Abstract 214: rAAV-mediated Heme Oxygenase-1 Gene Therapy Affords Permanent (1 Year) Cardioprotection without Adverse Functional Consequences
Extensive evidence indicates that HO-1 exerts potent cytoprotective effects in response to stress. Previous studies have shown that gene therapy with HO-1 protects against myocardial ischemia/reperfusion injury up to 8 weeks after gene transfer. However, the long-term effect of HO-1 gene therapy on myocardial ischemic injury and function is unknown. To address this issue, we created a recombinant adeno-associated viral vector carrying the HO-1 gene (rAAV/HO-1) which enables long-lasting transgene expression. Mice received injections in the anterior LV wall of rAAV/LacZ (LacZ group) or rAAV/HO-1 (HO-1 group); 1 year later, they were subjected to a 30-min coronary occlusion (O) and 4 h of reperfusion (R). Cardiac HO-1 gene expression was confirmed at 1 month and 1 year after gene transfer (Fig⇓). In the HO-1 group, infarct size (% of risk region) was dramatically reduced at 1 year after gene transfer (11.2 ± 2.1%, n = 12, vs. 41.3 ± 3.3%, n = 8, in LacZ group; Fig⇓). The infarct-sparing effects of HO-1 gene therapy at 1 year were as powerful as those observed 24 h after ischemic PC (six 4-min O/4-min R cycles) (19.3 ± 2.3%, n = 11; Fig⇓). HO-1 gene transfer (n = 14) had no effect on LV dimensions or function up to 1 year as compared with the LacZ group (n = 11) (at 1 year: LVEDD 4.5 ± 0.1 vs. 4.2 ± 0.2 mm; LVESD 3.0 ± 0.1 vs. 2.9 ± 0.2 mm; FS 34 ± 1.5 vs. 32 ± 2.6%; EF 63 ± 1.7 vs. 60 ± 2.9%) (echocardiography). Histology showed no inflammation. These data demonstrate, for the first time, that rAAV-mediated HO-1 gene transfer affords long-term (1 year), possibly permanent, cardioprotection without adverse functional consequences, providing a strong rationale for further preclinical testing of prophylactic gene therapy.