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 delta-sarcoglycan (delta-SG) gene in TO-2 hamsters, a congestive heart failure and muscular dystrophy model with a delta-SG gene mutation. METHODS AND RESULTS: A single injection of double-stranded AAV serotype 8 vector carrying human delta-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 delta-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 delta-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.
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 humandelta-sarcoglycan (delta-SG) gene in TO-2 hamsters, a congestive heart failure and muscular dystrophy model with a delta-SG gene mutation. METHODS AND RESULTS: A single injection of double-stranded AAV serotype 8 vector carrying humandelta-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 delta-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 delta-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.
Authors: Masahiko Hoshijima; Takeharu Hayashi; Young E Jeon; Zhenxing Fu; Yusu Gu; Nancy D Dalton; Mark H Ellisman; Xiao Xiao; Frank L Powell; John Ross Journal: Circ Heart Fail Date: 2010-10-29 Impact factor: 8.790