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Genetic Approach Could Aid Angioplasty Patients

An MIT research team led by Dr. Robert D. Rosenberg has prevented the reclosure of the carotid artery in animals after angioplasty by using an innovative genetic approach known as "antisense."

Artery reclosure, or restenosis, has been a key complication of human balloon angioplasty and coronary bypass procedures, despite technological advances.

According to national hospital discharge data, 260,000 persons underwent a first angioplasty and 262,000 a bypass in 1990. About 30 percent of the angioplasties and at least 10 percent of the bypasses will reclose-rates that would be dramatically improved by the new approach.

The work, published in the journal Nature in its September 3 issue, was done by Dr. Rosenberg, professor of medicine and biology, and colleagues under a grant from the National Heart, Lung, and Blood Institute. Dr. Rosenberg holds both MD and PhD degrees. His principal associates in the research were Dr. Michael Simons, a postdoctoral fellow in the laboratory, and Dr. Elizar Edelman, an associate professor in the Harvard-MIT Division of Health Sciences and Technology.

The research team is part af an NHLBI-funded Program of Excellence in Molecular Biology at MIT. Since 1988, the agency has created three such programs around the country to promote the application of molecular biology methods to important problems in heart, lung and blood research.

"The Institute is extremely proud of this research," said NHLBI director Dr. Claude Lenfant. "Balloon angioplasty and coronary bypass have been the two major treatments for coronary artery disease. This basic science development could give physicians a powerful new tool to treat that disease."

"This important research also could open a new door in medicine," he said, "leading to a novel type of therapy that is non-toxic and able to affect only a specific site rather than an organ system or the whole body."

Antisense technology, only 15 years old, previously had been applied in plants, animal cell cultures and primitive one-cell organisms. This is its first in vivo use in mammals.

The term "antisense" refers to the novel technique's method of interfering with a gene's activity. Normally, a gene delivers its instructions to messenger ribonucleic acid (mRNA), which then assembles the desired protein. With the new technique, researchers dispatch a string of specially designed nucleotides (called "antisense oligonucleotides") to bind to a complementary sequence of nucleotides on the mRNA. The process blocks the mRNA from carrying out its instructions.

In this case, the researchers blocked the production of c-myb protein, which is needed for division of smooth muscle cells. The proliferation of smooth muscle cells is a critical factor in artery reclosure after an angioplasty or bypass procedure.

The antisense nucleotides were applied in a solution that gelled upon contact with the rat artery. Rats underwent a form of balloon angioplasty that assured reclosure would occur.

Arteries treated with antisense oligonucleotides showed virtually no accumulation of smooth muscle cells two weeks after the therapy, the period during which reclosure normally occurs in rats, while arteries treated with only angioplasty displayed extensive cell accumulation. Preliminary tests with rabbits indicate similar positive results.

The researchers believe the same technique can be used to treat human coronary arteries. For instance, small quantities of antisense oligonucleotides could be applied locally at the time of an angioplasty or bypass procedure.

Such treatment would improve the lives of thousands of Americans because coronary artery disease is a major cause of morbidity and mortality in the United States, affecting at least six million people and causing 500,000 deaths each year.

Before its application to humans, however, safety tests must be conducted to assure against unwanted side effects. If these tests succeed, human trials could begin in two years.

A version of this article appeared in the September 16, 1992 issue of MIT Tech Talk (Volume 37, Number 5).

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