The CNS as a therapeutic target in multiple sclerosis

Abstract

Introduction All of the agents currently approved as therapies for multiple sclerosis (MS) are considered to act directly on the constituents of the systemic immune system and/or their capacity to cross the blood–brain barrier (BBB) and reach the central nervous system (CNS). Such treatments have proven effective in reducing the frequency and severity of disease relapses. Emergent systemic immunotherapies are even more effective but carry an enhanced risk of immunodefi ciencyrelated complications, and little evidence exists that they enhance recovery from relapses. When instituted early in the disease course, the current agents, interferon-β and glatiramer acetate, are suggested to reduce long-term disability. Long-term disability likely refl ects the combined cumulative effects of relapse-related tissue injury and actual disease progression. Both of these agents and therapeutic protocols that completely ablate the systemic immune system have proven ineffective for patients in the secondary progressive phase of disease in the absence of intercurrent relapses. This clinical experience indicates that further progress in developing therapies for the full spectrum of MS will require greater understanding of events occurring within the CNS, including the actual mechanisms underlying tissue injury associated with acute infl ammatory lesions, recovery from relapses, and the later disease progression occurring in absence of new lesion formation. All are as yet untapped therapeutic targets. A related issue is to ensure that agents that are effective as systemic immunomodulators do not have a negative impact on the CNS.