Genetic Engineering - New Approach To Prevent Blockages After Bypass Operations

November 09, 1997

ORLANDO, Nov. 9 -- A form of genetic engineering is being tested that may prevent blockages that occur after bypass surgery in the coronary arteries of the heart and the arteries of the legs, scientists reported today at the American Heart Association's 70th Scientific Sessions.

The gene therapy, designed to prevent grafted vessels attached in bypass surgery from failing, was performed successfully in four patients who underwent bypass surgery to circumvent blocked leg vessels in an initial phase of the current study.

Their grafted leg vessels have remained unobstructed in the nine months since they were genetically treated, says the study's author Michael Mann, M.D., instructor in medicine at Harvard Medical School, who directs the study with Victor J. Dzau, M.D., chairman of medicine at Brigham and Women's Hospital at Harvard.

Up to 50 percent of cardiac and leg bypass surgeries eventually fail because they become obstructed with atherosclerotic plaque and new cell growth, Mann says.

Researchers at other medical centers are expected to join the Harvard team in a large study of the technique in individuals who have blocked leg vessels. Pending the outcome of that study, gene therapy for coronary bypass surgery could be the next step, says Mann.

The gene therapy approach developed by Mann and his colleagues is designed to reduce the growth of new cells lining the grafted vein. This growth, a condition called neointimal hyperplasia, renders the vessel especially susceptible to the formation of atherosclerotic plaque, the waxy substance that can form in the arteries and block blood flow and trigger a heart attack.

The experimental gene therapy involves bathing the vein, before it is grafted, in a solution that contains an oligodeoxynucleotide (ODN), a short segment of the genetic material DNA. In laboratory experiments, the ODN, called a transcripton factor decoy, blocks the activity of genes necessary for neointimal hyperplasia by inhibiting the function of a protein inside the nuclei of cells. The protein, a transcription factor, is responsible for gene activation "It takes only 10 minutes to treat the graft, so there is no major delay in the surgery," says Mann.

The Harvard researchers now are testing the technique in a double-blind, randomized trial designed to compare the new treatment to conventional bypass surgery. About 40 patients have enrolled and have been randomly assigned to one of two groups: gene therapy is used in one group, and in the second, it is not. To prevent biasing the outcome of the study, neither the patients nor surgeons know whether a particular graft is treated genetically until after the results have been analyzed by the study's statisticians, says Mann. The analysis will occur in about two years.

A multi-center, randomized and double-blind trial with three study arms involving over 1,000 patients has been planned, says Dzau adding that similar studies will be conducted to evaluate this genetic therapy in cardiac bypass grafts.

"To my knowledge, this will be the first comprehensive, large clinical trial evaluating gene therapy and genetic engineering in the cardiovascular area," notes Dzau. "Previous efforts have focused on smaller observational studies. I believe that the impact of this research may be quite substantial, demonstrating the potential of genetic technology in human therapy."

The vein graft is vulnerable to atherosclerosis and new cell growth in part because it is being used to perform a function for which it was not intended, explains Mann. The majority of bypass procedures involve use of the saphenous vein, a long blood vessel located in the leg. Veins, which are vessels that carry blood back toward the heart, are exposed to relatively low pressure from circulating blood. When used as a bypass graft, the vein is asked to function as an artery, carrying blood from the heart. The higher blood pressure exposes the graft to more stress.

The increased stress and trauma of grafting stimulates neointimal hyperplasia, Mann explains.

"Essentially, we're trying to manipulate the biology of the vein graft and make it behave more like an artery," says Mann. "Even though we are evaluating the technique in peripheral bypass procedures, the approach is conceptually the same for coronary bypass."

"Experiments have also shown that when neointimal hyperplasia is genetically inhibited, vein grafts increase their normal muscle content and appear more like arteries," says Mann. "In addition they resist the rapid development of atherosclerosis usually seen in vein grafts."

Co-authors are Anthony Whittemore, Magruder Donaldson, Michael Belkin and E. John Orav.
Media advisory: Dr. Mann can be reached at (617) 732-8969. (Please do not publish telephone numbers.)

American Heart Association

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