TNF-INHIBITOR GENE THERAPY FOR NEOINTIMAL HYPERPLASIA

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Percutaneous coronary intervention (PCI) and coronary artery bypass graft surgery (CABG) are each performed on approximately 500,000 patients annually in the US. Both procedures are complicated by activation, migration and proliferation of cells in the vascular wall, leading to neointimal hyperplasia (NH). A preponderance of evidence suggests that the majority of these cells are of vascular smooth muscle origin. NH affects about 30 % of all PCI patients and necessitates reintervention in some 30 % of all CABG cases within two years. The annual cost needed to treat PCI restenosis alone exceeds $2 billion. PCI and saphenous vein CABG surgery both lead to significant injury of the underlying vessel wall, causing endothelial dysfunction and adherence of platelets, neutrophils and circulating cells of the monocyte / macrophage lineage. Locally released cytokines, such as tumor necrosis factor (TNF), synergize with growth factors, including platelet derived growth factor (PDGF) and basic fibroblast growth factor (bFGF), to activate SMCs in the injured vessel segment. In vitro TNF is a strong mitogen for SMCs and can act in concert with PDGF-BB, to stimulate cell growth. This work proposes to examine the contribution of TNF to the activation of SMCs, alone and in combination with various growth factors. To this end mitogen activated protein kinase (MAPK) activation, DNA synthesis, proliferation, chemotaxis and apoptosis will be examined in TNF treated and untreated SMCs. In addition, this proposal seeks to test the hypothesis that inhibition of TNF can decrease the degree of SMC activation in vitro and can reduce the size of neointima formation in vivo in an experimental animal model. To inhibit TNF, a chimeric TNF receptor extracellular domain - murine immunoglobulin heavy chain construct (TNF-I) was generated and inserted into a recombinant adenovirus (rec. AD-TNF-I). This virus will be used to infect rabbit jugular veins ex vivo that will be grafted across the rabbit's carotid artery in a well characterized model of neointima hyperplasia. Four weeks after bypass grafting the degree of neointima formation in rec.AD-TNF-I and rec.AD-control infected veins will be measured histologically. This will be done both in rabbits receiving a normal diet and also in animals given a high fat diet to examine the contribution of hyperlipidemia towards the development of neointimal hyperplasia in this setting. Reduction of vein graft neointimal hyperplasia by inhibition of TNF may have significant therapeutic implications for human vascular diseases.