P4 receptor modulator, and an S1P5 receptor modulator. In some embodiments, the SIP receptor modulator is an SIP 1 receptor modulator, an S1P2 receptor modulator, an S1P3 receptor modulator, an S1P4 receptor modulator, and / or an S1P5 receptor modulator. In some embodiments, the SIP receptor modulator is an SI Pl receptor modulator and an S1P5 receptor modulator. In some embodiments, an SIP receptor modulator is an S1P1 receptor modulator. In someembodiments, an S IP receptor modulator described herein is an S1P3 receptor modulator. In some embodiments, an SIP receptor modulator described herein is an S1P4 receptor modulator. In some embodiments, an SIP receptor modulator described herein is an S1P5 receptor modulator. In some embodiments, an SIP receptor modulator described herein is an S1P1 receptor modulator, an S1P3 receptor modulator, an S1P4 receptor modulator, an S1P5 receptor modulator, or some combination thereof. In some embodiments, an SIP receptor modulator described herein induces compensatory expression or signaling of S1P2 receptors. In some embodiments, the SIP receptor modulator is fmgolimod, ozanimod, siponimod, ponesimod, or etrasimod or a salt, metabolite, prodrug, or a derivative thereof of any of tire foregoing. In some embodiments, the SIP receptor modulator is fmgolimod, ozanimod, siponimod, ponesimod, or etrasimod or a salt of any of the foregoing. In some embodiments, an SIP receptor modulator described herein comprises fmgolimod. In some embodiments, an SIP receptor modulator described herein is fmgolimod. In some embodiments, an SIP receptor modulator described herein comprises a salt, a metabolite, a prodrug, or a derivative of fmgolimod. In some embodiments, an SIP receptor modulator described herein is a salt, a metabolite, a prodrug, or a derivative of fmgolimod. Fingolimod has a chemical name of 2-amino-2-[2-(4-octylphenyl)ethyl]propan- 1,3 -diol and has a structure of:

[0051] In some embodiments, an SIP receptor modulator described herein comprises a prodrug of fmgolimod. In some embodiments, an SIP receptor modulator described herein comprises a derivative of fmgolimod. In some embodiments, an SIP receptor modulator described herein comprises a metabolite of fmgolimod. In some embodiments, an SIP receptor modulator described herein comprises a salt of fmgolimod. In some embodiments, an SIP receptor modulator described herein comprises fmgolimod hydrochloride. In some embodiments, an S IP receptor modulator described herein comprises siponimod. In some embodiments, an SIP receptor modulator described herein comprises ponesimod. In some embodiments, an SIP receptor modulator described herein comprises etrasimod. In some embodiments, an SIP receptor modulator described herein comprises ozanimod. In some embodiments, an SIP receptor modulator described herein is a prodrug of fmgolimod. In some embodiments, an SIP receptor modulator described herein is a derivative of fmgolimod. In some embodiments, an SIP receptor modulator described herein is ametabolite of fmgolimod. In some embodiments, an S IP receptor modulator described herein is a salt of fmgolimod. In some embodiments, an SIP receptor modulator described herein is fmgolimod hydrochloride. In some embodiments, an SIP receptor modulator described herein is siponimod. In some embodiments, an SIP receptor modulator described herein is ponesimod. In some embodiments, an SIP receptor modulator described herein is etrasimod. In some embodiments, an SIP receptor modulator described herein is ozanimod.Dose Size

[0052] In some embodiments, the SIP receptor modulator is administered in a dose. In some embodiments, the SIP receptor modulator is administered at a dose of about 0.05 mg, about 0.1 rag, about 0.15 mg, about 0.2 rag, about 0.25 rag, about 0.3 rag, about 0.35 rag, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 rag, about 0.85 rag, about 0.9 rag, about 0.95 rag, or about 1.0 mg. In some embodiments, the SIP receptor modulator is administered at a dose of about 0.05 mg. In some embodiments, the SIP receptor modulator is administered at a dose of about 0.1 mg. In some embodiments, the SI receptor modulator is administered at a dose of about 0.15 mg. In some embodiments, the SIP receptor modulator is administered at a dose of about 0.2 rag. In some embodiments, the SIP receptor modulator is administered at a dose of about 0.25 mg. In some embodiments, the SIP receptor modulator is administered at a dose of about 0.3 mg. In some embodiments, the SIP receptor modulator is administered at a dose of about 0.35 mg. In some embodiments, the SIP receptor modulator is administered at a dose of about 0.4 mg. In some embodiments, the SIP receptor modulator is administered at a dose of about 0.45 mg. In some embodiments, the SIP receptor modulator is administered at a dose of about 0.5 mg. In some embodiments, the SIP receptor modulator is administered at a dose of about 0.55 mg. In some embodiments, the SIP receptor modulator is administered at a dose of about 0.6 mg. In some embodiments, the SIP receptor modulator is administered at a dose of about 0.65 mg. In some embodiments, the SIP receptor modulator is administered at a dose of about 0.7 mg. In some embodiments, the S IP receptor modulator is administered at a dose of about 0.75 mg. In some embodiments, the SIP receptor modulator is administered at a dose of about 0.8 mg. In some embodiments, the SIP receptor modulator is administered at a dose of about 0.85 mg. In some embodiments, the SIP receptor modulator is administered at a dose of about 0.9 mg. In some embodiments, the SIP receptor modulator is administered at a dose of about 0.95 mg. In some embodiments, the SIP receptor modulator is administered at a dose of about 1 mg. In some embodiments, the SIPreceptor modulator is administered at a dose of about 1.1 mg. In some embodiments, the S IP receptor modulator is administered at a dose of about 1.2 mg. In some embodiments, the SIP receptor modulator is administered at a dose of about 1.3 mg. In some embodiments, the SIP receptor modulator is administered at a dose of about 1.4 mg. In some embodiments, the SIP receptor modulator is administered at a dose of about 1.5 mg. In some embodiments, the S IP receptor modulator is administered at a dose of about 1.6 mg. In some embodiments, the S IP receptor modulator is administered at a dose of about 1.7 mg. In some embodiments, the SIP receptor modulator is administered at a dose of about 1.8 mg. In some embodiments, the SIP receptor modulator is administered at a dose of about 1.9 mg. In some embodiments, the SIP receptor modulator is administered at a dose of about 2 mg.

