GENE THERAPY OF CORONARY ARTERY DISEASE

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Our studies are aimed at evaluating whether gene therapy with replication-deficient, recombinant adenovirus vectors can be used to induce angiogenesis and restore blood supply to ischemic tissues and to prevent and treat restenosis after angioplasty. For the studies on angiogenesis, we have constructed adenoviral vectors which carry the cDNA for different angiogenic growth factors: VEGF165, aFGF1-154, recombinant secreted aFGF1-154 modified by the addition of the signal peptide for secretion from FGF-4, bFGF, PD-ECGF. The vectors which carry the cDNAs for VEGF and for aFGF induce endothelial cell proliferation and differentiation in vitro as well as angiogenesis in vivo when coinjected sucutaneously with reconstituted basement membrane proteins (Matrigel) in mice. Further, preliminary results show that autologous endothelial cells infected ex vivo with AdCMV.VEGF165 and subsequently injected into the iliac artery supplying the ischemic limb in a rabbit model of hindlimb ischemia induce angiogenesis in vivo. The construction of the remaining vectors has been completed only recently and the vectors are being evaluated for their biologic effects in vitro. For the studies on restenosis after angioplasty we have constructed adenoviral vectors which may act through one of the following steps: (1) selectively enhance endothelial cell regrowth at the site of vascular injury. (AdCMV.VEGF165 and AdCMV.PDECGF).(2) induce vascular smooth muscle cell death or growth arrest.(AdCMV.WAF-1, AdCMV.IGF1R-AS and AdCMV.MKP-1). In addition an adenovirus vector which carries the cDNA for human wild type p53 has been obtained from Dr. Vogelstein (Johns Hopkins University). (3) inhibit vascular smooth muscle cell migration from the media to the intima (AdCMV.TIMP-2). The above vectors are presently being evaluated to determine their biologic effects in vitro. Preliminary results show that AdCMV.p53 inhibits vascular smooth muscle cells (VSMC) proliferation while AdCMV.TIMP-2 inhibits VSMC invasion in the Boyden chamber.