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, the authors 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 treatment 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. This study provides compelling evidence for the therapeutic potential of micro-dystrophin/follistatin combinatorial therapy.