[0053] In some embodiments, the SIP receptor modulator is administered at a dose of about 0.05 mg to about 2 mg. In some embodiments, the SIP receptor modulator is administered at a dose of about 0.05 mg to about 1 mg. In some embodiments, the SIP receptor modulator is administered at a dose of about 0.05 mg to about 0.5 mg. In some embodiments, the SIP receptor modulator is administered at a dose of about 0.5 mg to about 1 mg.

[0054] In some embodiments, a fingolimod hydrochloride is administered in a dose. In some embodiments, a fingolimod hydrochloride is administered at a dose of about 0.05 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, or about 1.0 mg. In some embodiments, a fingolimod hydrochloride is administered at a dose of about 0.05 mg. In some embodiments, a fingolimod hydrochloride is administered at a dose of about 0.1 mg. In some embodiments, a fingolimod hydrochloride is administered at a dose of about 0.15 mg. In some embodiments, a fingolimod hydrochloride is administered at a dose of about 0.2 mg. In some embodiments, a fingolimod hydrochloride is administered at a dose of about 0.25 mg. In some embodiments, a fingolimod hydrochloride is administered at a dose of about 0.3 mg. In some embodiments, a fingolimod hydrochloride is administered at a dose of about 0.35 mg. In some embodiments, a fingolimod hydrochloride is administered at a dose of about 0.4 mg. In some embodiments, a fingolimod hydrochloride is administered at a dose of about 0.45 mg. In some embodiments, a fingolimod hydrochloride is administered at a dose of about 0.5 mg. In some embodiments, a fingolimod hydrochloride is administered at a dose of about 0.55 mg. In some embodiments, a fingolimod hydrochloride is administered at a dose of about 0.6 mg. In some embodiments, a fingolimod hydrochloride is administered at a dose of about 0.65 mg. In some embodiments, a fingolimod hydrochloride isadministered at a dose of about 0.7 mg. In some embodiments, a fmgolimod hydrochloride is administered at a dose of about 0.75 mg. In some embodiments, a fmgolimod hydrochloride is administered at a dose of about 0.8 mg. In some embodiments, a fmgolimod hydrochloride is administered at a dose of about 0.85 mg. In some embodiments, a fmgolimod hydrochloride is administered at a dose of about 0.9 mg. In some embodiments, a fmgolimod hydrochloride is administered at a dose of about 0.95 mg. In some embodiments, a fmgolimod hydrochloride is administered at a dose of about 1 mg. In some embodiments, a fmgolimod hydrochloride is administered at a dose of about 1.1 mg. In some embodiments, a fmgolimod hydrochloride is administered at a dose of about 1.2 mg. In some embodiments, a fmgolimod hydrochloride is administered at a dose of about 1.3 mg. In some embodiments, a fmgolimod hydrochloride is administered at a dose of about 1.4 mg. In some embodiments, a fmgolimod hydrochloride is administered at a dose of about 1.5 mg. In some embodiments, a fmgolimod hydrochloride is administered at a dose of about 1.6 mg. In some embodiments, a fmgolimod hydrochloride is administered at a dose of about 1.7 mg. In some embodiments, a fmgolimod hydrochloride is administered at a dose of about 1.8 mg. In some embodiments, a fmgolimod hydrochloride is administered at a dose of about 1.9 mg. In some embodiments, a fmgolimod hydrochloride is administered at a dose of about 2 mg.

[0055] In some embodiments, a fmgolimod hydrochloride is administered at a dose of about 0.05 mg to about 2 mg. In some embodiments, a fmgolimod hydrochloride is administered at a dose of about 0.05 mg to about 1 mg. In some embodiments, a fmgolimod hydrochloride is administered at a dose of about 0.05 mg to about 0.5 mg. In some embodiments, a fmgolimod hydrochloride is administered at a dose of about 0.5 mg to about 1 mg.Pharmaceutical Compositions / F orm illations

[0056] Provided herein, in certain embodiments, are compositions comprising a therapeutically effective amount of an SIP receptor modulator as described herein.

[0057] Pharmaceutical compositions may be formulated using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the pharmaceutical agent into preparations which are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, NewYork, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999).

