Transcription factor decoys for the prevention of vein bypass graft failure.

Abstract

Failure of vein bypass grafts, performed for either coronary or lower extremity arterial occlusions, is a common clinical problem that incurs significant morbidity and mortality. Vein grafts provide a unique opportunity for genetic interventions, since the target tissue is available for manipulation ex vivo prior to implantation, and prior to the onset of the pathophysiologic events that lead to graft disease. Smooth muscle cell proliferation is a hallmark of neointimal hyperplasia in vein grafts and arteries, and is an attractive target for molecular therapy. Gene blockade strategies can be accomplished by delivery of small oligodeoxynucleotides (ODN) that target specific mRNAs ('antisense') or that competitively inhibit transcription factors ('decoys'). Transcription factors are attractive targets for molecular therapy since they influence the expression of a large number of genes involved in a coordinated cellular program. An ODN decoy approach has been developed targeting the transcription factor E2F, which is critically involved in cell cycle progression. Brief (10 minute) incubation of the ODN in solution, using non-distending pressure, results in efficient delivery of the ODN to >80% of cells in the vein wall. Preclinical studies in a rabbit model of vein grafting and hypercholesterolemia demonstrated a marked reduction in neointima formation, as well as prolonged resistance to graft atherosclerosis. Phase I/II studies conducted in lower extremity and coronary bypass patients have demonstrated safety and feasibility, and have also suggested possible efficacy. Large, randomized multicenter, phase III trials are currently under way to evaluate the efficacy of E2F decoy treatment on preventing vein bypass failure in both peripheral and coronary grafting procedures. These studies herald the arrival of a new class of molecular agents into the armamentarium of cardiovascular therapies.