Genetic Manipulation of Human Coronary Artery Bypass Grafts with E2F Decoy Reduces Clinical Graft Failure


Eberhard Grube
The Heart Center
Siegburg, Germany

Investigators have conducted the first randomized, controlled study of genetic manipulation of coronary artery bypass grafts. They found a genetic decoy that interferes with an important transcription factor and might reduce morbidity and mortality in vein graft failure.

Neointimal hyperplasia, and the subsequent acceleration of atherosclerosis, result in a high rate of vein graft failure (30% to 40%). One potential approach to counteract this process is gene suppression using the E2F decoy. This is an oligonucleotide that binds and inactivates the E2F cell-cycle transcription factor.

Blocking this transcription factor prevents proliferation and growth of vascular cells and subsequent atherosclerotic lesions. In addition, the genetic intervention stimulates wall thickening of the graft. Thus, the vein works more like an artery and maintains better patency over time.

A 1999 Lancet article describes the pre-clinical experience with E2F decoy. Researchers reported that this agent inhibited vascular smooth muscle proliferation, and prevented vein graft disease in leg bypass graft procedures.

In a follow-up study, German investigators randomized 200 patients undergoing coronary artery bypass graft procedure to receive E2F decoy or placebo. At this meeting, those researchers reported a significant 30% relative reduction in the composite of vein graft failure and death for the group that received E2F decoy.

Intravenous ultrasound revealed that a 30% decrease in vessel wall volume in the E2F decoy group. Investigators said this supports the hypothesis that this treatment modifies the biology of the vein graft, making it more resistant to atherosclerosis.

This treatment was safe and well tolerated, and there was no difference in adverse events between groups. The graft is treated with the E2F decoy ex vivo, so the patient has minimal systemic exposure.

There was a trend suggesting fewer major adverse cardiac events in the E2F decoy treatment group, but the study did not have the statistical power to confirm this difference. Next, investigators plan to conduct a pivotal phase III study in coronary artery bypass graft patients.


Reporter: Andrew Bowser