[0058] The compositions and methods of the present disclosure may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the pharmaceutical agent, is preferably administered as a pharmaceutical composition comprising, for example, a pharmaceutical agent and a pharmaceutically acceptable carrier or excipient. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration, e.g., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier, the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as pill, tablet, capsule, granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop.

[0059] A pharmaceutically acceptable excipient can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a pharmaceutical agent. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable excipient, including a physiologically acceptabl e agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self emulsifying drug delivery system or a self microemulsifying drug delivery system . The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

[0060] A pharmaceutical composition (preparation) can be administered to a subject by anyof a number of routes of administration including, for example, orally, for example, drenches as in aqueous or non-aqueous solutions or suspensions, pills, tablets, capsules, including sprinkle capsules and gelatin capsules, boluses, powders, granules, pastes for application to the tongue; absorption through the oral mucosa, e.g., sublingually; anally, rectally or vaginally, for example, as a pessary, cream or foam; parenterally, including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension; nasally; intraperitoneally; subcutaneously; transdermally, for example, as a patch applied to the skin; and topically, for example, as a cream, ointment or spray applied to the skin, or as an eye drop. The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water.

[0061] A pharmaceutical composition may be a sterile aqueous or non-aqueous solution, suspension or emulsion, e.g., a microemulsion. The excipients described herein are examples and are in no way limiting. An effective amount or therapeutically effective amount refers to an amount of the one or more pharmaceutical agents administered to a subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.

[0062] In some embodiments, a pill is a pharmaceutical composition prepared to be swallowed whole. In some embodiments, a pill can be used interchangeably with tablet and / or capsule.

[0063] Subjects may generally be monitored for therapeutic effectiveness using assays and methods suitable for the condition being treated, which assays will be familiar to those having ordinary skill in the art and are described herein. For instance, with regard to achromotrichia, a therapeutically effective amount is the dosage or concentration of the SIP receptor modulator that when taken increases pigmentation in the hair, slows the progression of hair graying, maintains the amount of gray hair by preventing new gray hair, and / or reduces the percentage of the hair which is gray. In some embodiments, a therapeutically effective amount is the dosage or concentration of the SIP receptor modulator that when taken reduces the percentage of hair that is gray by about 5%, 10%, 15%, 20%, 25%, 50%, 75%, 80%, 90% or 100% compared to prior to taking the therapeutically effective amount. The therapeutically effective amount can vary depending, for example, but not limited to, on the compound, the disease or the condition and / or symptoms thereof, severity of the disease or the condition and / or symptoms thereof, the age, weight, and / or health of the subject to be treated, and the judgment of the prescribing physician. Pharmacokinetics of a pharmaceutical agent, or one or more metabolites thereof, that is administered to a subject may be monitoredby determining the level of the pharmaceutical agent or metabolite in a biological fluid, for example, in the blood, blood fraction, e.g., serum, and / or in the urine, and / or other biological sample or biological tissue from the subject. Any method practiced in the art and described herein to detect the agent may be used to measure the level of the pharmaceutical agent or metabolite during a treatment course.

[0064] The dose of a pharmaceutical agent described herein for treating a disease or disorder may depend upon the subject’s condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art. Pharmaceutical compositions may be administered in a manner appropriate to the disease to be treated as determined by persons skilled in the medical arts. In addition to the factors described herein and above related to use of pharmaceutical agent for treating a disease or disorder, suitable duration and frequency of administration of the pharmaceutical agent may also be determined or adjusted by such factors as the condition of the patient, the type and severity of the patient’s disease, the particular form of the active ingredient, and the method of administration. Optimal doses of an agent may generally be determined using experimental models and / or clinical trials. The optimal dose may depend upon the body mass, weight, or blood volume of the subject. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred. Design and execution of pre-clinical and clinical studies for a pharmaceutical agent, including when administered for prophylactic benefit, described herein are well within the skill of a person skilled in the relevant art. When two or more pharmaceutical agents are administered to treat a disease or disorder, the optimal dose of each pharmaceutical agent may be different, such as less than when either agent is administered alone as a single agent therapy. In certain particular embodiments, two pharmaceutical agents in combination may act synergistically or additively, and either agent may be used in a lesser amount than if administered alone. An amount of a pharmaceutical agent that may be administered per day may be, for example, between about 0.01 mg / kg and 100 mg / kg, e.g., between about 0.1 to 1 mg / kg, between about 1 to 10 mg / kg, between about 10-50 mg / kg, between about 50-100 mg / kg body weight. In other embodiments, the amount of a pharmaceutical agent that may be administered per day is between about 0.01 mg / kg and 1000 mg / kg, between about 100-500 mg / kg, or between about 500-1000 mg / kg body weight. The optimal dose, per day or per course of treatment, may be different for the disease or disorder to be treated and may also vary with the administrative route and therapeutic regimen.

[0065] Pharmaceutical compositions comprising a pharmaceutical agent can be formulated ina manner appropriate for the delivery method by using techniques routinely practiced in the art. The composition may be in the form of a solid, e.g., pill, tablet, capsule, semi-solid, e.g., gel, liquid, or gas, e.g., aerosol. In other embodiments, the pharmaceutical composition is administered as a bolus infusion.

