Embargoed For Release: August 27, 1998 - 5 p.m. (EST)
Contact: Karen Cummings or Steve Singer, (617) 632-4090, [email protected]
OFFSHOOT OF CANCER RESEARCH YIELDS HEART DISEASE DISCOVERY
Dana-Farber researchers achieve reduction in atherosclerosis
in mice through genetic "knock out" technique
BOSTON - In an unexpected spin-off of cancer research that began more than a decade ago, scientists at Dana-Farber Cancer Institute have succeeded in reducing atherosclerosis - hardening of the arteries - by 80 percent in mice by blocking a gene in mice that is virtually identical to one in humans.
The finding, reported in the August 28 issue of Molecular Cell, may lead to an entirely new approach to reducing coronary artery disease in humans, the number one killer in the Western world. Instead of lowering cholesterol levels as current treatments do, the new approach changes the behavior of cells involved in the arterial blockage that can lead to heart attacks.
"The clinical payoff may come relatively soon," says the study's senior author, Barrett Rollins, M.D., Ph.D., of Dana-Farber, "because drugs that block the effects of this gene are already under development at several pharmaceutical companies."
The study centers on a protein called MCP-1, which is responsible for attracting monocytes - a type of white blood cell - to parts of the body where infection or tissue damage has occurred. Researchers have long known that monocytes play a role in the formation of arterial plaque - a mixture of cholesterol and other substances that builds up in the inner lining of arteries and gradually impedes blood flow. This led scientists to hypothesize that if they could "knock out," or block, the gene for MCP-1, they could significantly slow the process of arterial blockage.
The MCP-1 gene was discovered in 1983 by Charles Stiles, Ph.D., also of Dana-Farber, during research into genes that control cell growth and division. Although the function of MCP-1 was not known initially, its ability to attract monocytes became clear later.
"This is a powerful example of how research that begins in one area - in this case, cancer - can benefit patients in a completely different area," Rollins says. "We're hopeful that therapies derived from this discovery can significantly reduce the chances of heart disease in people at risk for this condition."
In the current study, researchers used mice whose arterial systems had been genetically modified to resemble those of humans with heart disease. Researchers knocked out MCP-1 in a group of the mice and fed them a high-cholesterol diet, while feeding a similar diet to mice whose MCP-1 was intact.
They found that while all the mice developed high serum cholesterol levels, atherosclerotic deposits were reduced by 80 percent in the mice whose MCP-1 gene had been disabled. The reduction in blockage was accomplished without major side effects.
"We showed that by blocking the function of a single gene, we were able to reduce the formation of arterial plaque by a significant amount," says Rollins, who led the team that included Peter Libby, M.D., chief of the Division of Cardiology at Brigham and Women's Hospital. "Our findings suggest an entirely new way to treat people at risk for the disease. By giving drugs that block the effects of MCP-1, we may be able to reduce atherosclerotic buildup at its earliest stages."
Inhibitors of MCP-1 could be especially useful for patients who undergo so-called "balloon" angioplasties to clear arterial blockage, Rollins says. Between 30 and 40 percent of such patients develop restenosis, the re-emergence of blockage at the site from which it has been cleared.
News that a gene discovered in his laboratory may lead to a new treatment for atherosclerosis is "very satisfying," says Stiles, of Dana-Farber. "When you undertake basic molecular research, you never know where the ultimate benefit will be. It's rewarding to see the direction this work has taken."
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