Wellstone Muscular Dystrophy Specialized Research Center (Seattle)

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Overall Summary/Abstract: The major theme of the Seattle Wellstone center is to improve therapeutic approaches to muscular dystrophies by identifying and overcoming the emerging new barriers to successful clinical trials in muscular dystrophies. The overall goal is to develop the reagents, measurements, clinical trials methods, and clinical trials infrastructures to speed the development of effective therapies for Duchene muscular dystrophy (DMD) and FSHD, and to bring muscular dystrophy clinical trials and therapies to the families of the Northwest. The specific aims and objectives are to breach the major barriers to successful therapeutic clinical trials in muscular dystrophies in the Northwest and nationwide. Aim 1 (Project 1) will conduct translational and pre-clinical studies of muscular dystrophy gene therapy. Studies in this aim will (a) improve the function of the micro-dystrophin gene, with a focus on cardiac muscle, and identify therapies that act to improve the functional benefit conferred by micro-dystrophin; (b) adapt these AAV-mediated delivery methods to achieve the suppression of human DUX4 in a preclinical mouse model of FSHD; and (c) establish a clinical trials readiness in Seattle for participation in AAV-mediated therapeutic trials in DMD. Aim 2 (Project 2) will enhance facioscapulohumeral dystrophy (FSHD) clinical trial foundations. The prior funding period established correlations between functional assessments, MRI characteristics, and molecular markers in FSHD. Studies in this aim will: (a) determine whether the correlation between candidate molecular biomarkers and MRI characteristics identified in the prior funding period predict functional progression; (b) determine whether the correlation and predictive value of the candidate molecular biomarkers and MRI characteristics identified in the first cohort can be validated in an independent cohort; and (c) determine the molecular phenotype of the infiltrating mononuclear cells in areas of inflammation and whether this represents an oligoclonal T-cell response. Aim 3 (Cores A, B, C) will administer, provide resources for scientific research, and train future muscular dystrophy scientific and clinical researchers. The Center cores (Administrative, Scientific Research Resource, and Training Cores) will provide support and oversight of all activities, provide necessary biological resources to achieve the goals of the Center and serve as a national resource, and provide training of the next generation of scientific and clinical researchers in muscular dystrophy. Together, these aims will achieve the overall goal to bring muscular dystrophy clinical trials and therapies to the families of the Northwest and the nation.