Paul D. Wellstone Muscular Dystrophy Cooperative Research Center

DESCRIPTION (provided by applicant): Major Strengths of the University of Rochester Wellstone MDCRC are: 10 years of experience in operating our current Wellstone Center; a large group of highly motivated patients with myotonic dystrophy (DM1) eager to support translational research and participate in clinical studies; enthusiastic investigators with longstanding expertise in clinical studies; collaborators sharing our urgent commitment to identify and validate reliable endpoints and biomarkers to prepare for treatment trials in DM1; and a nurturing environment that includes a NIH CTSI network and support from major stakeholders in the DM1 community. These assets will allow a network of neuromuscular clinical trialists to become trial ready and permit further exploration of RNA toxicity (spliceopathy) as a disease pathomechanism and biomarker. Our renewal Wellstone Center will support 2 scientific projects and 1 scientific resources core and seeks to validate promising clinical endpoint measures and skeletal muscle splicing alterations identified in our current Wellstone study. Project 1 in our renewal includes a multicenter validation study to confirm the usefulness of promising endpoint measures and will evaluate feasibility and reliability of small needle muscle biopsy splicing assays as a useful biomarker. A cohort of 100 DM1 patients will undergo identical clinical evaluations at 0 and 12 months to answer these questions. A larger cohort of 400 DM1 patients will undergo clinical exams to assess disease severity and provide blood for DNA analysis of DMPK CTG repeat size and genetic variants at MBNL1 and other loci. Our current muscle biopsy data indicate CTG repeat size in tissue does not predict the severity of muscle weakness, suggesting that other genetic factors may influence DM1. Project 2 will examine therapeutic effects of antisense drugs on cardiac function in transgenic mouse models of DM. The Scientific Core contains the National Registry of DM Patients and Family Members and Repository. It supports Projects 1 and 2. The Training/Education Core trains 1 pre-doctoral and 1 post-doctoral fellow and will provide educational materials.