New gene therapy shows promise in improving success rate of leg bypass surgeries

November 06, 1999

ATLANTA, Nov. 7 -- Combining a new gene therapy technique with conventional bypass surgery may significantly reduce the rate of re-blockages, researchers reported today at the American Heart Association Scientific Sessions. "These results are very encouraging and could represent a new treatment that would vastly improve the long-term success rate of all bypass procedures," says study co-author Victor J. Dzau, M.D., professor of medicine at Harvard Medical School and chief of medicine at Brigham and Women's Hospital, Boston.

The patients in the study all needed surgery to bypass blocked vessels in the leg resulting from peripheral vascular disease (PVD). Without treatment, PVD can result in pain and possibly amputation due to the obstructed blood flow in the legs. Like bypass surgery for coronary arteries, surgery for PVD involves the harvesting of veins from other parts of the body, which are then grafted (attached) around the blocked section of artery. This procedure opens the flow of blood by bypassing the blocked vessel.

"As many as half of all bypass surgeries fail five to ten years after the operation because the vessels used to bypass the clogged arteries become blocked themselves. Further research is needed, but this procedure could end up having a major impact not only on long term success of all types of bypass surgery, but also on the cost of treating graft blockages," says Michael J. Mann, M.D., co-author and a surgical resident at Brigham and Women's Hospital. Graft blockages are treated with another operation or with angioplasty, which uses a balloon-tipped catheter to widen blood vessels.

Seventeen of the patients in the study received the gene therapy prior to the bypass surgery. The gene therapy technique called "pressure-mediated transfection" takes only about 10 minutes, and is relatively inexpensive. The vein to be grafted is bathed in a fluid containing small pieces of DNA -- the material from which genes are made -- which short-circuits the genes that can lead to growth of an abnormal layer in the wall of the vein, and eventually a blockage. The other 16 patients in the study had conventional bypass surgery without the gene therapy.

The researchers decided to study bypass surgeries of the leg rather than those of the heart because they are easier to monitor with non-invasive ultrasound test. The majority of graft blockages could be detected in their earliest stages and patients could receive the necessary treatment for these early graft failures.

Dzau and Mann have spent years refining the gene therapy technique. The researchers say the gene therapy is quick and inexpensive, and also doesn't appear to cause any side effects.

In the year following the bypass surgery, the patients who received the gene therapy had less than half of the failures of patients who received surgery alone (29 vs. 69 percent). A failure included blockage of the graft or a need for another procedure. Although statistically significant, Dzau stressed that the number of patients in the study was small.

"The grafts not treated with the 'gene blockade' continued to fail throughout one year of follow-up, whereas no failures were observed between six and twelve months in the patients who had received the gene therapy," Dzau says. He adds that this may be because the veins that received the gene blockade more closely resembled the arteries they were bypassing.

"The veins that we harvest for bypass surgery have much thinner walls than arteries, which makes it more difficult for the walls to withstand the tremendous pressure from the blood that flows through them. In developing the gene therapy, we targeted genes believed to influence how veins adapt after surgery, causing the veins to behave like the arteries," Dzau says.

The thin-walled veins normally respond to the increased pressure by producing a layer of cells that cause an abnormal thickening of the vein wall. In previous studies on animals, gene therapy seemed to encourage the veins to behave like the more muscular-walled arteries, without the buildup of cells, he says. "There were no failures after six months in the veins treated with gene therapy. This suggests that the human veins receiving our genetic treatment may have adapted the same way as in the previous animal studies. This gene therapy may have a significant impact on the success rate of all types of bypass procedures without much difficulty or expense," says Mann.

Co-authors are Anthony Whittemore, M.D.; Magruder C. Donaldson, M.D.; Michael Belkin, M.D.; Michael S. Conte, M.D.; Joseph F. Polak, M.D., and John Orav, Ph.D.

American Heart Association

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