Translational development of recombinant protein therapeutic for LGMD2B

PROJECT ABSTRACT This Phase I STTR project will accomplish key milestones in commercializing a protein therapeutic for dysferlinopathies that will enhance the repair capacity of muscle cell membranes compromised by mutations in the dysferlin gene. The dysferlinopathies include Limb Girdle Muscular Dystrophy Type 2B (LGMD2B), Miyoshi Myopathy (MMD1) and other, rarer myopathies that all present as adult-onset debilitating muscle diseases characterized by extensive muscle damage and progressive weakness. All these myopathies arise from mutations in the gene encoding an essential muscle membrane repair protein, dysferlin. Progress in treatment of dysferlinopathies has been hampered by the large size of the protein, which complicates gene therapy approaches, and the complex function of the native dysferlin protein. Myos proposes to develop a treatment for dysferlinopathies through protein supplementation therapy using a key binding partner of dysferlin, the tripartite motif protein 72/mitsugumin 53 protein (MG53). MG53 is an essential regulator of membrane repair in skeletal and cardiac muscle that binds dysferlin and can compensate for the loss of dysferlin in membrane repair. To provide protein supplementation therapy for dysferlinopathies, we will use recombinant human MG53 (rhMG53) protein. rhMG53 binds membrane damage sites to enhance membrane repair capacity in cultured cells and dystrophic animal models when applied outside the cell. Based on these studies, Myos seeks to develop MyoTRIM, novel engineered version of rhMG53, to treat dysferlinopathy. MyoTRIM is designed to enhance repair and restore the compromised membrane repair in dysferlinopathy muscle, providing a complementary treatment approach to other dysferlinopathy therapies in development. The objective of this project is to develop Chemistry, Manufacturing, and Control (CMC) methods to produce MyoTRIM,protein and to test whether MyoTRIM can rescue pathology in a dysferlinopathy mouse model using two specific aims. Aim 1 will develop initial CMC procedures for MyoTRIM. Aim 2 will complete pre-clinical trial for MyoTRIM efficacy in the Bla/J mouse model of dysferlinopathy. Successful completion of this Phase I project will advance the commercialization MyoTRIM and provide a significant impact on public health by improving muscle membrane repair to treat muscular dystrophies, independent of gene or mutation. MyoTRIM will provide a platform technology to target other diseases involving necrotic cell death. 1