Dystrophin Restoration

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Currently, proof-of-principle studies have established that gene replacement therapy represents a promising means of treatment for Duchenne muscular dystrophy (DMD). We have moved forward in a clinical phase I safety gene therapy trial for this disease by intramuscular delivery of an rAAV mini-dystrophin gene. It is acknowledged throughout the field that vascular delivery, reaching many muscle groups, is our best hope for improving patient function. In preliminary discussions with the FDA in preparation for this U54, we were encouraged to move forward with gene delivery through the circulation, being mindful of potential safety concerns. Our current project takes these considerations into account. We have found in preliminary studies that rAAVS can deliver micro-dystrophin efficiently to muscle in the mdx mouse. Further, we have data that predicts that this AAV serotype can cross species lines with delivery of a transgene to a large animal species. This sets the stage for our current proposal, integrating safety and efficacy concerns of vascular delivery. Our plan to bring this to IND and a phase I safety trial for vascular delivery is as follows: The first goal for this project (AIM1) is to establish that the micro-dystrophin transgene that we designed (based on the best information from the literature) can functionally improve dystrophic muscle. For our current IND we used an isolated muscle in the mdx mouse to prove functional efficacy and we will follow this example in this proposal. For our second goal (AIM 2) we will deliver the rAAVS.micro-dystrophin to the rhesus macaque. There have been many issues raised regarding the immunogenicity of both AAV and the cargo it carries. The rhesus macaque permits us to address all of these issues in an environment that closely simulates a clinical trial. Two concerns are at hand, safe passage of virus to achieve transduction and safety to the patient avoiding undesirable spread of virus. Thus, we will deliver our viral construct through a balloon catheter placed in the femoral artery. We will also test appropriateness of immunosuppression regimens for gene delivery using some monkeys with pre-existing immunity to AAV and others naTve to the virus. In the final AIM 3, we will do the toxicology/biodistribution studies in accordance with our discussions with FDA. The information derived from this project will permit us to submit an IND for a phase I safety trial in DMD boys.