Benjamin M Blumberg
In recent years, two outstandingly effective drugs for the treatment of multiple sclerosis (MS) have appeared on the market: Tysabri® (Biogen Idec/Elan, 2008) and Gilenya® (Novartis, 2010). Tysabri (Natalizumab) is a humanized monoclonal antibody that binds to the cellular adhesion molecule alpha-4 integrin, which is used by lymphocytes to cross vascular walls and penetrate the blood-brain barrier. Tysabri thus reduces the flux of infected or autoimmune lymphocytes into the CNS. Gilenya (Fingolimod) is an immunomodulatory drug that acts on the sphingosine-1-phosphate receptor to sequester lymphocytes in peripheral lymph nodes, thus also indirectly reducing the flux of infected or autoimmune lymphocytes into the CNS. Both drugs have great clinical promise for treating MS, but both have revealed a critical shortcoming: their use increases the risk of Progressive Multifocal Leucoencephalopathy (PML), a demyelinating disease worse than MS and quickly fatal if not controlled. PML arises in individuals whose immune function is compromised, such as patients undergoing chemotherapy for various kinds of cancer. During the early years of the AIDS epidemic (approximately from 1986-1999), the incidence of PML rose in parallel with increasing numbers of immunocompromised AIDS patients, then fell after effective combined aggressive retrovirus treatment (cART) for HIV-1/AIDS became widely available (after 2000-2001). Unfortunately, the incidence of PML is now rising again in conjunction with the increased use of Tysabri and Gilenya in treating MS. It is therefore important to identify effective treatment modalities for PML.
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