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Gene therapy for the prevention of vein graft disease

Published:January 02, 2013DOI:https://doi.org/10.1016/j.trsl.2012.12.003
      Ischemic cardiovascular disease remains the leading cause of death worldwide. Despite advances in the medical management of atherosclerosis over the past several decades, many patients require arterial revascularization to reduce mortality and alleviate ischemic symptoms. Technological advancements have led to dramatic increases in the use of percutaneous and endovascular approaches, yet surgical revascularization (bypass surgery) with autologous vein grafts remains a mainstay of therapy for both coronary and peripheral artery disease. Although bypass surgery is highly efficacious in the short term, long-term outcomes are limited by relatively high failure rates as a result of intimal hyperplasia, which is a common feature of vein graft disease. The supply of native veins is limited, and many individuals require multiple grafts and repeat procedures. The need to prevent vein graft failure has led to great interest in gene therapy approaches to this problem. Bypass grafting presents an ideal opportunity for gene therapy, as surgically harvested vein grafts can be treated with gene delivery vectors ex vivo, thereby maximizing gene delivery while minimizing the potential for systemic toxicity and targeting the pathogenesis of vein graft disease at its onset. Here we will review the pathogenesis of vein graft disease and discuss vector delivery strategies and potential molecular targets for its prevention. We will summarize the preclinical and clinical literature on gene therapy in vein grafting and discuss additional considerations for future therapies to prevent vein graft disease.

      Abbreviations:

      Ad (adenovirus), AAV (adeno-associated virus), COX-1 (cyclooxygenase-1), EC (endothelial cell), ECM (extracellular matrix), eNOS (endothelial nitric oxide synthase), HDAd (helper-dependent adenovirus), HVJ (hemagglutinating virus of Japan), IH (intimal hyperplasia), IL (interleukin), I/M (intima to media), IVC (inferior vena cava), MCP-1 (monocyte chemoattractant protein-1), NFκB (nuclear factor κB), NO (nitric oxide), NP (nanoparticle), O2− (superoxide), ODN (oligodeoxynucleotide), ONOO− (peroxynitrite), PD-ECGF (platelet-derived endothelial cell growth factor), PGI2 (prostaglandin I2), PI3K (phosphoinositide 3-kinase), PREVENT (Project of Ex Vivo Vein Graft Engineering via Transfection), PTEN (phosphatase and tensin homology deleted on chromosome 10), ROS (reactive oxygen species), siRNA (small interfering RNA), SMC (smooth muscle cell), SOD (superoxide dismutase), TIMP (tissue inhibitor of metalloproteinase), TM (thrombomodulin), tPA (tissue plasminogen activator), VGD (vein graft disease)
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