[0066] Pharmaceutical acceptable excipients are well known in the pharmaceutical art and described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5thEd., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)). Exemplary7pharmaceutically acceptable excipients include sterile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, and the like may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used. In general, the type of excipient is selected based on the mode of administration, as well as the chemical composition of the active ingredient(s). Alternatively, compositions described herein may be formulated as a lyophilizate. A composition described herein may be lyophilized or otherwise formulated as a lyophilized product using one or more appropriate excipient solutions for solubilizing and / or diluting the pharmaceutical agent(s) of the composition upon administration. In other embodiments, the pharmaceutical agent may be encapsulated within liposomes using technology known and practiced in the art. In certain particular embodiments, a pharmaceutical agent is not formulated within liposomes for application to a stent that is used for treating highly, though not totally, occluded arteries. Pharmaceutical compositions may be formulated for any appropriate manner of administration described herein and in the art.

[0067] A pharmaceutical composition, e.g., for oral administration or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery or other method, may¬ be in the form of a liquid. A liquid phar aceutical composition may include, for example, one or more of the following: a sterile diluent such as water, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils that may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents; antioxidants; chelating agents; buffers and agents for the adjustment of tonicity such as sodium chloride or dextrose. A parenteral composition can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. The use of physiological saline is preferred, and an injectable pharmaceutical composition is preferably sterile. In another embodiment, for treatment of an ophthalmological condition or disease, a liquid pharmaceutical composition may be applied to the eye in the form of eyedrops. A liquid pharmaceutical composition may be delivered orally.

[0068] For oral formulations, at least one of the pharmaceutical agents described herein can be used alone or in combination with appropriate additives to make pills, tablets, powders, granules or capsules, and if desired, with diluents, buffering agents, moistening agents, preservatives, coloring agents, and flavoring agents. The pharmaceutical agents may be formulated with a buffering agent to provide for protection of the compound from low pH of the gastric environment and / or an enteric coating. A pharmaceutical agent included in a pharmaceutical composition may be formulated for oral delivery with a flavoring agent, e.g., in a liquid, solid or semi-solid formulation and / or with an enteric coating.

[0069] A pharmaceutical composition comprising any one of the pharmaceutical agents described herein may be formulated for sustained or slow release, also called timed release or controlled release. Such compositions may generally be prepared using well known technology and administered by, for example, oral, rectal, intradermal, or subcutaneous implantation, or by implantation at the desired target site. Sustained-release formulations may contain the compound dispersed in a carrier matrix and / or contained within a reservoir surrounded by a rate controlling membrane. Excipients for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of active component release. The amount of pharmaceutical agent contained within a sustained release formulation depends upon the site of implantation, the rate and expected duration of release, and the nature of the condition, disease or disorder to be treated or prevented.

[0070] As used herein, the terra “medicament” refers to a pharmaceutical composition intended for use in the mitigation, treatment, or prevention of a disease or condition in a subject.

[0071] In some embodiments, the medicament can comprise one or more active pharmaceutical ingredients (or pharmaceutical agents) and one or more pharmaceutically acceptable carriers, excipients, diluents, or adjuvants. In some embodiments, the medicament can be formulated in any suitable dosage form, including solid, liquid, semi-solid, or suspension forms, and can be adapted for administration by any suitable route, including oral, rectal, parenteral, topical, transdermal, inhalation, or mucosal administration. In some embodiments, the S IP receptor modulator is formulated as a medicament.

[0072] In certain embodiments, the pharmaceutical compositions comprising a pharmaceutical agent are formulated for transdermal, intradermal, or topical administration. The compositions can be administered using a syringe, bandage, transdermal patch, insert, orsyringe-like applicator, as a powder / talc or other solid, liquid, spray, aerosol, ointment, foam, cream, gel, paste. This preferably is in the form of a controlled release formulation or sustained release formulation administered topically or injected directly into the skin adjacent to or within the area to be treated, e.g., intradermally or subcutaneously. The active compositions can also be delivered via iontophoresis. Preservatives can be used to prevent the growth of fungi and other microorganisms. Suitable preservatives include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cety pyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and combinations thereof.

[0073] Pharm ceutical compositions comprising a pharmaceutical agent can be formulated as emulsions for topical application. An emulsion contains one liquid distributed in the body of a second liquid. The emulsion may be an oil-in-water emulsion or a water-in-oil emulsion. Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients. The oil phase may contain other oily pharmaceutically approved excipients. Suitable surfactants include, but are not limited to, anionic surfactants, non-ionic surfactants, cationic surfactants, and amphoteric surfactants. Compositions for topical application may also include at least one suitable suspending agent, antioxidant, chelating agent, emollient, or humectant.

[0074] Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Liquid sprays may be delivered from pressurized packs, for example, via a specially shaped closure. Oil-in-water emulsions can also be used in the compositions, patches, bandages and articles. These systems are semisolid emulsions, micro-emulsions, or foam emulsion systems.

