Targeted Therapies for Myasthenia Gravis

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DESCRIPTION (provided by applicant): Myasthenia gravis (MG) is an antibody-mediated autoimmune disorder, which compromises neuromuscular junction function. The disease may involve skeletal muscle diffusely producing life-threatening weakness, but also produce ocular muscle dysfunction leading to significant visual disability. The final effector mechanism of the myasthenia gravis is the formation of the membrane attack complex of complement at the neuromuscular junction. Complement regulatory proteins normally serve an important role as negative regulators of complement activation. Our preliminary studies and the established disease mechanism strongly support the strategy of enhancing the negative regulation of complement formation as a therapy for myasthenia. This study weaves together the strengths of established investigators in the fields of complement, extraocular muscle biology and physiology, myasthenia gravis pathophysiology, and drug development in order to produce complement inhibitor therapies to target the neuromuscular junction pathology of myasthenia gravis. The investigators propose to achieve this therapeutic goal by first evaluating the complement-mediate pathogenesis at three levels: (a) a global analysis of operative events and mechanisms using genome-wide profiling with DNA microarray, (b) specific measures of complement regulatory transcripts and proteins, and (c) structural/functional measures of skeletal muscle and ocular muscle performance in animal models of experimental autoimmune myasthenia gravis (EAMG) and human MG. The most effective stage of the complement cascade is determined for drug development using transgenic animal models. Our group already has developed complement inhibitors, and additional agents to target the neuromuscular junction will be developed. These will be tested for efficacy and tolerability for use in future clinical trials. The goal of the therapy is to provide a drug, which will moderate the severity of acute myasthenic deteriorations and chronically serve as an adjuvant to limit use of immunosuppressants with poor side effect profiles. Because of the ocular muscles' sensitivity to the low-grade autoimmune process of ocular myasthenia, the complement Inhibitor-based therapy developed should be particularly effective for treatment of visual dysfunction.