DESCRIPTION (provided by applicant): This Wellstone application is focused on preclinical and clinical studies of Duchenne muscular dystrophy (DMD) and facioscapulohumeral muscular dystrophy (FSHD), the two most common forms of dystrophy. This is a collaborative venture between scientists and clinicians at the University of Washington, Fred Hutchinson Cancer Research Center, Seattle Children's Hospital and The University of Rochester. Project 1 focuses on adapting methods for AAV-mediated gene transfer to large animal models for DMD by focusing on expression cassette design, AAV serotypes, physical delivery methods and scale-up to test the hypothesis that AAV vectors expressing microdystrophin can be used to treat all the major muscle groups involved in DMD. In parallel, we will adapt AAV systems for targeting the dominant disorder FSHD by delivering RNAi cassettes to cell lines and mouse models followed by safety testing in dogs. Thus, we are performing preclinical studies to develop clinical trials for dominant and recessively inherited dystrophies by modeling DMD and FSHD. This latter work provides a link to project 2, which will leverage the collaborative research programs on FSHD in Seattle and Rochester for studies of advanced biomarker assessments of disease, and to explore immune mediated events in FSHD. The clinical infrastructure to be developed in Project 2 will lay a foundation for future clinical trials of gen therapy for DMD, FSHD and other MDs at the University of Washington. These studies will be supported by three Cores. An Administrative Core to facilitate communication and coordination between the components of the Center and for overseeing data management and distribution. A Scientific Research Resource Core to provide stocks of AAV and lentiviral vectors to members of the Center and to muscular dystrophy researchers worldwide. This Core will also provide training, consulting and reagents related to muscular dystrophy research and gene transfer. Lastly, an Investigator Development and Patient Outreach Core (IDPO) for a mentored research program in basic and clinical research, and ethics that will prepare new investigators to address the critical needs of individuals with dystrophy. The IDPO will also provide outreach programs to the public and patient communities.

PUBLIC HEALTH RELEVANCE: This is a highly collaborative project between basic scientists, translational researchers and clinicians to advance the development of therapeutics for the two most common forms of muscular dystrophy: DMD, & FSHD. The studies will advance basic and clinical research while facilitating training, collaboration and outreach activities that will advace the overall goal of developing therapies. Pre-clinical studies will be a focus, as will clinical studies of FSHD that will lead to future gene therapy and other clinical studies of MD.