Nature Medicine
8, 864 - 871 (2002)
Published online: 22 July 2002; | doi:10.1038/nm739
Chronic suppression of heart-failure progression by a pseudophosphorylated mutant of phospholamban via in vivo cardiac rAAV gene deliveryMasahiko Hoshijima1, 2, 5, Yasuhiro Ikeda2, 5, Yoshitaka Iwanaga2, Susumu Minamisawa1, 2, Moto-o Date1, 2, Yusu Gu2, Mitsuo Iwatate2, Manxiang Li3, Lili Wang4, James M. Wilson4, Yibin Wang3, John Ross Jr1, 2
& Kenneth R. Chien1, 21
University of California, San Diego (UCSD) Institute of Molecular Medicine, La Jolla, California, USA
2
Department of Medicine, UCSD, La Jolla, California, USA
3
Department of Physiology, University of Maryland, Baltimore, Maryland, USA
4
Institute For Human Gene Therapy, University of Pennsylvania, Philadelphia, Pennsylvania, USA
5
M.H. and Y.I. contributed equally to this study.
Correspondence should be addressed to Kenneth R. Chien kchien@ucsd.eduThe 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.
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