Chronic total occlusion (CTO) of the coronary artery represents between 10-20% of all cases of coronary artery disease, the leading cause of death in the developed world. CTOs are currently inadequately treated and it has proven very difficult to improve distal vessel perfusion in this setting with conventional revascularization strategies such as angioplasty or stenting. One approach which may improve distal vessel perfusion in CTO patients is therapeutic angiogenesis. We have recently developed a novel """"""""felt-stent"""""""" consisting of a felt-like stainless steel mesh backbone on a conventional stent which can incorporate seeded vascular smooth muscle cells. These cells can be genetically altered and reimplanted on a stent platform in the vasculature. Our central hypothesis is that targeted cell based gene delivery using a regulated retroviral VEGF vector will induce functional and sustained angiogenesis. This will be examined using the felt stent platform in a porcine model of CTO. The overall goal of this proposal is to provide better options for VEGF gene transfer in the vasculature. This will be achieved through use of a novel felt-stent as a platform for regionally targeted cell-based VEGF gene transfer in vivo. The specific objectives of the proposal will be to establish VEGF gene transfer which is durable, temporally regulated efficient, safe and ultimately therapeutic for angiogenesis in the setting of CTO.
The specific aims are as follows: 1. To optimize cell based retroviral VEGF gene transfer using a felt-stent in the normal porcine coronary artery. 2. To determine, using the same in vivo stent delivery, the feasibility of long-term temporal control of VEGF gene transfer using a rapamycin transcription regulation system. 3. To determine the therapeutic efficacy of this combined delivery and regulated VEGF vector system for induction of angiogenesis in a porcine models of CTO.
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