期刊
CIRCULATION-HEART FAILURE
卷 4, 期 1, 页码 89-U153出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCHEARTFAILURE.110.957258
关键词
gene therapy; cardiomyopathy; muscles; heart failure; respiration
资金
- Muscular Dystrophy Foundation [MDA3758]
- NIH [R01AR045967, R01HL081823]
- NIH/National Center for Research Resources [P41RR004050]
- American Heart Association [0840013N]
- NATIONAL CENTER FOR RESEARCH RESOURCES [P41RR004050] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL081401, R01HL081823] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R01AR045967] Funding Source: NIH RePORTER
Background-The BIO14.6 hamster provides a useful model of hereditary cardiomyopathies and muscular dystrophy. Previous delta-sarcoglycan (delta SG) gene therapy (GT) studies were limited to neonatal and young adult animals and prevented the development of cardiac and skeletal muscle dysfunction. GT of a pseudophosphorylated mutant of phospholamban (S16EPLN) moderately alleviated the progression of cardiomyopathy. Methods and Results-We treated 4-month-old BIO14.6 hamsters with established cardiac and skeletal muscle diseases intravenously with a serotype-9 adeno-associated viral vector carrying delta SG alone or in combination with S16EPLN. Before treatment at age 14 weeks, the left ventricular fractional shortening by echocardiography was 31.3% versus 45.8% in normal hamsters. In a randomized trial, GT halted progression of left ventricular dilation and left ventricular dysfunction. Also, respiratory function improved. Addition of S16EPLN had no significant additional effects. delta SG-GT prevented severe degeneration of the transverse tubular system in cardiomyocytes (electron tomography) and restored distribution of dystrophin and caveolin-3. All placebo-treated hamsters, except animals removed for the hemodynamic study, died with heart failure between 34 and 67 weeks of age. In the GT group, signs of cardiac and respiratory failure did not develop, and animals lived for 92 weeks or longer, an age comparable to that reported in normal hamsters. Conclusions-GT was highly effective in BIO14.6 hamsters even when given in late-stage disease, a finding that may carry implications for the future treatment of hereditary cardiac and muscle diseases in humans. (Circ Heart Fail. 2011;4:89-97.)
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