Abstract 5590: Therapeutic Neovascularization by AAV 2/9-based Gene Transfer of hVEGF-A and hPDGF-b in Chronic Ischemia (Pig and Rabbit Model)
In patients suffering from ischemic cardiomyopathy or peripheral artery disease, lacking interventional or surgical treatment options, induction of neovascularization via vascular growth factor application is a novel therapeutic concept. Here we tested an approach by combining hVEGF-A with hPDGF-B and prolonging the expression period by using a AAV as viral vector.
Methods: In rabbits (n=5 per group), 0.5×1011 rhAAV-VEGF-A with or without 1×1012 rAAV-hPDGF-B were retroinfused at d7 of femoral artery excision. At d7 and 35 angiography of both hindlimbs was performed for collateral score and frame count score (cinedensitometry, % d7). Capillary/muscle fiber ratio (C/MF) was determined at d35. In pigs, a reduction stent graft was implanted into the circumflex artery (Cx), leading to complete occlusion at day 28, when retroinfusion of rAAV-VEGF-A/PDGF-B (2×1012 particles each) or rAAV-LacZ (4×1012 particles) was performed. Global myocardial function (EF and LVEDP) and regional myocardial perfusion (fluorescent microspheres) were assessed at d28 and d56, were as regional myocardial function was ovbtained at day 56.
Results: In rabbits, rAAV-hVEGF-A strongly induced angiogenesis (C/MF 1,32±0,07 vs. 0.96±0,08 in LacZ-controls), but not collateral growth (125±7% d7 vs. 95±6% d7, p=0.09) or perfusion (136±12% vs. 107±9%, p=0.07). hVEGF-A/hPDGF-B co-transfection, however, enhanced collateral growth (146±9%, p=0.01) and perfusion (163±8%, p<0.05) at a similar capillary density (1,44±0,10 CM/F). In the pig model, retroinfusion of rAAV-hVEGF-A/hPDGF-B increased regional myocardial blood flow (1,5±0,1ml/g vs. 1,0±0,1ml/g in mock-transfected controls, p<0.05), based on growth of collaterals (9,5±0,3 vs. 5,5±0,5 in controls, p<0.01) and capillary density (146±8 vs. 66±6/field in controls). rAAV-hVEGF-A/hPDGF-B improved global myocardial function (EF: 48±1% vs. 33±1% in control; LVEDP: 14.7±0.9 vs. 19.6±0.8mmHg in controls, p<0.05) accompanied by an improved regional myocardial function in the RCx area (11±3 % SES vs 2±6 %, controls).
Conclusions: Longterm overexpression of hVEGF and PDGF substantially enhanced angiogenesis and arteriogenesis in the ischemic region followed by an improved function, wich is superior to hVEGF alone.