Jan. 25, 2000 DALLAS, Jan. 25 – A gene therapy that packs a one-two punch may eventually lead to new treatments designed to keep arteries from re-blocking following bypass surgery, British researchers reported today in Circulation: Journal of the American Heart Association.
"Coronary bypass surgery is the most common surgery in the United States, with more than 600,000 procedures performed each year. However, up to half of the procedures fail within 10 years because the vessel re-blocks, and 20 percent of all bypass surgeries are now repeat procedures," says lead author Sarah J. George, Ph.D., a non-clinical lecturer at the Bristol Heart Institute, University of Bristol, U.K.
The gene therapy procedure is significant because it appears to work on two different levels – first by inhibiting a molecule that encourages an overproduction of cells that can block a blood vessel and secondly, by destroying those cells when they do form – writes Joseph Loscalzo, M.D., Ph.D., of the Boston University School of Medicine and the Whitaker Cardiovascular Institute, in an editorial that accompanies George's study.
Atherosclerosis is caused by a build up of fatty deposits and an overgrowth of cells that collect on the inside walls of the arteries, eventually leading to blood clots that can prevent the heart from getting enough oxygen-rich blood. To restore blood flow, surgeons bypass the blocked arteries with veins that are usually taken from the leg. However, the new stretch of vessel – known as the bypass graft – is susceptible to re-blockage either from a blood clot that develops in the days following surgery or from an overgrowth of cells on the inner wall of the vein.
"If we could find a way to block that abnormal layer from growing, it could make the grafts last longer and delay or even avoid second bypass surgeries," George says. "Gene therapy could also prolong life in these patients."
George and her colleagues targeted molecules called matrix metalloproteinases (MMPs) that encourage the growth of cells, a process that is similar to scar tissue formation, with the molecule playing an important role in the process.
Previous studies in lab dishes had indicated that a type of molecule called tissue inhibitor of metalloproteinase (TIMP-3) could inhibit the overgrowth of cells and destroy those that did form.
The researchers found that the molecule reduced abnormal cell growth by 84 percent in the human organ cultures two weeks after it was introduced. The molecule stayed in the grafts and did not spread to surrounding tissue.
In the live pig experiments, the cell proliferation was 58 percent lower in the vein grafts 28 days after introduction, the researchers report.
Researchers say the study is the first to demonstrate that increasing the production of a TIMP-3 in human tissue can reduce the undesirable thickening of the vessel. This is also the first to show these effects in a live animal.
"This study shows the potential of this type of gene therapy for re-blockage of vessels following bypass surgery," she says.
In his editorial, Loscalzo pointed out that further study is needed to make sure that the cellular death caused by the gene therapy does not cause any adverse effects to the vessels near the bypass graft.
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