GENE THERAPY TO INDUCE THERAPEUTIC ANGIOGENESIS

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The objective of these studies is to determine whether replication-deficient adenovirus vectors which carry the cDNA for angiogenic growth factors may provide a novel approach to induce angiogenesis and enhance collateral blood flow to ischemic tissues in clinically relevant animal models of myocardial and hindlimb ischemia/infarction. We have constructed adenovirus vectors which carry the cDNA for vascular endothelial growth factor (VEGF),for acidic fibroblast growth factor (aFGF) and for a recombinant, secreted form of aFGF. In vitro studies have shown that these vectors enhance endothelial cell proliferation and differentiation into capillary-like structures. In addition, when these vectors were resuspended in reconstituted basement membrane proteins (Matrigel) and the Matrigel was injected subcutaneously in mice, the viral vectors diffused out of the gel and induced angiogenesis in vivo. Subsequently, the therapeutic potential of the vectors coding for VEGF and for secreted aFGF was addressed in rabbit models of hindlimb ischemia and myocardial infarction, respectively. In one study severe hindlimb ischemia was induced by dissecting the femoral artery. Approximately 5 weeks after this surgical procedure autologous endothelial cells were infected ex vivo with the vector coding for VEGF and were injected in the iliac artery supplying the ischemic territory. The cells lodged in the capillaries of the ischemic hindlimb an produced VEGF which led to an improvement in collateral blood flow. In another study the adenovirus vector coding for secreted aFGF was injected along the proximal circumflex coronary artery. Approximately 2-3 weeks later the coronary artery was ligated near the site where the adenovirus vector had been injected and the area at risk for myocardial infarction was assessed with Monastral blue. The group injected with the vector coding for secreted aFGF exhibited a 50% decrease in the area at risk for myocardial infarction vs. both infected and uninfected controls.