Novel therapeutics for FSHD

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PROJECT SUMMARY Facioscapulohumeral muscular dystrophy (FSHD) causes lifelong severe disability and is one of the most prevalent muscular dystrophies, afflicting both children and adults. While major advances in genetics have strongly implicated the inappropriate expression of a powerful transcription factor, DUX4, and its target genes in the degeneration of muscle fibers in FSHD, no protective pharmacologic treatments yet exist for this disease. The University of Massachusetts School of Medicine (UMMS) Wellstone Muscular Dystrophy Cooperative Research Center is a network of collaborative investigators whose research and training programs focus on developing novel and effective therapeutics for FSHD. The long-term objectives are to meet this need through three highly synergistic projects directed toward drug discovery and optimization, supported by our Cores, collaborators and advisors. Specific Center goals are: 1) identifying FSHD disease modifiers through expanded genomic investigations of a large Utah FSHD kindred in Project 1 to discern native gene variants and regulatory pathways that influence the FSHD clinical phenotype; 2) discovering modulators of DUX4 toxicity in Project 2 using the novel Wellstone FSHD cell and animal models and CRISPR-based inhibition approaches to identify gene and regulatory pathway therapeutic targets; 3) optimizing our lead DUX4 RNA therapeutics and DUX4 signaling compounds in Project 3, in collaboration with industry; 4) partnering with FSHD and patient advocacy groups to support and participate in FSHD research and clinical trials; 5) expanding collaborations with industry partners who have tools and experience to develop FSHD therapeutics; and 6) training the next generation of clinician- scientists and translational researchers, who will be the driving force of our Wellstone therapeutic development program. Three Center Cores will support the research and training activities of this Wellstone Center and also the greater FSHD research and patient communities. These include an Administrative Core to facilitate communication between our investigators at all sites and to connect investigators with patient advocacy groups, particularly the FSH Society, so that we may continue to engage and provide education to individuals with FSHD and their families. The Education and Training Core will continue to oversee the research and clinical training of students and fellows. The Resources Core will expand a unique repository of FSHD biomaterials, including DNA, muscle tissues, myogenic primary cells and muscle cell lines derived from biopsies, and iPSC cells derived from patient fibroblasts to support Wellstone and greater FSHD community research. These materials are available to academic and industry groups and have increasingly been used as FSHD models for biomarker and preclinical therapeutic studies. The Resources Core will utilize novel inducible DUX4 mouse and zebrafish models and a xenograft model that will support our proposed preclinical projects and also will share these models with other FSHD research groups to accelerate FSHD therapeutic development.