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Blood-vessel growth genes stop making sense.

Using a new genetic technology called antisense, researchers have completely shut down the operation of a gene that can cause the walls of arteries to thicken, reducing blood flow to a trickle. The scientists hope their strategy will one day benefit patients undergoing balloon angioplasty. a vessel-widening procedure that sometimes backfires, prompting the growth of cells within arterial walls.

The research team, led by Robert D. Rosenberg of the Massachusetts Institute of Technology in Cambridge, used antisense to prevent arterial thickening among rats whose neck arteries had been reamed by balloon angioplasty Rosenberg, who also holds a post at the Harvard Medical School's Beth Israel Hospital in Boston, and his colleagues report their results in the Sept. 3 NATURE.

Each year, roughly 260,000 people in the United States undergo balloon angioplasty. Surgeons snake a catheter tipped with an uninflated balloon through the fat-clogged arteries of atherosclerosis patients. By inflating the balloon, the surgeons compress the deposits, widening the arteries.

However, balloon angioplasty has an undesired effect on an estimated onethird of those who receive the therapy. In these patients, the friction of the inflating balloon spurs smooth-muscle cells lining the arteries to grow and divide, causing the arteries to narrow again.

Earlier this year, Rosenberg's team and a separate research group reported that smooth-muscle cells grown in laboratory culture switch on a gene named c-myb before they begin dividing. This "protooncogene" spurs normal cell growth and differentiation in a wide range of tissues. When it becomes damaged through mutation, it can cause the uncontrolled growth characteristic of cancer.

Rosenberg and his co-workers set out to determine whether they could prevent arterial thickening by inactivating this growth-promoting gene. They applied a gel containing short oligonucleotides-- the chemical building blocks of genetic material - to the neck arteries of angioplasty-treated rats. These "antisense oligonucleotides" were designed to bind to and block the "sense" of a chemical message called RNA, which genes use to direct a cell to make proteins. By specifically blocking the RNA of the c-myb gene, Rosenberg's team hoped to prevent it from prompting the inappropriate growth of smooth-muscle cells in the rats' arteries.

The researchers found that the arteries of rats treated with the antisense therapy contained no detectable levels of c-myb RNA, while the arteries of rats treated with a control compound had high levels of the substance. Moreover, the arteries of the antisense-treated rats showed virtually no muscle-cell growth after two weeks, whereas those of the control rats thickened considerably.

Rosenberg says he is "enthusiastic but cautious" about the prospects of using a similar approach in humans who undergo balloon angioplasty. He has applied for a U.S. patent on the technique, and is helping to form a company to commercialize the therapy.

"This is a very flexible approach to turning off [artery-thickening] genes," Rosenberg asserts. "[The c-myb gene] is one target, but there could be many other targets." He hopes to begin human clinical trials of antisense compounds within two years.

Volkhard Lindner, a vascular biologist at the University of Washington in Seattle, calls antisense "an interesting concept" for preventing arterial thickening after balloon angioplasty But he cautions that Rosenberg's team has not proved that the antisense compound specifically blocks c-myb without interfering with other genes. He also suggests that the group may have jumped the gun by looking for arterial thickening among the rats after waiting only two weeks. Such thickening sometimes takes six weeks to develop, Lindner says.

-- C Ezzell
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Title Annotation:new technology can stop genes that cause thickening of artery walls
Author:Ezzell, Carol
Publication:Science News
Date:Sep 5, 1992
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