Gene therapy with extracellular superoxide dismutase protects conscious rabbits against myocardial infarction

Background-Extracellular superoxide dismutase (Ec-SOD) may protect the hear t against myocardial infarction (MI) because of its extended half-life and capacity to bind heparan sulfate proteoglycans on cellular surfaces. Accord ingly, we used direct gene transfer to increase systemic levels of Ec-SOD a nd determined whether this gene therapy could protect against MI. Methods and Results-The cDNA for human Ec-SOD was incorporated into a repli cation-deficient adenovirus (Ad5/CMV/Ec-SOD). Injection of this virus produ ced a high level of Ec-SOD in the liver, which was redistributed to the hea rt and other organs by injection of heparin. Untreated rabbits (group I) un derwent a 30-minute coronary occlusion and 3 days of reperfusion, For compa rison, preconditioned rabbits (group II) underwent a sequence of six 4-minu te-occlusion/4-minute-reperfusion cycles 24 hours before the 30-minute occl usion. Control-treated rabbits (group III) were injected intravenously with Ad5/CMV/nls-LacZ, and gene-therapy rabbits (group IV) were injected with A d5/CMV/Ec-SOD 3 days before the 30-minute occlusion. Both groups treated wi th Ad5 received intravenous heparin 2 hours before the 30-minute occlusion. Infarct size (percent risk area) was similar in groups I (57 +/-6%) and II I (58 +/-5%). Ec-SOD gene therapy markedly reduced infarct size to 25 +/-4% (P<0.01, group TV versus group III), a protection comparable to that of th e late phase of ischemic preconditioning (29<plus/minus>3%, P<0.01 group II versus group I). Conclusions-Direct gene transfer of the cDNA encoding membrane-bound Ec-SOD affords powerful cardioprotection, providing proof of principle for the ef fectiveness of antioxidant gene therapy against MI.