[0075] In some embodiments, the pharmaceutical agent(s) can be formulated with oleaginous bases or ointments to form a semisolid composition with a desired shape. In addition to the pharmaceutical agent, these semisolid compositions can contain dissolved and / or suspended bactericidal agents, preservatives and / or a buffer system. A petrolatum component that may be included may be any paraffin ranging in viscosity from mineral oil that incorporates isobutylene, colloidal silica, or stearate salts to paraffin waxes. Absorption bases can be used with an oleaginous system. Additives may include cholesterol, lanolin (lanolin derivatives,beeswax, fatty alcohols, wool wax alcohols, lowHLB (hydrophobellipophobe balance) emulsifiers, and assorted ionic and nonionic surfactants, singularly or in combination.Oral Formulation

[0076] In some embodiments, an S IP receptor modulator described herein is formulated as a pharmaceutical formulation. In some embodiments, an SIP receptor modulator is formulated as a solution. In some embodiments, a solution is administered orally.

[0077] In some embodiments, a solution described herein comprises an aqueous solution. In some embodiments, a solution comprises 2-hydroxypropyl-P-cyclodextrin. In some embodiments, a solution comprises about 2% 2-hydroxypropyl-P-cyclodextrin. In some embodiments, a solution comprises a polyunsaturated fatty acid (PUFA). In some embodiments, a solution comprises about 2% of a PUFA. In some embodiments, a PUFA comprises corn oil. In some embodiments, a PUFA comprises soybean oil. In some embodiments, a PUFA comprises sunflower oil. In some embodiments, a PUFA comprises walnut oil. In some embodiments, a PUFA comprises flaxseed oil. In some embodiments, a PUFA comprises safflower oil. In some embodiments, a PUFA comprises canola oil. In some embodiments, a PUFA comprises grapeseed oil. In some embodiments, a PUFA comprises sesame oil. In some embodiments, a PUF A comprises cottonseed oil.

[0078] In some embodiments, the SIP receptor modulator is administered as a pill, a capsule, or a tablet (e.g., an orally disintegrating tablet). In some embodiments, the SIP receptor modulator is administered as multiple pills, capsules and / or tablets (e.g., orally disintegrating tablets).Topical Formulation

[0079] In some embodiments, an SIP receptor modulator formulated as a pharmaceutical formulation described herein is formulated as a topical formulation. In some embodiments, a topical formulation is in the form of a foam, a cream, an ointment, a gel, a lotion, a paste, a liquid, a spray, a suspension, or an emulsion. In some embodiments, a topical formulation is in the form of a foam. In some embodiments, a topical formulation is in the form of a cream . In some embodiments, a topical formulation is in the form of an ointment. In some embodiments, a topical formulation is in the form of a gel. In some embodiments, a topical formulation is in the form of a lotion. In some embodiments, a topical formulation is in the form of a paste. In some embodiments, a topical formulation is in the form of a liquid. In some embodiments, a topical formulation is in the form of a spray. In some embodiments, atopical formulation is in the form of a suspension. In some embodiments, a topical formulation is in the form of an emulsion.Definitions

[0080] The following definitions supplement those in the art and are directed to the current application and are not to be imputed to any related or unrelated case, e.g., to any commonly owned patent or application. Although any methods and materials similar or equivalent to those described herein can be used in the practice for testing of the present disclosure, the preferred materials and methods are described herein. Accordingly, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise.

[0081] In this application, the use of “or” means “and / or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.

[0082] Reference in the specification to “some embodiments,” “an embodiment,” “one embodiment” or “other embodiments” means that a particular feature, structure, or characteristic described in connection with the embodiments is included in at least some embodiments, but not necessarily all embodiments, of the inventions.

[0083] As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method or composition of the invention, and vice versa. Furtherm ore, compositions of the invention can be used to achieve methods of the invention.

[0084] The term “about” in relation to a reference numerical value and its grammatical equivalents as used herein can include the numerical value itself and a range of values plus or minus 10% from that numerical value. For example, the amount “about 10” includes 10 and any amounts from 9 to 11. For example, the term “about” in relation to a reference numerical value can also include a range of values plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from that value.

[0085] Ranges: throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. As another example, a range such as 95-99% identity, includes something with 95%, 96%, 97%, 98% or 99% identity, and includes subranges such as 96-99%, 96-98%, 96-97%.

[0086] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3II,nC,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0087] Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0088] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,nC,l3C,]4C,15C,] 2N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35C1,37C1,79Br,81Br,125I are all contemplated. In some embodiments, isotopic substitution with18F is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0089] In certain embodiments, the compound s disclosed herein have some or all of theatoms replaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art.

[0090] In one embodiment, the compounds disclosed herein contain one deuterium atom. Inanother embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeablehydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.

[0091] " Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the fmgolimod, ozanimod, siponimod, ponesimod, etrasimod, Mirtazapine and / or gabapentin compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0092] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biol ogical effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl -substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenyl acetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al.,"Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0093] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethy I aminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, A(A-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, A-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N- ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0094] "Pharmaceutically acceptable solvate" refers to a composition of matter that is the solvent addition form. In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. The compounds provided herein exist in either unsolvated or solvated forms.

[0095] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0096] As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and / or a prophylactic benefit. By “therapeutic benefit” it is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.

[0097] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0098] All terms are intended to be understood as they would be understood by a person skilled in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure pertains.

