期刊
CIRCULATION
卷 112, 期 17, 页码 2650-2659出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.105.565598
关键词
viruses; cardiomyopathy; gene therapy
资金
- NHLBI NIH HHS [HL-66949] Funding Source: Medline
- NIAMS NIH HHS [AR45967] Funding Source: Medline
- NINDS NIH HHS [NS46546] Funding Source: Medline
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.
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