Chronic suppression of heart-failure progression by a pseudophosphorylated mutant of phospholamban via in vivo cardiac rAAV gene delivery.
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.
Hoshijima
Masahiko
M
University of California, San Diego Institute of Molecular Medicine, La Jolla, California, USA.
Ikeda
Yasuhiro
Y
Iwanaga
Yoshitaka
Y
Minamisawa
Susumu
S
Date
Moto-o
MO
Gu
Yusu
Y
Iwatate
Mitsuo
M
Li
Manxiang
M
Wang
Lili
L
Wilson
James M
JM
Wang
Yibin
Y
Ross
John
J
Chien
Kenneth R
KR
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002303:Cardiac Output, Low / Q000503:physiopathology* / Q000628:therapy; D002478:Cells, Cultured; D006224:Cricetinae; D000229:Dependovirus / Q000235:genetics; D018450:Disease Progression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006439:Hemodynamics; D006801:Humans; D008099:Liver / Q000033:anatomy & histology / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D016415:Sequence Alignment; D000099211:Phospholamban
D000251:Adenosine Triphosphatases; D002118:Calcium; D002135:Calcium-Binding Proteins; D000099211:Phospholamban