Senator Paul D. 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 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) identify optimized AAV variants for skeletal and cardiac muscle, modify micro-dystrophin sequences to diminish immunogenicity and increase function, and test split intein vector strategies for delivering more potent dystrophin constructs to skeletal and cardiac muscle; (b) will apply parallel AAV-mediated methods to achieve the suppression of human DUX4 in a mouse model of FSHD and in a large animal porcine model of FSHD, extending the use of similar vector technologies as a general delivery platform for dominant muscular dystrophies and opening new therapeutic opportunities for FSHD. Aim 2 (Project 2) will establish facioscapulohumeral dystrophy clinical trial foundations. Studies in this aim will (a) perform clinical and MRI assessment in a long-term extension of the prior Seattle Wellstone FSHD cohorts and apply newer methods of MRI data analysis to generate a multi-year composite dataset of FSHD disease progression for correlations with disease progression; (b) perform a dose-escalation safety and tolerability study of a therapeutic candidate that will incorporate the most current MRI and molecular characteristics to assess their performance for the design of future clinical trials; and (c) perform functional, MRI, and molecular characterization of a new porcine model of FSHD to determine its utility as a preclinical model for human studies. 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, and Training) 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, provide training of the next generation of scientific and clinical researchers in muscular dystrophy and conduct outreach and educational activities. Together, these aims will achieve the overall goal to develop the reagents, measurements, clinical trials methods, and clinical trials infrastructures to speed the development of effective therapies for DMD and FSHD, and to bring muscular dystrophy clinical trials and therapies to the families of the Northwest and beyond.