Researchers at Jefferson Medical College have found that a normally protective anticancer gene may be an effective add-on to angioplasty in treating blocked coronary arteries. The gene, Rb2/p130, puts the brakes on runaway cells, halting rapid growth.
The scientists, led by Pier Paolo Claudio, M.D., Ph.D., assistant professor of pathology, anatomy and cell biology at Thomas Jefferson University in Philadelphia, and Giancarlo Condorelli, M.D., Ph.D., associate professor of cardiology at the University La Sapienza in Rome, showed in rats for the first time that the gene, termed a "tumor suppressor gene," may have therapeutic potential for treating clogged arteries.
"In addition to Rb2's potential use in gene therapy for cancer," Dr. Claudio says, "we found that it could be useful in stopping normal smooth muscle cells from growing."
In some chronic diseases, arteries are blocked due to excessive smooth muscle cell buildup. Coronary arteries may become blocked because normal cells clump and cake on artery walls. Physicians frequently turn to angioplasty, which entails expanding a balloon attached to a catheter, breaking up the blockage. But a third or more patients, within three months, experience reclogged arteries. Some researchers suspect angioplasty triggers biochemical signals to cause cells to grow again, stopping up arteries.
Dr. Claudio and his co-workers used harmless viruses called adenoviruses as syringes to deliver the Rb2/p130 gene into the arteries of rats with simulated coronary disease. The researchers looked at the levels of Rb2/p130 after 20 days using biochemical analysis. The Rb2/p130 gene continued to show a "pronounced expression in the arterial walls, preventing the proliferation of smooth muscle cells and restenosis," he says.
The scientists reported their findings Nov. 26 in Circulation Research, a journal of the American Heart Association.
In angioplasty, "the wall injury stimulates smooth muscle cells to proliferate," Dr. Claudio says. "We want to give the wall time to repair the damage but we don't want to allow the smooth muscle cells to proliferate and clog the artery." He proposes using the gene as an adjunct to angioplasty, which he believes, will have long-lasting effects.
He plans to test the treatment in transgenic mice, which carry the human genes for high cholesterol and which have chronic heart disease and clogged arteries. "We're going to see if we can use this same treatment with the viruses on the chronic disease model, which is closer to the human disease condition," he says.
The gene, he explains, prevents cell growth by acting on a particular part of the cell development cycle to suppress various biochemical factors that promote growth.
Dr. Claudio believes this is the first reported application of Rb2/p130 for heart disease. If continuing studies of chronic disease work as well, he says, they might be able to use the gene someday in human trials.
In earlier work, Dr. Claudio and Antonio Giordano, M.D., Ph.D., associate professor of pathology, anatomy and cell biology, demonstrated for the first time in laboratory animals that Rb2/p130 could actually block tumors from growing. A damaged version of the gene has been implicated in several cancers, such as lung, breast and endometrial. Rb2's normal job is to put a halt on potential tumors from growing, essentially "holding back cells' cancerous state," Dr. Claudio explains.
Journal
Circulation Research