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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mayo Clinic, Rochester
United States
Zip Code
Ricci, D; Mennander, A A; Miyagi, N et al. (2010) Prolonged cardiac allograft survival using iodine 131 after human sodium iodide symporter gene transfer in a rat model. Transplant Proc 42:1888-94
Katusic, Zvonimir S; d'Uscio, Livius V; Nath, Karl A (2009) Vascular protection by tetrahydrobiopterin: progress and therapeutic prospects. Trends Pharmacol Sci 30:48-54
Santhanam, Anantha Vijay R; d'Uscio, Livius V; Peterson, Timothy E et al. (2008) Activation of endothelial nitric oxide synthase is critical for erythropoietin-induced mobilization of progenitor cells. Peptides 29:1451-5
He, Tongrong; Lu, Tong; d'Uscio, Livius V et al. (2008) Angiogenic function of prostacyclin biosynthesis in human endothelial progenitor cells. Circ Res 103:80-8
Ricci, Davide; Mennander, Ari A; Pham, Linh D et al. (2008) Non-invasive radioiodine imaging for accurate quantitation of NIS reporter gene expression in transplanted hearts. Eur J Cardiothorac Surg 33:32-9
Miyagi, Naoto; Rao, Vinay P; Ricci, Davide et al. (2008) Efficient and durable gene transfer to transplanted heart using adeno-associated virus 9 vector. J Heart Lung Transplant 27:554-60
Metharom, Pat; Liu, Chunsheng; Wang, Shaohua et al. (2008) Myeloid lineage of high proliferative potential human smooth muscle outgrowth cells circulating in blood and vasculogenic smooth muscle-like cells in vivo. Atherosclerosis 198:29-38
Rao, Vinay P; Branzoli, Stefano E; Ricci, Davide et al. (2007) Recombinant adenoviral gene transfer does not affect cardiac allograft vasculopathy. J Heart Lung Transplant 26:1281-5
Nath, Karl A; Katusic, Zvonimir S; Gladwin, Mark T (2004) The perfusion paradox and vascular instability in sickle cell disease. Microcirculation 11:179-93
Russell, Stephen J; Peng, Kah-Whye (2003) Primer on medical genomics. Part X: Gene therapy. Mayo Clin Proc 78:1370-83

Showing the most recent 10 out of 14 publications