BACKGROUND OF THE INVENTION

Multiple sclerosis (MS) is a chronic and often debilitating disease affecting approximately 2.5 million people worldwide (Compston A & Coles A, 2002, Multiple sclerosis,Lancet359(9313):1221-1231). The hallmark pathological characteristic of MS is the formation of inflammatory plaques in the central nervous system. The plaques contain a number of immune cells which are believed to orchestrate the autoimmune-mediated destruction of the myelin sheath surrounding neuronal axons (Noseworthy J H, Lucchinetti C, Rodriguez M, and Weinshenker B G, 2000, Multiple sclerosis.N Engl J Med343(13):938-952). Demyelination leads to altered neuronal signal conduction and a myriad of adverse neurological symptoms.

Although the exact cause of MS is unknown, a number of genetic and environmental factors are thought to influence MS development (Ebers G C, 2008, Environmental factors and multiple sclerosis.Lancet Neurol7(3):268-277). Epidemiological studies have demonstrated that MS incidence typically follows a latitudinal gradient in both hemispheres. In the northern hemisphere, including Europe and North America, MS is more common in the northern regions, whereas in the southern hemisphere, including Australia MS is more prevalent in the southern regions (Ebers G C and Sadovnick A D, 1993, The geographic distribution of multiple sclerosis: a review.Neuroepidemiology12(1):1-5). This apparent correlation or “latitude gradient” has led to speculation that because sunlight exposure decreases with increased latitude, decreased sunlight exposure may be an underlying cause of the MS latitude gradient (Acheson E D, Bachrach C A, and Wright F M, 1960, Some comments on the relationship of the distribution of multiple sclerosis to latitude, solar radiation, and other variables.Acta Psychiatr Scand Suppl35(147):132-147). Findings that the average annual hours of sunlight exposure in an individual's place of birth is inversely correlated with MS development support this hypothesis (Acheson E D, Bachrach C A, and Wright F M, 1960, Some comments on the relationship of the distribution of multiple sclerosis to latitude, solar radiation, and other variables.Acta Psychiatr Scand Suppl35(147):132-147; and Sutherland J M, Tyrer J H, and Eadie M J, 1962, The prevalence of multiple sclerosis in Australia.Brain85:149-164). Furthermore, individuals with the highest residential and occupational solar exposure have the lowest rate of MS incidence (Freedman D M, Dosemeci M, and Alavanja M C, 2000, Mortality from multiple sclerosis and exposure to residential and occupational solar radiation: a case-control study based on death certificates.Occup Environ Med57(6):418-421). These results suggest that decreased sunlight exposure may be a significant environmental factor contributing to the development of MS.

The sun emits a wide range of electromagnetic radiation, including ultraviolet (UVR) (100-400 nm), visible (400-800 nm), and infrared (≥800 nm) radiation. Exposure to all radiation has profound impacts on human health. For instance, UVR can cause direct damage to DNA and is a leading cause of skin carcinomas. In addition to directly damaging DNA, UVR can induce carcinogenesis by suppressing the immune system (Fisher M S and Kripke M L, 1977, Systemic alteration induced in mice by ultraviolet light irradiation and its relationship to ultraviolet carcinogenesis.Proc Natl Acad Sci U S A74(4):1688-1692; and Kripke M L, 1974, Antigenicity of murine skin tumors induced by ultraviolet light.J Natl Cancer Inst53(5): 1333-1336).

UVR can also be absorbed by photoreceptors in human cells, resulting in the release of a number of secondary mediators capable of suppressing cell-mediated immunity through multiple mechanisms (Leitenberger J, Jacobe H T, and Cruz P D, Jr., 2007, Photoimmunology—illuminating the immune system through photobiology.Semin Immunopathol29(1):65-70). These mechanisms lead to both local and systemic immunosuppression, thereby eliminating natural defense mechanisms against aberrant cell growth.