[0099] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise.ExamplesExample 1. Fingolimod mediated gamma irradiation mitigation

[0100] The effect of fingolimod treatment on gamma irradiation and achromotrichia is illustrated in FIG. 1A and FIG. IB. Irradiation is a well-established experimental model for inducing achromotrichia in mice used to study achromotrichia. Without wishing to be bound by theory, it may be that ionizing radiation (e.g. gamma radiation or x-rays) can trigger DNA damage, oxidative stress, and / or cellular senescence, which may mimic aging and stress that causes achromotrichia in individuals. The initial experiment involved irradiating 10-week-old wild type mice with 850 cGy of gamma radiation. Subsequently, the mice were orally administered FTY720 -HCL (“FTY” as used herein in, refers to fingolimod; provided byTocris Biosciences) in 200 pl of 2% hydroxypropyl-P-cyclodextrin (referred to as “vehicle”) every other day. Stocks of FTY were dissolved in sterile H2O, diluted in vehicle, and administered orally at a dose of 1.0 mg / kg starting 24 hours post-irradiation. Mice under the same conditions but administered only vehicle were used as a control. The oral administration of FTY or vehicle continued until 15 days post irradiation. Photographs of the mice were taken 30 days post-irradiation and are depicted in FIG. 1A, highlighting a significant reduction in the level of achromotrichia, or coat-graying, in the group of mice administered FTY 102, as compared to the control group that only received vehicle 101.

[0101] A second experiment followed a similar protocol, but with slight variations. Here, 10-week-old mice were exposed to a slightly lower gamma irradiation dose of 750 cGy. The same FTY solution was administered orally at 1.0 mg / kg, starting 24 hours post irradiation. Mice only administered vehicle were again used as a control. Administration of FTY or vehicle was for every other day until 15 days post-irradiation. The resulting reduction in the level of achromotrichia in the group of mice administered FTY 104 versus the control 103 was captured by photo 60 days post-irradiation and is shown in FIG. IB.Example 2. Fingolimod mediated X-ray radiation mitigation

[0102] For assessing the X-ray radio mitigation effect of fingolimod, a Precision X-Ray XRad320 set to 320kVp, 12.5mA with Thoraeus filter installed and SSD = 50 for an average dose rate of 1.075 cGy / min was used. 10-week-old wild type mice were irradiated with 693 cGy of X-ray radiation. 28 hours post-irradiation, mice were orally administered either vehicle or 1 mg / kg of FTY solution every day for five days, then every other day until 13 days post-irradiation. 36 days post irradiation, the resulting levels of achromotrichia in the mice administered vehicle 201 and the mice administered FTY 202 were photographed and are depicted in FIG. 2.

[0103] These results demonstrate that SIP receptor modulators (e.g., agonists, antagonists, and functional antagonists) can effectively prevent achromotrichia.Example 3. S1PR receptor modulator can mitigate achromotrichia caused by X-ray radiation exposure

[0104] Mice shown in FIG. 3 were exposed to 650 cGy total body X-ray irradiation with Thoraeus filter. Beginning 28h post-irradiation, mice were treated p.o. with either vehicle 2% hydroxypropyl-B-cyclodextrin or 1.0 mg / kg FTY (200ul / dose). Treatment continued every day for 5 days, then every other day until day 15 post-irradiation. Mice were sacrificed 320days after radiation. Mice treated with vehicle had substantial graying compared to mice treated with FTY.

[0105] These results demonstrate that SIP receptor modulators (e.g., agonists, antagonists, and functional antagonists) can effectively mitigate achromotrichia.Example 4. S1PR receptor modulator can mitigate DEARE bone marrow architecture damage caused by gamma irradiation exposure

[0106] Representative bone marrow immunofluorescence imaging of irradiated vehicle-versus FTY-treated animals were used to evaluate DEARE. Mice were exposed to 800 cGy total body gamma irradiation (y-IR). Beginning 72h post-irradiation, mice were treated p.o. with either vehicle 2% hydroxypropyl -B-cyclodextrin or 1.0 mg / kg FTY (200ul / dose).Treatment continued every other day until day 15 post-irradiation. Mice were sacrificed 6 months after irradiation and femurs collected, fixed in 4% PF A, and imbedded in OCT medium for cryosectioning and immunofluorescence. Shown in FIG. 4 are femurs from a control mouse (left panel), a mouse exposed to 800 cGy and treated with vehicle (middle panel) and a mouse exposed to 800 cGy and treated with FTY. Sections were stained with DAPI (nuclei, blue), VE Cadherin (blood vessels, red), and cKit (stem and progenitor cells, green).

[0107] These results demonstrate that SIP receptor modulators (e.g., agonists, antagonists, and functional antagonists) can effectively mitigate DEARE bone marrow architecture damage caused by radiation exposure (e.g., gamma irradiation exposure).

[0108] Example 5. SI PR receptor modulator can mitigate mortality caused by ionizing radiation exposure and. confer significant protection from ARS and D 4.RE

[0109] With reference to FIG. 5, mice were exposed to 7.5 Gy gamma radiation. 24h later, mice were started on a treatment regimen of 200 ul vehicle or 1 mg / kg FTY, administered every other day until day 14 post-IR. n == 6. Mice treated with FTY had higher survival rate post irradiation.

