Artery de-clogging gene therapy shows promise for future

August 09, 1994|By Gina Kolata | Gina Kolata,New York Times News Service

Every year, about 400,000 Americans have a procedure called angioplasty, in which tiny balloons are inflated in their coronary arteries in an attempt to push artery-clogging plaque against the blood-vessel walls.

And every year, one-third to one-half of these operations fail within six months: The plaque comes back with a vengeance.

Cardiologists have tried about 50 drugs to stop this process, called restenosis, but none have worked.

Now two groups of investigators have shown that, in animals at least, they can use gene therapy to prevent plaque from growing back. The technique involves inserting a suicide gene into the cells that proliferate to clog the arteries.

One group, led by Dr. Elizabeth G. Nabel and Dr. Gary J. Nabel of the University of Michigan in Ann Arbor, who are married, worked with pigs, a species that closely resembles humans in the size of their blood vessels and in their propensity to develop atherosclerosis. The balloon angioplasty was done in the pigs' groin arteries. The Nabels' work is published in the current issue of the journal Science.

The second group, led by Dr. Toren Finkel and Dr. Stephen E. Epstein of the National Heart, Lung and Blood Institute in Bethesda, Md., did virtually the same experiment with the same results in the neck arteries of rats.

Their paper, based on work with 70 rats, will be published next month in The Proceedings of the National Academy of Sciences.

Cardiologists were enthusiastic about the results but said that more work must be done before the method can be tried in human patients.

Wave of the future

"It's exciting," says Dr. David Hathaway, director of the Krannert Institute of Cardiology at Indiana University.

"It is definitely the wave of the future." But, he adds: "It's a little bit like the first car or the first airplane. There is a long way to go before it becomes standard therapy."

Dr. R. Sanders Williams, the chief of cardiology at the University of Texas Southwestern Medical Center in Dallas, says, "This work is quite high-tech and futuristic, but it's also extraordinarily promising."

Nonetheless, he adds, "it's probably overly enthusiastic to think that it will move directly to the clinic."

The reclogging of an artery after it has been opened with a balloon is caused by a tumorlike growth of the smooth-muscle cells that line the artery wall. The balloon scrapes off the lining of the artery, leaving a raw surface and exposing the smooth- muscle cells underneath. Then these cells start to divide and may pile one on top of another until they form a mass large enough to block the artery.

The conventional approach has been to try to treat patients with drugs to prevent the cells from proliferating.

But even if researchers had found a drug that worked, says Dr. Judith Swain, chief of cardiovascular medicine and professor of medicine and genetics at the University of Pennsylvania School of Medicine in Philadelphia, it would be far from an ideal approach: "There are miles of blood vessels in the body, but all you want to treat is a quarter to an eighth of an inch.

"Every drug you can give has side effects, and if somebody is taking pills in an attempt to treat something that is a quarter of inch, it's a bit of overkill."

Another alternative would be to deliver drugs precisely to the area where they are needed, but Dr. Gary Nabel says they would be washed away by the bloodstream before they had a chance to act.

"You can never give enough drugs in an artery because they are washed away very, very quickly," he says.

Altering the cells

That left investigators with the gene therapy approach.

Their aim was to alter the cells themselves so they would die, stop dividing or be uniquely susceptible to drugs that otherwise would not harm them.

"We and probably 25 to 30 labs across the country are working on restenosis with a gene therapy approach," Dr. Swain says.

Dr. Elizabeth Nabel says she began by looking at genes for substances that cells normally use to stimulate growth, reasoning that if the smooth-muscle cells activate just one of these genes, it might be possible to block the gene and so block the growth.

But it turned out that cells use a variety of growth-stimulating genes. "There are multiple redundant pathways," she says, and it was not feasible to think of blocking them all.

That led her to think of trying to simply destroy all proliferating cells in the area, regardless of what genes they were using to make themselves grow.

Infecting the genes

To do this, the Nabels and, independently, Dr. Finkel and Dr. Epstein infected the smooth-muscle cells with a genetically engineered adenovirus, a type of virus that ordinarily causes colds in humans. These adenoviruses were designed so that once they got into cells, they would not be able to multiply and spread to other cells.

Instead, they would park their DNA in the cells' nuclei, next to the DNA in the cells. When cellular genes were turned on, so were the viral genes.

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