Chronic suppression of heart-failure progression by a pseudophosphorylated mutant of phospholamban via in vivo cardiac rAAV gene delivery.

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) Ca(2+) cycling in BIO14.6 cardiomyopathic hamsters. The rAAV/S16EPLN treatment enhanced myocardial SR Ca(2+) 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.
Authors	Masahiko Hoshijima, Yasuhiro Ikeda, Yoshitaka Iwanaga, Susumu Minamisawa, Moto-o Date, Yusu Gu, Mitsuo Iwatate, Manxiang Li, Lili Wang, James M Wilson, Yibin Wang, John Ross Jr, Kenneth R Chien
Journal	Nature medicine (Nat Med) Vol. 8 Issue 8 Pg. 864-71 (Aug 2002) ISSN: 1078-8956 [Print] United States
PMID	12134142 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Calcium-Binding Proteins phospholamban Adenosine Triphosphatases Calcium
Topics	Adenosine Triphosphatases (metabolism) Amino Acid Sequence Animals Aorta (cytology, metabolism) Calcium (metabolism) Calcium-Binding Proteins (chemistry, genetics, metabolism) Cardiac Output, Low (physiopathology, therapy) Cells, Cultured Cricetinae Dependovirus (genetics) Disease Progression Gene Transfer Techniques Genetic Therapy Genetic Vectors Hemodynamics Humans Liver (anatomy & histology, metabolism) Mice Molecular Sequence Data Mutation Myocardium (cytology, metabolism) Sarcoplasmic Reticulum (metabolism) Sequence Alignment

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