[0110] With reference to FIG. 6, mice were exposed to 6.5 or 7.15 Gy X-ray radiation. 28h later, mice were started on a treatment regimen of 200 ul vehicle or 1 mg / kg FTY, administered every other day until day 14 post-IR. Mice treated with FTY had significantly higher survival rate at early (ARS) and late (DEARE) time points post irradiation (left panel ). After 452 days, mice treated according to this FTY treatment regimen had more lymphocytes than mice administered vehicle (right panel), demonstrating prevention of DEARE.[OHl] These results demonstrate that SIP receptor modulators (e.g., agonists, antagonists, and functional antagonists) can mitigate mortality caused by ionizing radiation exposure and confer significant protection from ARS and DEARE.

[0112] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMSWhat is claimed is:

1. A method of treating or preventing achromotrichia, comprising administering to a subject in need thereof a therapeutically effective amount of an SIP receptor modulator.

2. The method of claim 1 wherein the SIP receptor modulator is fmgolimod.

3. A method of reducing the amount of achromotrichia, or reducing the development of achromotrichia in a subject, the method comprising administering a therapeutically effective amount of an SIP receptor modulator to the subject.

4. A method of reversing achromotrichia in a subject, the method comprising administering a therapeutically effective amount of an SIP receptor modulator to the subject.

5. A method of treating or preventing a radiation induced disease, disorder, or condition, comprising administering to a subject in need thereof a therapeutically effective amount of an SIP receptor modulator.

6. A method of mitigating a radiation induced disease, disorder, or condition, comprising administering to a subject in need thereof a therapeutically effective amount of an SIP receptor modulator.

7. A method of decreasing or preventing senescence, comprising administering to a subject in need thereof a therapeutically effective amount of an SIP receptor modulator.

8. The method of any one of claims 5-6, wherein the radiation induced disease, disorder, or condition is achromotrichia, acute radiation syndrome (ARS), nausea, vomiting, loss of appetite, skin conditions, bleeding, delayed effects of acute radiation exposure (DEARE), or gastrointestinal conditions.

9. The method of claim 7, wherein the senescence is induced by radiation.

10. The method of any one of claims 1-4, wherein achromotrichia is radiation-induced achromotrichia, stress-related achromotrichia, or age-related achromotrichia, or any combination thereof.

11. The method of any one of claims 1-4, wherein the achromotrichia is stress-related achromotrichia or age-related achromotrichia.

12. The method of any one of claims 1-4, wherein achromotrichia is radiation-induced achromotrichia.

13. The method of any one of claims 5-12, wherein the subject has been exposed to alphaparticle irradiation, beta-particle irradiation, gamma ray irradiation, X-ray irradiation, or positron irradiation.

14. The method of any one of claims 5-13, wherein the subject has been exposed to acute radiation.

15. The method of any one of claims 5-13, wherein the subject has been exposed to chronic radiation.

16. The method of any one of claims 5-15, wherein the subject has been exposed to a dose of radiation of at least about 0.1 cGy, at least about 0.5 cGy, at least about 1 cGy, at least about 5 cGy, at least about 10 cGy, at least about 30 cGy, at least about 50 cGy, at least about 100 cGy, at least about 200 cGy, at least about 300 cGy, at least about 500 cGy, at least about 600 cGy, at least about 650 cGy, at least about 700 cGy, at least about 750 cGy, at least about 800 cGy, at least about 850 cGy, at least about 900 cGy, at least about 1000 cGy, at least about 1500 cGy, at least about 2000 cGy, at least about 3000 cGy, at least about 4000 cGy, or at least about 5000 cGy.

17. The method of claim 16, wherein the subject has been exposed to a dose of acute onetime radiation of at least about 0.1 cGy, at least about 0.5 cGy, at least about 1 cGy, at least about 5 cGy, at least about 10 cGy, at least about 30 cGy, at least about 50 cGy, at least about 100 cGy, at least about 200 cGy, at least about 300 cGy, at least about 500 cGy, at least about 600 cGy, at least about 650 cGy, at least about 700 cGy, at least about 750 cGy, at least about 800 cGy, at least about 850 cGy, at least about 900 cGy, or at least about 1000 cGy.

18. The method of claim 15, wherein the subject has been exposed to a cumulative dose of chronic radiation of at least about 0.1 cGy per year, at least about 0.5 cGy per year, at least about 1 cGy per year, at least about 5 cGy per year, at least about 10 cGy per year, at least about 30 cGy per year, at least about 50 cGy per year, at least about 100 cGy per year, at least about 200 cGy per year, at least about 300 cGy per year, at least about 500 cGy per year, at least about 600 cGy per year, at least about 650 cGy per year, at least about 700 cGy per year, at least about 750 cGy per year, at least about 800 cGy per year, at least about 850 cGy per year, at least about 900 cGy per year, at least about 1000 cGy per year, at least about 1500 cGy per year, at least about 2000 cGy per year, at least about 3000 cGy per year, at least about 4000 cGy per year, or at least about 5000 cGy per year.

