Gene Therapy for the Extension of Vein Graft Patency: A Review

Abstract

The mainstay of treatment for long-segment small-vessel chronic occlusive disease not amenable to endovascular intervention remains surgical bypass grafting using autologous vein. The procedure is largely successful and the immediate operative results almost always favorable. However, the lifespan of a given vein graft is highly variable, and less than 50% will remain primarily patent after 5 years. The slow process of graft malfunction is a result of the vein's chronic maladaptive response to the systemic arterial environment, its primary component being the uncontrolled proliferation of vascular smooth muscle cells (SMCs). It has recently been suggested that this response might be attenuated through pre-implantation genetic modification of the vein, so-called gene therapy for the extension of vein graft patency. Gene therapy seems particularly well suited for the prevention or postponement of vein graft failure since: (1) the stimulation of SMC proliferation appears to largely be an early and transient process, matching the kinetics of current gene transfer technology; (2) most veins are relatively normal and free of disease at the time of bypass allowing for effective gene transfer using a variety of systems; and (3) the target tissue is directly accessible during operation because manipulation and irrigation of the vein is part of the normal workflow of the surgical procedure. This review briefly summarizes the current knowledge of the incidence and basic mechanisms of vein graft failure, the vector systems and molecular targets that have been proposed as possible pre-treatments, the results of experimental genetic modification of vein grafts, and the few available clinical studies of gene therapy for vascular proliferative disorders.

Ex vivo Pulsatile Perfusion of Human Saphenous Veins Induces Intimal Hyperplasia and Increased Levels of the Plasminogen Activator Inhibitor 1

“…Histomorphometry demonstrated significant changes in intimal thickness and media thinning after 7 and 14 days of pulsatile perfusion. The enlargement of the venous wall in response to increased flow is generally correlated with tissue proliferation [18,19] . Concerning the media, the role of pulsatility, flow, pulse pressure, and medium viscosity in medial hypertrophy has not been clearly de- fined in ex vivo models [20,21] .…”

Factors affecting arteriovenous fistula dysfunction: A narrative review

“…173 Another useful approach is local gene therapy to prevent NIH or induce remodelling. 192 In addition, the use of infrared radiation therapy has been reported to improve AVF maturation and primary and secondary patency rates by inhibiting intimal hyperplasia, reducing oxidative stress and inflammation and improving endothelial function. [174][175][176][177][178]193 Although new preventive and therapeutic approaches are in development and aimed at targeting certain mechanisms associated with AVF dysfunction, in order to promote outward remodelling and inhibit NIH formation, a multi-target approach is necessary, considering the complexity of this pathogenic process.…”

The effect of storage solutions, gene therapy, and antiproliferative agents on endothelial function and saphenous vein graft patency

“…Gene therapies primarily target the proliferative and inflammatory processes leading to IH . PREVENT IV was the first major clinical trial to apply genetic therapy on vein grafts in CABG surgery.…”