Modulation of sphingosine 1-phosphate signaling in neurologic disease
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In this supplement to Neurology®, we discuss the role of sphingosine 1-phosphate (S1P) and its receptors in the pathophysiology of multiple sclerosis (MS), and how S1P receptor (S1PR) modulation is being used as an effective new therapeutic approach for the treatment of MS. Particular emphasis is given to fingolimod (FTY720), which leads this class of therapeutic compounds and has shown efficacy as a therapy for relapsing forms of MS. Fingolimod is the first orally administered MS-directed immunotherapeutic to receive US Food and Drug Administration (FDA) regulatory approval for use in clinical practice for relapsing MS. Fingolimod targets MS via actions in the immune system, and data from animal models suggest that it may also have direct effects in the CNS. The extensive preclinical and clinical trial data generated during the development program for fingolimod provide direction regarding its use in the postapproval phase, while raising opportunities and challenges regarding how its novel mechanism of action may impact the biological processes that underlie the recovery and progressive phases of MS. Additionally, information derived from the necessarily short-term in vitro and animal-based studies and from the relatively long-term extension-phase clinical programs (and the expected postmarketing-phase surveillance program) will permit the characterization of rare but potentially serious adverse events.
This supplement is designed to provide overviews that address different aspects of the biology of S1P, the effects of S1PR modulation and its therapeutic potential in MS, and the potential issues raised above regarding fingolimod. The mechanisms implicated in the development of the characteristic disease course of MS (relapse, recovery, and progression) and potential sites where fingolimod would interact with …
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