Journal Article

Systemic AAV-Mediated β-Sarcoglycan Delivery Targeting Cardiac and Skeletal Muscle Ameliorates Histological and Functional Deficits in LGMD2E Mice

Pozsgai, Eric R., Mendell, Jerry R., Heller, Kristin N., Rodino-Klapac, Louise R., Griffin, Danielle A.

2017

Overview

Limb-girdle muscular dystrophy type 2E (LGMD2E), resulting from mutations in β-sarcoglycan (SGCB), is a progressive dystrophy with deteriorating muscle function, respiratory failure, and cardiomyopathy in 50% or more of LGMD2E patients. SGCB knockout mice share many of the phenotypic deficiencies of LGMD2E patients. To investigate systemic SGCB gene transfer to treat skeletal and cardiac muscle deficits, we designed a self-complementary AAVrh74 vector containing a codon-optimized human SGCB transgene driven by a muscle-specific promoter. We delivered scAAV.MHCK7.hSGCB through the tail vein of SGCB−/− mice to provide a rationale for a clinical trial that would lead to clinically meaningful results. This led to 98.1% transgene expression across all muscles that was accompanied by improvements in histopathology. Serum creatine kinase (CK) levels were reduced following treatment by 85.5%. Diaphragm force production increased by 94.4%, kyphoscoliosis of the spine was significantly reduced by 48.1%, overall ambulation increased by 57%, and vertical rearing increased dramatically by 132% following treatment. Importantly, no adverse effects were seen in muscle of wild-type mice injected systemically with scAAV.hSGCB. In this well-defined model of LGMD2E, we have demonstrated the efficacy and safety of systemic scAAV.hSGCB delivery, and these findings have established a path for clinically beneficial AAV-mediated gene therapy for LGMD2E.

• Publisher: Elsevier Inc,Elsevier Limited,American Society of Gene & Cell Therapy
• Subject: AAV / Animals / Biopsy / Cardiac muscle / Cardiomyopathies - diagnosis / Cardiomyopathies - genetics / Cardiomyopathy / Creatine / Creatine kinase / Dependovirus - genetics / Diaphragm / Disease / Disease Models, Animal / Experiments / Gene Order / Gene therapy / Gene Transfer Techniques / Genetic Vectors - administration & dosage / Genetic Vectors - genetics / Genetic Vectors - pharmacokinetics / Heart / Humans / Kyphosis / Kyphosis - diagnosis / Kyphosis - genetics / Kyphosis - therapy / LGMD2E / limb-girdle muscular dystrophy / Mice / Mice, Knockout / Motor Activity / Muscle, Skeletal - metabolism / Muscle, Skeletal - pathology / Muscle, Skeletal - physiopathology / Muscular dystrophy / Musculoskeletal system / Myocardium - metabolism / Myocardium - pathology / Original / Patients / Proteins / Recovery of Function / Respiratory failure / Sarcoglycanopathies - diagnosis / Sarcoglycanopathies - genetics / Sarcoglycanopathies - therapy / Sarcoglycans - genetics / Scoliosis / Scoliosis - diagnosis / Scoliosis - genetics / Scoliosis - therapy / Skeletal muscle / Tissue Distribution / Transduction, Genetic / Vectors (Biology) / Veins & arteries / X-Ray Microtomography / β-sarcoglycan