Complement-based Therapeutics in Demyelinating Disease

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DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is the most common autoimmune demyelinating disease, affecting millions of individuals worldwide. In the last two decades, therapeutic options for the treatment of MS have become available, however they are limited in terms of effectiveness and safety issues have plagued others (Tysabri, anti- VLA-4 antibody). The currently available treatment options target relapsing remitting forms of MS and are not effective in the more progressive forms of the disease. These limitations highlight a significant unmet treatment need for MS. It is well established that the complement system, a major component of the innate immune response, contributes to the development and progression of demyelinating disease, based on clinical pathology and studies using experimental autoimmune encephalomyelitis (EAE), the animal model for MS. Furthermore, immunohistochemical studies analyzing postmortem MS lesions have demonstrated the deposition of numerous complement activation fragments in both active and chronic active MS lesions, and implicated complement in so- called Type II MS. In EAE studies from our laboratory, we have shown, using a number of complement mutant and transgenic mice, that inhibition of the alternative complement pathway and the C3 convertase confers significant protection from disease. Our preliminary studies demonstrate significant attenuation of EAE severity on treatment with anti-factor B antibody (an inhibitor of the alternative pathway or CR2-Crry (a recombinantly engineered C3 convertase inhibitor. Together these data indicate that inhibition of complement may be a viable therapeutic option in MS, however several important questions remain, particularly with respect to treatment of ongoing disease. We hypothesize that inhibition of complement early in activation by multiple mechanisms represents a viable therapeutic approach in demyelinating disease, independent of the mouse strain and disease-inducing myelin antigen. To address this hypothesis, we propose the following specific aims: 1) determine the effectiveness of alternative pathway (anti-factor B antibody) versus C3 convertase (CR2-Crry) inhibitors after disease development and, 2) determine if complement inhibition is effective in attenuating EAE development regardless of the disease inducing myelin-derived antigen. If successful, these studies will set the stage for pre-clinical translational efforts. PUBLIC HEALTH RELEVANCE: The utility of complement therapeutics in demyelinating disease remains poorly explored. Studies in this application are designed to examine the role of C3 convertase and factor B inhibitors in reducing established disease in experimental autoimmune encephalomyelitis, the animal model for multiple sclerosis.