The Models Core (Core C) will provide four essential support elements for Projects 1 and 2. First, the Models Core will be responsible for breeding and maintaining mdx mice for experiments described in both projects 1 and 2. The mdx mouse model for Duchenne muscular dystrophy is essential for verifying gene therapeutic efficacy as proposed in this U54 application. Second, the Models Core will provide all physiological assessments of gene function in the mdx mouse. These consist offeree and eccentric contraction measurements of the extensor digitorum longus muscle. These measures are known to be impaired in this FDA accepted animal model for DMD, and thus will provide important criteria for each Project to demonstrate a physiologically significant clinical measure of improvement in muscle function. Such validation is critical for demonstrating efficacy. Third, the core will be responsible for the housing and care of rhesus macaque monkeys for experiments described in both projects. Non-human primate animals are essential to evaluate the immunology, distribution, and efficacy in a larger animal species for review by the FDA. Fourth, the Core will perform and optimize regional vascular delivery protocols, in both the mdx mouse and rhesus macaque, to deliver human micro-dystrophin and CT GAINAc transferase via rAAVSmediated gene delivery to the muscles of the lower limb via the femoral artery. The skills involved in this delivery system are best acquired by repeated performance. Providing this technique in the Core is essential to achieve uniformity for both projects, and is essential for consistent distribution of transgenes within the targeted muscle (gastrocnemius).
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