19. The method of any one of claims 1-18, wherein the SIP receptor modulator is administered immediately after exposure to radiation, about 30 min after exposure to radiation, about 1 hour after exposure to radiation, about 2 hours after exposure to radiation, about 3 hours after exposure to radiation, about 6 hours after exposure to radiation, about 10 hours after exposure to radiation, about 12 hours after exposure to radiation, about 18 hours after exposure to radiation, about 24 hours after exposure to radiation, about 36 hours afterexposure to radiation, about 48 hours after exposure to radiation, about 3 days after exposure to radiation, about 4 days after exposure to radiation, about 5 days after exposure to radiation, about 7 days after exposure to radiation, about 14 days after exposure to radiation, about 21 days after exposure to radiation, about 1 month after exposure to radiation, about 2 months after exposure to radiation, about 3 months after exposure to radiation, or about 6 months after exposure to radiation.

20. The method of claim 15, wherein the SIP receptor modulator is administered at a time while exposure to chronic radiation is ongoing.

21. The method of any one of claims 1-20, wherein the SIP receptor modulator is administered three times daily, twice daily, once daily, once every other day, once every 3 days, once every week, once every two weeks, once every month, once every two months, once every three months, once every six months, or once every year.

22. The method of any one of claims 13-21, wherein the SIP receptor modulator is administered in a dosing regimen which comprises a loading dose after exposure to radiation and a maintaining dose.

23. The method of any one of claims 1-22, wherein the SIP receptor modulator is administered for at least 5 days, at least 7 days, at least 10 days, at least 14 days, at least 1 month, at least 2 months, at least 3 months, at least 6 months, or at least 1 year.

24. The method of any one of claims 1-22, wherein the SIP receptor modulator is administered once daily for 5 days and then administered every other day for additional 10 days.

25. The method of any one of claims 1-24, wherein the SIP receptor modulator is administered orally.

26. The method of any one of claims 1-24, wherein the SIP receptor modulator is administered topically.

27. The method of any one of claims 1-24, wherein the SIP receptor modulator is administered subcutaneously.

28. The method of any one of claims 1-27, wherein the SIP receptor modulator is an S1P1 receptor modulator, an S1P2 receptor modulator, an S1P3 receptor modulator, an S1P4 receptor modulator, or an S1P5 receptor modulator or any combination thereof.

29. The method of any one of claims 1-27, wherein the SIP receptor modulator is an S1P1 receptor modulator.

30. The method of any one of claims 1-27, wherein the SIP receptor modulator is an S1P2 receptor modulator.

31. The method of any one of the claims 1 -27, wherein the S IP receptor modulator is an S1P3 receptor modulator.

32. The method of any one of the claims 1-27, wherein the SIP receptor modulator is an S1P4 receptor modulator.

33. The method of any one of the claims 1-27, wherein the SIP receptor modulator is an S1P5 receptor modulator.

34. The method of any one of claims 1-27, wherein the SIP receptor modulator is an S1P1 receptor modulator, an S1P3 receptor modulator, an S1P4 receptor modulator, and an S1P5 receptor modulator.

35. The method of any one of claims 1-34, wherein the S IP receptor modulator is fmgolimod, ozanimod, siponimod, ponesimod, or etrasimod or a salt, metabolite, prodiug, or a derivative thereof of any of the foregoing.

36. The method of any one of claims 1-34, wherein the SIP receptor modulator is fmgolimod, or a salt, a metabolite, a prodrug, or a derivative thereof.

37. The method of any one of claims 1-36, wherein the SIP receptor modulator is fmgolimod.

38. The method of any one of claims 1-36, wherein the SIP receptor modulator is fmgolimod hydrochloride.

39. The method of any one of claims 1-38, wherein the subject does not have multiple sclerosis or has not been diagnosed with multiple sclerosis.

40. The method of any one of claims 1-39, wherein the SIP receptor modulator is formulated as a pharmaceutical formulation.

41. The method of any one of claims 1-40, wherein the SIP receptor modulator is formulated as a solution.

42. The method of claim 41, wherein the solution is an aqueous solution.

43. The method of any one of claims 41-42, wherein the solution further comprises 2-hydroxypropyl-P-cyclodextrin.

44. The method of claim 43, wherein the solution comprises about 2% 2-hydroxypropyl-P-cyclodextrin.

45. The method of claims 41-42, wherein the solution further comprises a polyunsaturated fatty acid (PUFA).

46. The method of claim 45, wherein the solution comprises about 2% of PUFA.

47. The method of any one of claims 45-46, wherein the PUFA comprises corn oil.

48. The method of any one of claims 38-47, wherein fmgolimod hydrochloride is administered at a dose of about 0.05 mg to about 2 mg.

49. The method of any one of claims 38-47, wherein fmgolimod hydrochloride is administered at a dose of about 0.05 mg to about 1 mg.

50. The method of any one of claims 38-47, wherein fmgolimod hydrochloride is administered at a dose of about 0.05 mg to about 0.5 mg.

51. The method of any one of claims 38-47, wherein fmgolimod hydrochloride is administered at a dose of about 0.5 mg to about 1 mg.

52. The method of any one of claims 1-40, wherein the SIP receptor modulator is formulated as a topical formulation.

53. The method of claim 52, wherein the topical formulation is in a form of a foam, a cream, an ointment, or an emulsion.

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