The goal of this proposal is to design, test, and produce a recombinant adeno-associated viral (AAV) vector carrying a functional mini-dystrophin gene which will be extensively studied in vivo for therapeutic efficacy as well as long-term safety in animal models. The clinical grade vector will be produced in the final year for a Phase I gene therapy safety trial for Duchenne muscular dystrophy (DMD). This proposal is highly integrated, involving scientists in both basic research and clinical studies, with the objective of generating an optimized AAV vector in five years for a Phase I safety trial in DMD patients. The design, test and production of the gene vectors and the pre-clinical safety studies, as required by FDA, will be carried out at the University of Pittsburgh in collaboration with other institutions. A parallel study that is equally important for the success of the clinical trial, but through a different funding mechanism outside this proposal, will be conducted by a team led by Dr. Jerry R. Mendell at the Ohio State University, where a DMD patient cohort will be characterized at the pathological, immunological and molecular levels for future recruitment. To successfully execute this challenging translational research project, we plan to accomplish five Specific Aims. The first three Aims will be devoted to optimization of mini-dystrophin genes, selection of a small but strong muscle-specific promoter, and the investigation of gene delivery methods. The last two Aims will concentrate on preclinical vector toxicology study and clinical grade AAV vector production under the GMP conditions. The success of this grant will lead to the IND filing and RAC submission of the DMD gene therapy protocol.
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