Although UV-induced immunosuppression clearly has detrimental effects in the context of skin cancer, it may have beneficial effects on organ-specific autoimmune diseases such as MS (McMichael A J and Hall A J, 1997, Does immunosuppressive ultraviolet radiation explain the latitude gradient for multiple sclerosis?Epidemiology8(6):642-645). A recent study demonstrated that MS relapse rates are lower in the summer than in the winter, suggesting UV exposure may be a contributing factor in relapses (Tremlett H et al., 2008, Monthly ambient sunlight, infections and relapse rates in multiple sclerosis.Neuroepidemiology31(4):271-279). Furthermore, experiments conducted in the experimental autoimmune encephalomyelitis (EAE) animal model of MS have demonstrated that seven-day pretreatment with UVR prevents disease induction in SJL mice (Hauser S L et al., 1984, Prevention of experimental allergic encephalomyelitis (EAE) in the SJL/J mouse by whole body ultraviolet irradiation.J Immunol132(3):1276-1281). Our attempt to reproduce the preventative effect of irradiation discussed in the above-mentioned study demonstrated no protective effect (seeFIG. 1and the related description below). Thus, while avoiding UVR exposure may reduce the risk of various skin cancers, it could inadvertently increase the risk of developing autoimmune diseases such as MS.

UVR also modulates the immune response by stimulating the endogenous production of vitamin D in the skin. UVB wavelengths between 270 and 300 nm stimulate the production of pre-vitamin D3from the cholesterol derivative 7-dehydrocholesterol (Jones G, Strugnell S A, and DeLuca H F, 1998, Current understanding of the molecular actions of vitamin D.Physiological Reviews78(4):1193-1231). Pre-vitamin D3undergoes a spontaneous isomerization to produce vitamin D3. Vitamin D3undergoes two successive hydroxylation steps to form the active hormone 1α,25-dihydroxyvitamin D3(1,25(OH)2D3). The first activation step occurs in the liver, where vitamin D3is hydroxylated at carbon-25 to generate 25-hydroxyvitamin D3(25(OH)D3) (Blunt J W, DeLuca H F, and Schnoes H K, 1968, 25-hydroxycholecalciferol. A biologically active metabolite of vitamin D3. Biochemistry7(10):3317-3322). The 25(OH)D3metabolite is the primary circulating form of vitamin D3and is commonly used as a clinical indicator of vitamin D status (DeLuca H F, 2004, Overview of general physiologic features and functions of vitamin D.Am J Clin Nutr80(6 Suppl):1689S-1696S). The second activation step occurs in the kidney and involves the stereospecific hydroxylation of 25(OH)D3at carbon-1 to yield 1,25(OH)2D3(Holick M F, Schnoes H K, and DeLuca H F, 1971, Identification of 1,25-dihydroxycholecalciferol, a form of vitamin D3metabolically active in the intestine.Proc Natl Acad Sci USA68(4):803-804; and Fraser D R and Kodicek E, 1970, Unique biosynthesis by kidney of a biological active vitamin D metabolite.Nature228(5273):764-766). The classical biological function of 1,25(OH)2D3is to maintain sufficient serum calcium and phosphorus levels for proper mineralization of bone and calcium for neuromuscular function.

In addition to its role in regulating serum calcium levels, vitamin D may also be an environmental factor in MS and other autoimmune diseases (Hayes C E, Nashold F E, Spach K M, and Pedersen L B, 2003, The immunological functions of the vitamin D endocrine system.Cell Mol Biol(Noisy-le-grand) 49(2):277-300). The potential link between vitamin D deficit and MS was first proposed by David Goldberg, based on the geographic “latitude gradient” distribution patterns of MS and the relationship between UVR and vitamin D production (Goldberg P, 1974, Multiple Sclerosis: Vitamin D and calcium as environmental determinants of prevalence (a viewpoint). Part 1: Sunlight, dietary factors, and epidemiology.International Journal of Environmental Studies6:19-27). Goldberg postulated that decreased exposure to UVR and subsequent vitamin D insufficiency at higher latitudes pre-disposes individuals residing in these regions to developing MS.

