Long-Term Systemic Myostatin Inhibition via Liver-Targeted Gene Transfer in Golden Retriever Muscular Dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is a lethal, X-linked recessive disease affecting 1 in 3,500 newborn boys for which there is no effective treatment or cure. One novel strategy that has therapeutic potential for DMD is inhibition of myostatin, a negative regulator of skeletal muscle mass that may also promote fibrosis. Therefore, our goal in this study was to evaluate systemic myostatin inhibition in the golden retriever model of DMD (GRMD). GRMD canines underwent liver-directed gene transfer of a self-complementary adeno-associated virus type 8 vector designed to express a secreted dominant-negative myostatin peptide (n = 4) and were compared with age-matched, untreated GRMD controls (n = 3). Dogs were followed with serial magnetic resonance imaging (MRI) for 13 months to assess cross-sectional area and volume of skeletal muscle, then euthanized so that tissue could be harvested for morphological and histological analysis. We found that systemic myostatin inhibition resulted in increased muscle mass in GRMD dogs as assessed by MRI and confirmed at tissue harvest. We also found that hypertrophy of type IIA fibers was largely responsible for the increased muscle mass and that reductions in serum creatine kinase and muscle fibrosis were associated with long-term myostatin inhibition in GRMD. This is the first report describing the effects of long-term, systemic myostatin inhibition in a large-animal model of DMD, and we believe that the simple and effective nature of our liver-directed gene-transfer strategy makes it an ideal candidate for evaluation as a novel therapeutic approach for DMD patients.

Duchenne muscular dystrophy gene therapy in the canine model

“…109 To determine whether myostatin inhibition can ameliorate muscle disease in GRMD dogs, Bish et al expressed a secreted dominant negative myostatin peptide in the liver of four 9-10-month-old GRMD dogs using AAV-8. 110 Thirteen months after injection, they observed the expected increase in muscle mass. Furthermore, treatment reduced the serum creatine kinase level and muscle fibrosis.…”

Review of Phase II and Phase III clinical trials for Duchenne muscular dystrophy

“…MYO-29, the first antibody to myostatin evaluated in human clinical trials, has been trialed in muscular dystrophy patients (facioscapulohumeral muscular dystrophy; BMD; forms of limb girdle muscular dystrophy). Despite positive results in canines (increased muscle mass, decreased serum CK and decreased muscle fibrosis), human results showed no improvement in any endpoints of muscle strength or function [40,41]. Alternative agents under investigation to target myostatin include follistatin and ACE-031.…”

Duchenne Muscular Dystrophy: Therapeutic Approaches to Restore Dystrophin

“…Some aim at addressing specific issues of pathology such as Idebenone, or green tea extract to reduce oxidative stress (Dorchies et al, 2009;Nagy & Nagy, 1990), or myostatin inhibition to increase muscle mass (Bish et al, 2011;Dumonceaux et al, 2010), while others directly aim at dystrophin restoration. In this chapter we will focus on the latter.…”