Abstract 3030: rAAV-mediated Extracellular Superoxide Dismutase (ecSOD) Gene Therapy Produces Permanent Cardioprotection
ecSOD is critical for protecting from oxidative stress because of its strategic location in the interstitial compartment. Although gene therapy with ecSOD has been shown to protect against myocardial infarction for 3 days, no data are available beyond this time-point. Since the ultimate goal of prophylactic gene therapy is permanent protection against ischemia, long-term assessment is essential for clinical translation. Thus, we created a recombinant adeno-associated viral vector carrying the ecSOD gene (rAAV/ecSOD), which enables long-lasting transgene expression without pathogenic and immunogenic reactions in the host. Mice received injections of rAAV/LacZ or rAAV/ecSOD in the anterior LV wall; 1 year later, they underwent a 30-min coronary occlusion (O) and 4 h of reperfusion (R). ecSOD gene transfer elevated myocardial ecSOD protein expression at both 3 months (+ 3.6-fold vs. LacZ group, n=4, P<0.05) and 1 year (Fig⇓). Infarct size (% of risk region) was dramatically reduced at 1 year after ecSOD gene transfer (17.6+/−3.0%, n=8, vs. 41.3+/−3.3%, n=8, in LacZ group; Fig⇓). The infarct-sparing effects of ecSOD gene therapy at 1 year were as powerful as those observed 24 h after ischemic preconditioning (six 4-min O/4-min R cycles) (Fig⇓). Chronic overexpression of ecSOD (n=9) had no effect on LV dimensions or function for up to 1 year (echocardiography). These data demonstrate, for the first time, that rAAV-mediated ecSOD gene transfer affords long-term (1 year) cardioprotection without adverse functional consequences, supporting the therapeutic potential of this strategy for achieving long-term prophylactic cardioprotection in patients with heart ischemic diseases.