© 2000 American Heart Association, Inc.
MiniReview |
Gene Therapy for Restenosis
From the Department of Surgery, University of Pittsburgh, Pittsburgh, Pa.
Correspondence to Melina R. Kibbe, MD, University of Pittsburgh, Department of Surgery, 677 Scaife Hall, Pittsburgh, PA 15261. E-mail kibbemr@msx.upmc.edu
Key Words: gene therapy • gene transfer • restenosis • adenovirus
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Introduction |
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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.
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Cytotoxic Gene Therapy |
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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 ß-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 ß-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
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