Multiple sclerosis (MS) is a slowly progressive CNS disease characterized by disseminated patches of demyelination in the brain and spinal cord and results in multiple and varied neurologic symptoms and signs, usually with remissions and exacerbations. MS affects more than 350,000 persons in the US. Around the world, northern Europe and the northern tier of the United States have the highest prevalence, with rates exceeding 30 cases per 100,000 population. Age at onset is typically 20 to 40 years old, and women are affected somewhat more often than men. About 25% of people with multiple sclerosis become wheelchair-bound, while more than 70% eventually have limited capacity. The MS market currently stands at about $2 billion in global pharma sales and in second only to Alzheimer’s disease with respect to market growth. Hence pharmaceutical interest in identifying an effective treatment of MS is considerable.

The cause of MS is unknown, but an immunologic abnormality is suspected. Active lesions contain large numbers of macrophages and patchy infiltrates of autoreactive T cells and antigen-nonspecific monocytes and macrophages. Viral antigens have been suggested to mimic myelin antigens thereby activating T cells to recognize host myelin. Th1 lymphocytes and their proinflammatory products (including IL-2, IFN-gamma, and TNFalpha), possibly activated by viral infection and host proteins containing homologous epitopes, seem to play a primary role in initiation and/or propagation of autoimmune diseases, including the inflammatory MS lesion. FTY-720 is an orally active immunosuppressant, under development by Mitsubishi Pharma for use in transplantation and autoimmune diseases. It reduces the number of lymphocytes in the blood by redirecting them to the lymph nodes. FTY-720 is currently in phase II evaluation in a cohort of kidney transplant patients and is expected to enter phase II trials this year with registration filing expected in 2005, with launch in 2006.

Japanese researchers have recently investigated the efficacy and mechanism of immunosuppression produced by FTY720 in the autoimmune encephalomyelitis (EAE) animal model of MS. FTY720 treatment almost completely protected against disease in this model. The protection by FTY720 was associated with a dramatic reduction in the number of lymphocytes staining for T-cell receptors in the spinal cord as examined by immunohistochemistry. The mRNA expression of Th1 cytokines interleukin (IL)-2, IL-6, and interferon-gamma in the spinal cord was also reduced dramatically as assessed by reverse-transcription polymerase chain reaction. Furthermore, lymphocytes isolated from the spleen of FTY720-treated rats reduced both disease incidence and clinical score in untreated animals with experimental MS. These results suggested that the protective anti-inflammatory effect of treatment with FTY720 was, to a large extent, due to the inhibition of encephalitogenic T-cell responses and/or their migration into the central nervous system and may be a potential candidate for use in treating patients with MS.

Entry date Monday, May 19, 2003

Adapted from Fujino et al, J Pharmacol Exp Ther 2003 Apr;305(1):70-7 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk