Gene therapy for restenosis.

Abstract

Atherosclerosis is one of the leading causes of major morbidity and mortality in the United States. Arterial insufficiency resulting from flow-limiting lesions can lead to myocardial, renal, mesenteric, and extremity dysfunction. Treatments for these atherosclerotic arterial lesions include arterial bypass and angioplasty. These therapies are limited by the development of intimal hyperplasia (IH), thus reducing hemodynamic improvement significantly. A number of pharmacological agents with antiplatelet and anticoagulant properties have failed to reduce the incidence and rate of restenosis. Because of the magnitude of the patient population affected by IH, there has been a tremendous need to develop a therapy that will successfully reduce its incidence. Over the last decade, the field of vascular gene therapy has emerged as a viable therapeutic approach, permitting the targeting of genes to produce local and transient effects on the development of IH. This review will discuss the rationale and preliminary data for the different genes that have been evaluated to date. One of the first reports of successful gene transfer to vascular cells was by Nabel et al in 1989.1 These investigators transfected porcine endothelial cells ex vivo with a retrovirus encoding the β-galactosidase gene and reintroduced the cells onto the denuded iliofemoral artery of a syngeneic animal. The arterial segments isolated 2 to 4 weeks later demonstrated endothelial cells that expressed the β-galactosidase gene, thus indicating successful incorporation of the transgene into the transduced cells. Landmark follow-up experiments in which herpes simplex virus thymidine kinase (HSV-tk) was delivered to injured porcine iliac2 or rat carotid3 arteries using an adenoviral vector were published 5 years later (see Table online; http://www.circresaha.org). This approach, which is based on the conversion of coadministered ganciclovir to a toxic metabolite by HSV-tk, decreased the neointima by 86% in the porcine model2 and 46% in the …