MDSRC for Next Directions in Muscular Dystrophy Research

Abstract The Center for Gene Therapy at the Abigail Wexner Research Institute of Nationwide Children’s Hospital (NCH) hosts a robust and active research community in the muscular dystrophies, with extensive expertise in unraveling disease pathogenesis and developing new treatment paradigms that can be translated from the bench to the bedside. We propose an MDSRC with Cores

designed to share this expertise with the Wellstone and broader muscular dystrophy research communities, with Projects intended to address questions raised or left unanswered by current therapies, such as microdystrophin gene therapy. Project 1 (PI, Paul Martin, PhD) seeks to utilize a novel bicistronic AAV vector to both prevent muscle disease and simultaneously build new

muscle function in muscular dystrophy patients with Limb Girdle Muscular Dystrophy 2I (LGMD2I). Project 2 (PI, Kevin Flanigan, MD) will develop vectors containing U7 small nuclear RNAs (U7snRNAs) reprogrammed with antisense sequences directed toward splice site or splice enhance elements to restores highly functional dystrophin expression. Project 3 (PI, Nizar Saad,

PhD) seeks to identify novel circulating biomarkers through the investigation of circulating extracellular vesicles (EVs) and to develop a new generations of gene therapy that increase transduction efficiency, dystrophin expression, and reduce the development of humoral immunity against AAV gene therapies. All three projects make use of the critical resource core, the

Muscular Dystrophy Cell and Serum Banking Core (Director, Nicolas Wein, PhD) by establishing primary fibroblasts from patients with muscular dystrophies, a critical resource for early therapy development, while collaborating with Penny Gilbert, PhD, at the University of Toronto, to develop improved protocols leading to superior reagents for Center Projects. We have a longstanding

dedication to serving as a national training resource, as demonstrated by our Myology Course, held annually since 2012, and our Training Core (Director, Scott Harper) will expand the number of attendees and the range of topics covered in the Course, offer individualized career development guidance to Wellstone Fellowship trainees, and develop new curricula of benefit to

the community. Our Administrative Core will implement a meaningful community outreach program and develop a highly functional MDSRC website to provide access to the muscular dystrophy community. Altogether, our longstanding efforts and the highly collaborative multidisciplinary environment of our two institutions will be synergized by a MDSRC that leverages

existing structures and collaborations, and develops outward-facing resources of benefit to the broader Wellstone and muscular dystrophy research communities.