Micro-dystrophin and follistatin co-delivery restores muscle function in aged DMD model | DuchenneXchange

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Scientific Articles

Micro-dystrophin and follistatin co-delivery restores muscle function in aged DMD model

key information

source: Human Molecular Genetics

year: 2013

authors: Rodino-Klapac LR, Janssen PM, Shontz KM, Canan B, Montgomery CL, Griffin D, Heller K, Schmelzer L, Handy C, Clark KR, Sahenk Z, Mendell JR, Kaspar BK

summary/abstract:

Pharmacologic strategies have provided modest improvement in the devastating muscle-wasting disease, Duchenne muscular dystrophy (DMD). Pre-clinical gene therapy studies have shown promise in the mdx mouse model; however, studies conducted after disease onset fall short of fully correcting muscle strength or protecting against contraction-induced injury. Here we examine the treatment effect on muscle physiology in aged dystrophic mice with significant disease pathology by combining two promising therapies: micro-dystrophin gene replacement and muscle enhancement with follistatin, a potent myostatin inhibitor. Individual treatments with micro-dystrophin and follistatin demonstrated marked improvement in mdx mice but were insufficient to fully restore muscle strength and response to injury to wild-type levels. Strikingly, when combined, micro-dystrophin/follistatin treatment restored force generation and conferred resistance to contraction-induced injury in aged mdx mice. Pre-clinical studies with miniature dystrophins have failed to demonstrate full correction of the physiological defects seen in mdx mice. Importantly, the addition of a muscle enhancement strategy with delivery of follistatin in combination with micro-dystrophin gene therapy completely restored resistance to eccentric contraction-induced injury and improved force. Eccentric contraction-induced injury is a pre-clinical parameter relevant to the exercise induced injury that occurs in DMD patients, and herein, we demonstrate compelling evidence for the therapeutic potential of micro-dystrophin/follistatin combinatorial therapy.

organisation: Molecular, Cellular & Developmental Biology Graduate Program, The Ohio State University, Columbus, USA; Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, USA

DOI: 10.1093/hmg/ddt342

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