Much of the evidence supporting this hypothesis is derived from epidemiological data demonstrating an association between UVR and MS prevalence and the assumption that the immunosuppressive effects of UVR are mediated through vitamin D production. However, UVR suppresses the immune system through mechanisms independent of vitamin D (Lucas R M and Ponsonby A L, 2006, Considering the potential benefits as well as adverse effects of sun exposure: can all the potential benefits be provided by oral vitamin D supplementation?Prog Biophys Mol Biol92(1):140-149). Therefore, this assumption may not be valid.

Additional evidence suggesting that vitamin D may play a role in MS stems from population-based studies which have correlated high serum 25(OH)D3levels with a decreased risk for developing MS (Munger K L, Levin L I, Hollis B W, Howard N S, and Ascherio A, 2006, Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis.Jama296(23):2832-2838). However, since 25(OH)D3levels largely reflect an individual's exposure to UVR, it is impossible to determine if the decreased risk is attributable specifically to vitamin D or UVR.

Perhaps the most compelling evidence supporting a role for vitamin D in MS is derived from studies conducted using the experimental autoimmune encephalomyelitis (EAE) model of MS. A number of in vivo studies have demonstrated that 1,25(OH)2D3can suppress disease induction and progression in the EAE model of MS (Lemire J M and Archer D C, 1991, 1,25-dihydroxyvitamin D3prevents the in vivo induction of murine experimental autoimmune encephalomyelitis.J Clin Invest87(3):1103-1107; Cantorna M T, Hayes C E, and DeLuca H F, 1996, 1,25-Dihydroxyvitamin D3reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis.Proc Natl Acad Sci USA93(15):7861-7864; and Nashold F E, Hoag K A, Goverman J, and Hayes C E, 2001, Rag-1-dependent cells are necessary for 1,25-dihydroxyvitamin D(3) prevention of experimental autoimmune encephalomyelitis.J Neuroimmunol119(1):16-29). However, complete disease suppression is only achieved using supraphysiological doses of 1,25(OH)2D3which cause vitamin D toxicity and hypercalcemia (Cantorna M T, Humpal-Winter J, and DeLuca H F, 1999, Dietary calcium is a major factor in 1,25-dihydroxycholecalciferol suppression of experimental autoimmune encephalomyelitis in mice.Journal of Nutrition129(11):1966-1971). Vitamin D toxicity and hypercalcemia do not typically occur upon exposure to sunlight due to a number of factors that limit the endogenous production of vitamin D. These factors include the photochemical conversion of previtamin D3into biologically inert compounds, skin pigmentation, and latitude (Holick M F, MacLaughlin J A, and Doppelt S H, 1981, Regulation of cutaneous previtamin D3photosynthesis in man: skin pigment is not an essential regulator.Science211(4482):590-593). Thus, the levels of 1,25(OH)2D3required to suppress MS are well above those that can be produced naturally upon exposure to sunlight. Furthermore, results from our laboratory suggest that hypercalcemia may be more than simply an unfortunate consequence of 1,25(OH)2D3treatment, and may play an essential role in the immunosuppressive effects of 1,25(OH)2D3(Meehan T F, Vanhooke J, Prahl J, and Deluca H F, 2005, Hypercalcemia produced by parathyroid hormone suppresses experimental autoimmune encephalomyelitis in female but not male mice.Arch Biochem Biophys442(2):214-221).

Considering the undesired effects that large doses of vitamin D, which are associated with reduction of clinical parameters of MS, there exists a need for a methodology for suppressing symptoms of MS without the dangerous and unpleasant side effects associated with 1,25(OH)2D3treatment.

SUMMARY OF THE INVENTION

Embodiments of the invention address methods and apparatus for treating and preventing MS that encompass irradiating the subject with a first dose of light from a light source and detecting a suppression of the clinical symptoms in the subject. According to the embodiments, irradiation is generally characterized by a chosen dose of radiation and repetition time intervals, and, in a specific embodiment, may be continuous. In one embodiment, irradiating a subject with light, preferably UV light, is adapted to be unassociated with permanently elevated levels of vitamin D and independent from production of vitamin D in the irradiated subject.

