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

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.

Efficacy of exogenous pyruvate in TremblerJ mouse model of Charcot‐Marie‐Tooth neuropathy

“…When compared to pyruvate alone, failure to show an increase in the mean MF density with combinatorial therapy may suggest an apparent discrepancy between grip strength improvement and CMAP/nerve density changes . It is, however, likely that the functional tests were reflection of improvements in multiple muscle groups and other factors including improved force generation related to muscle diameter increase (Rodino‐Klapac et al, ) and increased axonal sprouting in muscle, both of which can occur from NT‐3 effect.…”

Follistatin Gene Therapy Improves Ambulation in Becker Muscular Dystrophy

“…Careful selection of targeted muscle groups at earlier stages of pathology may lead to the enhancing effects of follistatin on muscle mass and strength. The fundamental role of follistatin in augmenting myofiber growth supports its potential use in conjunction with other disease-specific gene replacement therapies [46]. It should also be noted that pre-clinical studies in Pompe mice show that follistatin could be used as an adjuvant therapy to alpha-glucosidase deficiency [47].…”

Clinical development on the frontier: gene therapy for duchenne muscular dystrophy

“…Furthermore, because muscle cells are non-dividing and long-lived, there is potential that a one-time treatment could have long-term and perhaps even life-long benefits. In fact, preclinical and clinical studies in neuromuscular diseases to date indicate no loss in durability [25,[52][53][54][55]. The objective of gene therapy for DMD is to deliver a gene encoding a functional version of dystrophin systemically to all target tissues involved in DMD pathology and thereby ameliorate the progression of the disease.…”