Exploring systemic AAV gene delivery in the dystrophic dog

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DESCRIPTION (provided by applicant): Abstract Duchenne muscular dystrophy (DMD) is the most prevalent lethal childhood genetic disease. It is caused by dystrophin gene mutation. Numerous progresses have been made in the last decade in developing DMD gene therapy. Impressive whole body rescue has been reported in DMD mouse models with adeno-associated virus (AAV)-mediated micro-dystrophin gene therapy. An important next step prior to human trial is to demonstrate the therapeutic efficacy of the micro-dystrophin gene in canine DMD models. Canine muscle has been notoriously difficult to transduce because of the strong cellular immune response. Furthermore, DMD affects nearly every muscle in the body. Only systemic gene transfer can truly ameliorate the disease. We recently developed an efficient whole body muscle transduction protocol in normal neonatal dogs. This is the first demonstration that systemic AAV delivery can reach multiple muscles in a large animal. To advance DMD gene therapy studies, we have recently established a Corgi dog model for DMD. The affected dogs share the same dystrophin gene mutation and display the same clinical phenotype as human patients. In this translational R21 project, we will apply these exciting findings to the therapeutic canine R4-23/C microgene. We will perform systemic AAV delivery in neonatal dystrophic Corgi dogs. The primary goal is to achieve wide spread muscle transduction. We will also perform preliminary efficacy evaluation using a comprehensive set of histopathology endpoints. Our study will set up a foundation to thoroughly evaluate AAV micro-dystrophin gene therapy in dog models in the future. PUBLIC HEALTH RELEVANCE: Project Narrative Duchenne muscular dystrophy (DMD) is caused by dystrophin gene mutation. Currently, there is no cure. Adeno-associated virus-mediated gene therapy has shown a great promise to ameliorate this disease. In this study we will develop novel techniques to achieve whole body gene transfer in newborn DMD dogs. The majority of DMD patients can be diagnosed through neonatal screening. Our study will open the door for neonatal gene therapy in human patients in the future.