Translational program for molecular therapeutics in DMD

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DESCRIPTION (provided by applicant): Duchenne muscular dystrophy is one of the most common lethal genetic diseases in man. Progress in our understanding of the molecular basis of the disease has been paralleled by technological developments in the field of molecular therapy. Engineered versions of dystrophin, the DMD gene product, and its autosomal homologue utrophin have been shown to protect against muscle degeneration in mouse models for DMD. The laboratory of the project P.I. has developed a highly efficient and safe modality for limb-wide gene transfer in the dog. Studies in non-dystrophic dogs have revealed a transduction efficiency approaching 100% of the muscle fibers in the dog limb, while studies using self-transgenes in the context of AAV provide evidence of long-term stability. To address a series of critical steps in the translational process, we will harness the combined power of AAV vector and vascular delivery technology to achieve widespread genetic complementation of dystrophin deficiency in a large animal model for DMD. We will use objective measures of efficacy and toxicity to analyze an optimized vector in the context of a preferred infusion approach, thereby informing the rational design of clinical studies. The central thrust of the proposed experimental plan is technology development relevant to Duchenne muscular dystrophy, with the expectation of indirect relevance for a wider range of genetic disorders, including but not limited to other forms of muscular dystrophy. As such the proposal mandates a cooperative, reiterative process with exchange of ideas and reagents between basic scientists, clinical scientists, statisticians, and collaborators with extensive experience in industry. Questions addressed include: What is the appropriate starting dose of vector for clinical investigation? What is the therapeutic window relative to the stage of the degenerative process? Can the vector be safely and effectively readministered? What are appropriate expectations for therapeutic benefit following scale-up? Are any unforeseen risks are identified during the translational process? The proposal is structured to meet the needs of the technology development process, and the experimental plan is centered around the achievement of well-defined milestones, culminating if appropriate in the submission of an investigational new drug application to the FDA.