The goal of this combined Phase I/II SBIR project is to accomplish key milestones in commercializing aprotein therapeutic for Becker muscular dystrophy (BMD) that will enhance the repair capacity of muscle cellsarcolemmal membranes compromised by mutations in the dystrophin gene that reduce the expression levelor function of the dystrophin protein. Many mutations in the dystrophin gene result can in BMD while othersresult in the more severe Duchenne muscular dystrophy (DMD). Myos Inc. is developing a novel recombinantconstruct of the tripartite protein 72/mitsugumin 53 (TRIM72/MG53), an essential regulator of membrane repairin skeletal and cardiac muscle. It is known that rhMG53 therapy ameliorates disease pathology in a dystrophindeficient mouse model and models of other muscular dystrophies, strongly suggesting that it may enhancerepair and restoration of muscle function in BMD. However, recent potential toxicity concerns make the originalrhMG53 protein sequence suboptimal for protein therapy. Therefore, we engineered a new version of therhMG53 protein for use in treating BMD by optimizing its functional and biochemical properties. This Phase I/IIproject will further develop this novel protein by producing the data necessary to support an investigational newdrug (IND) application to the U.S. Food and Drug Administration (FDA) through three specific aims. Aim 1 willdevelop Chemistry, Manufacturing, and Control (CMC) protocols for production of this protein. Optimization ofprotein production from Chinese Hamster Ovary (CHO) cell cultures will be conducted at a CMO focused onprotein production in CHO cells. We will also conduct stability testing up to 24 months for the protein as part ofthe studies in this aim. The deliverables will be a scale-up protocol for production of this protein and generationof protein for aims 2 and 3. Aim 2 will complete a pre-clinical trial for the efficacy of this protein in treating amouse model of BMD. This aim will involve a preclinical efficacy trial for three doses of the protein in a mousemodel of BMD. Randomized cohorts of BMD mice will be treated with for 8-45 weeks and changes in thedystrophy phenotype will be determined through various measurements of skeletal and cardiac musclestructure and function. The deliverable for this aim will be to resolve if the protein can effectively treat a rodentmodel of BMD. Aim 3 will conduct immunogenicity and toxicity studies for protein in mice. This assessment willinvolve toxicity studies, including repeated-dose studies, toxicokinetic assessment, metabolic studies andimmunogenicity assessment, in BALB/c mice. These studies will be conducted at Myos and a CRO with a longhistory of conducting such studies. The deliverable here will be completing these studies so the data can beused to guide regulatory filings. Successful completion of this project will result in sufficient data to prepare anIND application to the FDA for use in clinical trials for the treatment of BMD.
Public Health Relevance Statement: PROJECT NARRATIVE
Muscular dystrophies are severe genetic disorders involving progressive muscle wasting that leads to
compromised muscle structure, decreased muscle function, loss of independence and eventual death. Becker
muscular dystrophy (BMD) is a common lethal genetic disease that represents a truly unmet medical need, as
there is currently no cure for any form of muscular dystrophy. Our commercialization effort proposed in this
project will generate proof-of-principle data and other data to prepare a new protein therapeutic product for future
clinical trials for the treatment of BMD in patients without other impactful treatment options for this lethal disease.
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