Pre-emptive gene therapy using recombinant adeno-associated virus delivery of extracellular superoxide dismutase protects heart against ischemic reperfusion injury, improves ventricular function and prolongs survival.
In high-risk patients, the ideal cardiovascular gene therapy requires a strategy that provides long-term protection of myocardium against episodes of ischemic/reperfusion injury. We report the development of an efficient, long-lasting pre-emptive gene therapy strategy in a rat model of ischemic-reperfusion (I/R) injury of heart. At 6 weeks prior to myocardial injury, the human extracellular superoxide dismutase (Ec-SOD) gene was delivered by direct intramyocardial injections, using a recombinant adeno-associated virus vector. Significant myocardial protection was documented by the decrease in infarct size at 24 h post I/R, improved left ventricular function at 7 weeks postinjury, and enhanced long-term survival in the SOD treated group. This concept of preinjury delivery and 'pre-emptive' gene therapy via the expression of a secreted protein that renders paracrine therapeutic action can be an effective strategy for organ protection against future injury.
Agrawal
R S
RS
Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA.
Muangman
S
S
Layne
M D
MD
Melo
L
L
Perrella
M A
MA
Lee
R T
RT
Zhang
L
L
Lopez-Ilasaca
M
M
Dzau
V J
VJ
D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D045604:Extracellular Fluid / Q000201:enzymology; D015316:Genetic Therapy / Q000379:methods*; D008297:Male; D009203:Myocardial Infarction / Q000503:physiopathology / Q000628:therapy; D015428:Myocardial Reperfusion Injury / Q000401:mortality / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000235:genetics*; D015996:Survival Rate; D013997:Time Factors; D014161:Transduction, Genetic / Q000379:methods*; D016276:Ventricular Function
D013482:Superoxide Dismutase