Long-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is an incurable X-linked muscle-wasting disease caused by mutations in the dystrophin gene. Gene therapy using highly functional microdystrophin genes and recombinant adeno-associated virus (rAAV) vectors is an attractive strategy to treat DMD. Here we show that locoregional and systemic delivery of a rAAV2/8 vector expressing a canine microdystrophin (cMD1) is effective in restoring dystrophin expression and stabilizing clinical symptoms in studies performed on a total of 12 treated golden retriever muscular dystrophy (GRMD) dogs. Locoregional delivery induces high levels of microdystrophin expression in limb musculature and significant amelioration of histological and functional parameters. Systemic intravenous administration without immunosuppression results in significant and sustained levels of microdystrophin in skeletal muscles and reduces dystrophic symptoms for over 2 years. No toxicity or adverse immune consequences of vector administration are observed. These studies indicate safety and efficacy of systemic rAAV-cMD1 delivery in a large animal model of DMD, and pave the way towards clinical trials of rAAV–microdystrophin gene therapy in DMD patients.

AAV-mediated gene transfer restores a normal muscle transcriptome in a canine model of X-linked myotubular myopathy

“…In the past years, treatment breakthroughs have been made in small and large animal models of NMDs (Bengtsson, Hall et al, 2017a, Bengtsson, Hall et al, 2017b, Childers, Joubert et al, 2014, Le Guiner, Servais et al, 2017, Malerba, Klein et al, 2017, Pozsgai, Griffin et al, 2017 and clinical benefits have been reported after a single injection of recombinant adeno-associated virus (rAAV) in patients with spinal muscular atrophy (Mendell, Al-Zaidy et al, 2017). In most of these studies, results consist of correlations between transgene expression levels and clinical outcome measures.…”

Canine Models of Inherited Musculoskeletal and Neurodegenerative Diseases

“…However, a gradual loss of dystrophin-positive myofibers was seen during a 5-year follow up (220,222). Furthermore, the new study showed that limb perfusion of the U7snRNA AAV8 vectors did not induce the T cell response to newly synthesized dystrophin nor to AAV capsid (207). Cardiac rescue is attained with U7snRNA AAV6 vectors by percutaneous transendocardial delivery in the GRMD dog heart (219,221).…”

“…Micro-dystrophin also improved growth, increased limb muscle force, and enhanced activity and gait. Collectively, preclinical studies in the canine model have provided compelling supporting data for conducting systemic AAV micro-dystrophin therapy in human patients (204)(205)(206)(207)(208). Three independent clinical trials (conducted by Solid Bioscience, Pfizer, and Sarepta) are currently ongoing (209).…”

Concise Review: Canine Diabetes Mellitus as a Translational Model for Innovative Regenerative Medicine Approaches

“…Pioneering translational research in the gene therapy and immunotherapy fields was conducted in dogs with hemophilia B , Duchenne muscular dystrophy and cancer , respectively. Such pioneering projects in dog models have accelerated the development of groundbreaking novel therapeutics for the parallel human disease .…”