Gene therapy for the prevention of vein graft disease

Abstract

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.

Efficient Gene Transfer and Durable Transgene Expression in Grafted Rabbit Veins

“…5,8 Despite evidence that both aspirin and lipid-lowering therapy improve SVG patency 9,10 -as well as widespread implementation of these therapies 7there is no evidence that SVG patency rates have increased since 1968. 11 One study suggested that modern SVG patency rates may be decreasing (*55% by 18 months) and confirmed that loss of SVG patency is associated with poor clinical outcomes. 12 Moreover, SVG stenosis and occlusion are difficult to treat: percutaneous intervention is often unsuccessful, 13 and the morbidity of both percutaneous intervention and redo CABG is high.…”

“…Gene therapy is an attractive approach for improving SVG patency because it offers the possibility to treat a vein segment (potentially ex vivo) before it is grafted into the arterial circulation. 11,15 Delivery of a durable biological therapy at the time of vein grafting might prevent the processes that cause SVG occlusion (thrombosis, intimal hyperplasia, and accelerated atherosclerosis). 5,16,17 However, because SVG disease (especially atherosclerosis) develops over many years, optimal SVG gene therapy will likely require a vector that can express a therapeutic transgene in blood vessels for years.…”

An appropriately sized soft polyester external stent prevents enlargement and neointimal hyperplasia of a saphenous vein graft in a canine model

“…Intimal hyperplasia in the vein graft wall is thought to be one of the main causes for such poor long-term findings. As such, many studies have tried to inhibit intimal hyperplasia (5)(6)(7)(8)(9). External stent placement around the vein graft has shown remarkable success in suppressing intimal hyperplasia (10)(11)(12).…”

Medical Biotechnology: Problems and Prospects in Bangladesh

“…[58][59][60] Whatever the vector, there are two methods by which gene therapy can be carried out: 1. in vivo gene therapy, in which the vector is injected into the body and has to find its way to the target tissue 2. ex vivo in which a sample of tissue is taken from the patient, treated with the vector and then replaced. 61 Currently active trials of gene therapy are going on over such varied diseases cystic fibrosis, vein graft rejection, psychiatric d i sorders, inner ear developmental anomalies, brain tumors, mitochondrial genetic diseases. [61][62][63][64][65][66][67][68][69] The use of viruses to deliver genes has shown risks to human health, making trials with these viruses controversial.…”

“…61 Currently active trials of gene therapy are going on over such varied diseases cystic fibrosis, vein graft rejection, psychiatric d i sorders, inner ear developmental anomalies, brain tumors, mitochondrial genetic diseases. [61][62][63][64][65][66][67][68][69] The use of viruses to deliver genes has shown risks to human health, making trials with these viruses controversial. Another method involves the use of liposomes, hollow membranous spheres which encapsulate the gene.…”