Sustained Whole-Body Functional Rescue in Congestive Heart Failure and Muscular Dystrophy Hamsters by Systemic Gene Transfer

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Abstract
Background— The success of muscular dystrophy gene therapy requires widespread and stable gene delivery with minimal invasiveness. Here, we investigated the therapeutic effect of systemic delivery of adeno-associated virus (AAV) vectors carrying human δ-sarcoglycan (δ-SG) gene in TO-2 hamsters, a congestive heart failure and muscular dystrophy model with a δ-SG gene mutation. Methods and Results— A single injection of double-stranded AAV serotype 8 vector carrying human δ-SG gene without the need of any physical or pharmaceutical interventions achieved nearly complete gene transfer and tissue-specific expression in the heart and skeletal muscles of the diseased hamsters. Broad and sustained (>12 months) restoration of the missing δ-SG gene in the TO-2 hamsters corrected muscle cell membrane leakiness throughout the body and normalized serum creatine kinase levels (a 50- to 100-fold drop). Histological examination revealed minimal or the absence of central nucleation, fibrosis, and calcification in the skeletal muscle and heart. Whole-body functional analysis such as treadmill running showed dramatic improvement, similar to the wild-type F1B hamsters. Furthermore, cardiac functional studies with echocardiography revealed significantly increased percent fractional shortening and decreased left ventricular end-diastolic and end-systolic dimensions in the treated TO-2 hamsters. The survival time of the animals was also dramatically extended. Conclusions— Systemic gene transfer of δ-SG by the AAV serotype 8 vector could effectively ameliorate cardiac and skeletal muscle pathology, profoundly improve cardiac and whole-body functions, and significantly prolong the lifespan of the treated TO-2 hamsters.