In one embodiment, the present invention comprises a method of suppressing clinical symptoms of multiple sclerosis comprising irradiating the subject with a first dose of light from a light source and detecting a suppression of the clinical symptoms in this subject. The irradiation may either be with repeated doses or a continuous dose.

One embodiment of the present invention provides a method for suppressing clinical symptoms of MS in a subject having a reference level of serum calcium and a reference level of a serum 25(OH)D3. Such method includes irradiating the subject with such a first dose of light from a light source that is adapted to cause a change of a serum 25(OH)D3level in the subject from the reference level of a serum 25(OH)D3to a first level that is lower than a threshold level associated with suppression of the clinical symptoms. In addition, such method may include repeatedly irradiating the subject at repetition time intervals with a second dose of light from the light source. Here, the second dose and repetition time intervals are judiciously chosen as to maintain a serum 25(OH)D3level below the threshold level. Repeatedly irradiating the subject may require, in one implementation, irradiating with the second dose for at least 10 minutes every 24 hours for seven days. Furthermore, the embodiment includes detecting a suppression of the clinical symptoms that is independent of a vitamin D production in the subject. These repeated doses may be, part of a continuous dose.

In one specific embodiment, the first dose may be further adapted to maintain the level of serum calcium within 0.5 mg/dL with respect to the reference level of serum calcium, while the second dose and repetition time intervals may be further adapted to cause variation of a serum 25(OH)D3level by no more than 5 ng/mL. In another specific embodiment, each of the first and second doses of light is associated with UV irradiance of at least 2.5 kJ/m2and, alternatively or in addition, with UVB irradiance of at least 2.5 kJ/m2.

The suppression of clinical symptoms of MS, according to one embodiment, includes at least one of a decrease of the cumulative disease index (CDI), a delay of onset of MS symptoms, and a reduction of peak of severity of MS symptoms, and, in particular, delay or reduction in the appearance of plaques or lesions.

Without the loss of generality, each of the embodiments of the method of the invention may further include identifying the subject with the use of pre-defined diagnostic criteria.

Embodiments of the invention further provide a computer program product for use on a computer system for irradiating a subject, having a reference level of serum calcium and a reference level of a serum 25(OH)D3, with light from a light source and detecting changes in at least one of a level of serum calcium and a level of a serum 25(OH)D3, where the computer program product includes a computer usable tangible medium having computer readable program code thereon, and where the computer readable program code includes at least a) program code for irradiating the subject with a first dose of light from a light source, the first dose being adapted to cause a change of a serum 25(OH)D3level from the reference level of a serum 25(OH)D3to a first level that is lower than a threshold level associated with suppression of the clinical parameters; and b) program code for repeatedly irradiating the subject, oriented with respect to a light source, at repetition time intervals with a second dose of light from the light source, the second dose and repetition time intervals being such as to maintain a serum 25(OH)D3level below the threshold level.

In one embodiment, the program code for irradiating the subject with a first dose includes program code for administering the first dose adapted to maintain the level of serum calcium within 0.5 mg/dL with respect to the reference level of serum calcium. In addition or alternatively, the program code for repeatedly irradiating the subject includes program code for defining such second dose and repetition time intervals as to not cause variation of a serum 25(OH)D3level in excess of 5 ng/mL.

Embodiments of the invention additionally provide a computer program product for use on a computer system for irradiating a subject having MS with light from a light source, where the computer program product includes a computer usable tangible medium having computer readable program code thereon, which, when loaded into the computer system, establishes an apparatus, implemented in the computer system, the apparatus comprising at least an input for receiving a set of energy data characterizing exposure to light prescribed to the subject and a processor that operates to determine at least one of components of the light source and location of said components based on the received set of energy data. In addition, in one embodiment, the apparatus may include an output, in which appears a display of results of the prescribed exposure of the subject to light.

