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- Title
Chronic suppression of heart-failure progression by a pseudophosphorylated mutant of phospholamban via in vivo cardiac rAAV gene delivery.
- Authors
Hoshijima, Masahiko; Ikeda, Yasuhiro; Iwanaga, Yoshitaka; Minamisawa, Susumu; Date, Moto-o; Gu, Yusu; Iwatate, Mitsuo; Li, Manxiang; Wang, Lili; Wilson, James M.; Wang, Yibin; Ross, John; Chien, Kenneth R.
- Abstract
The feasibility of gene therapy for cardiomyopathy, heart failure and other chronic cardiac muscle diseases is so far unproven. Here, we developed an in vivo recombinant adeno-associated virus (rAAV) transcoronary delivery system that allows stable, high efficiency and relatively cardiac-selective gene expression. We used rAAV to express a pseudophosphorylated mutant of human phospholamban (PLN), a key regulator of cardiac sarcoplasmic reticulum (SR) Ca2+ cycling in BIO14.6 cardiomyopathic hamsters. The rAAV/S16EPLN treatment enhanced myocardial SR Ca2+ uptake and suppressed progressive impairment of left ventricular (LV) systolic function and contractility for 28?30 weeks, thereby protecting cardiac myocytes from cytopathic plasma-membrane disruption. Low LV systolic pressure and deterioration in LV relaxation were also largely prevented by rAAV/S16EPLN treatment. Thus, transcoronary gene transfer of S16EPLN via rAAV vector is a potential therapy for progressive dilated cardiomyopathy and associated heart failure.
- Subjects
HEART failure; ADENOVIRUSES; GENE expression; LEFT heart ventricle; DNA viruses
- Publication
Nature Medicine, 2002, Vol 8, Issue 8, p864
- ISSN
1078-8956
- Publication type
Article
- DOI
10.1038/nm739