Efficient and long-term intracardiac gene transfer in delta-sarcoglycan-deficiency hamster by adeno-associated virus-2 vectors.
Intracardiac gene transfer and gene therapy have been investigated with different vector systems. Here we used adeno-associated virus (AAV) vectors to deliver either a reporter gene or a therapeutic gene into the heart of golden Syrian hamsters. The method of gene delivery was direct infusion of the AAV2 vectors into the coronary artery ex vivo in a heterotopically transplanted heart. When an AAV2 vector carrying the Lac-Z gene driven by CMV promoter was delivered into the heart of healthy hamsters, effective gene transfer was achieved in up to 90% of the cardiomyocytes. Lac-Z gene expression persisted for more than 1 year without immune rejection or promoter shutoff. Furthermore, when an AAV2 vector carrying human delta-sarcoglycan gene was similarly delivered into the heart of Bio14.6 Syrian hamster, a congestive heart failure and limb girdle muscular dystrophy animal model, widespread therapeutic gene transfer was achieved in a majority of the cardiomyocytes. Efficient expression of the human delta-sarcoglycan gene in the dystrophic hamster hearts restored the entire sarcoglycan complex that was missing due to the primary deficiency of delta-sarcoglycan. Transgene expression persisted for 4 months (the duration of the study) without immune rejection or promoter shutoff. These results indicate that AAV is a promising vector system for cardiac gene therapy.
Li
J
J
Department of Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Wang
D
D
Qian
S
S
Chen
Z
Z
Zhu
T
T
Xiao
X
X
D000818:Animals; D003331:Coronary Vessels; D006224:Cricetinae; D003598:Cytoskeletal Proteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D006333:Heart Failure / Q000628:therapy*; D016027:Heart Transplantation; D007269:Injections, Intra-Arterial; D007763:Lac Operon; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D008647:Mesocricetus; D009136:Muscular Dystrophies / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000378:metabolism; D049031:Sarcoglycans; D014161:Transduction, Genetic / Q000379:methods
D003598:Cytoskeletal Proteins; D008562:Membrane Glycoproteins; D049031:Sarcoglycans