Muscle-specific AAV Vectors for DMD Gene Therapy

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DESCRIPTION (provided by applicant): Duchenne Muscular Dystrophy (DMD), which affects one in 3500 males, causes progressive myopathy of skeletal and cardiac muscles and premature death due to a lack of expression of the protein dystrophin in muscle tissues. Genetic replacement of defective protein with a functional, miniaturized form of dystrophin represents a promising approach for the treatment of DMD. The aforementioned minidystrophin transgene is currently being evaluated in human clinical trials using AAV vectors as agents for intramuscular delivery. The current exploratory/developmental research proposal is focused on the design and development of novel AAV vectors with enhanced gene delivery efficiency in dystrophic skeletal muscle using the mdx mouse model. Rationale for the exploratory phase of the translational research hinges on the overexpression of integrin a7¿1 in dystrophic muscle and our seminal finding that modulation of a putative integrin-binding domain on AAV2 capsids affects their ability to transduce normal skeletal muscle. We have formulated specific design strategies based on the aforementioned finding that include: (a) rational engineering of the integrin-binding domain to develop integrin a7¿1-targeted AAV vectors that transduce dystrophic muscle with high efficiency and (b) combinatorial engineering of AAV vectors that efficiently transduce dystrophic muscle in mdx mice. During the developmental phase, novel AAV vectors selected through this process will be utilized to deliver an enhanced minidystrophin transgene for therapeutic application in the mdx mouse model. Research design involves rational insertion peptide ligands to generate integrin a7¿1-targeted AAV vectors, directed evolution of dystrophic muscle-specific vectors obtained from an AAV mutant library administered into mdx mice through different routes of administration, and therapeutic application of an enhanced mini-dystrophin transgene construct in the mdx mouse model. The novel reagents developed and optimized in this proposal will be advanced for further therapeutic testing in larger animal models of muscular dystrophy and eventually in human muscular dystrophy clinical trials in the near future. Duchenne Muscular Dystrophy (DMD), which affects one in 3500 males, causes progressive myopathy of skeletal and cardiac muscles and premature death due to a lack of expression of the protein dystrophin in muscle tissues. The current exploratory/developmental research proposal is focused on the design and development of novel AAV vectors with enhanced gene delivery efficiency in dystrophic skeletal muscle using the mdx mouse model. The novel reagents developed and optimized in this proposal will be advanced for further therapeutic testing in larger animal models of muscular dystrophy and eventually in human clinical trials in the near future.