Duchenne muscular dystrophy (DMD) is the most common, disabling and lethal genetic muscle disorder, afflicting one of every 3,500 males. No effective treatment is currently available for DMD. The long term goal of this proposal is to develop a gene therapy strategy for DMD. We plan to investigate the gene therapy strategies in golden retriever muscular dystrophy (GRMD) dogs, the best characterized large animal model of DMD, in collaboration with Dr. Kornegay at the University of Missouri. Unlike the mdx mice that show milder symptoms, the GRMD dogs display remarkable clinical and pathological similarities to the human DMD patients. GRMD is conceived as a clinically more relevant DMD model in terms of both pathology and the size of the animal. We plan to use adeno-associated virus (AAV), a highly efficient vector for muscle gene therapy, to deliver the mini-dystrophin genes into the muscles of GRMD dogs to study the therapeutic effects as well as the immunological issues. We have the following specific Aims: 1) to study gene delivery efficiency and immune responses with reporter AAV vectors in normal and GRMD dogs; 2) to clone dog dystrophin cDNA and generate dog versions of mini-dystrophin genes; 3) to produce and purify large quantity of AAV vectors under the GLP conditions; 4) to perform local injection of the AAV mini-dystrophin vectors into various leg muscle tissues and examine the biochemical and histological effects; 5) to perform systemic delivery of the AAV vectors in large groups of muscles by different routes. If gene expression and immune outcomes are favorable, muscle contractile functions will also be examined by the non-invasive force transducer method developed and performed by the Large Animal Core.
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