Researchers in Iowa are working on a gene therapy solution for a surgical problem that kills perhaps 25,000 Americans each year.

The problem is cerebral vasospasm, a sudden and deadly tightening of arteries in the brain that too often occurs after surgery for what is called a subarachnoid stroke, says Dr. Donald Heistad, professor of cardiology at the University of Iowa College of Medicine. Each year about 100,000 Americans experience such hemorrhages, in which a blood vessel bursts in the brain.

While this kind of stroke accounts for only 10 percent of all strokes in the United States, it is responsible for 25 percent of all stroke deaths, and it often occurs in young people.

"The surgical approach is standard," Heistad says. "We take care of the ruptured vessel and clip it to prevent rebreaking. The problem is that whether we clip or not, about 30 to 40 percent of patients have terrible vasospasm [a sudden constriction of a blood vessel] and a second stroke. It is a clinical problem without a treatment."

The proposed solution is to deliver a gene for a molecule that prevents vasospasm to the site of the stroke, Heistad and his colleagues report in the Oct. 27 issue of Circulation Research: Journal of the American Heart Association. The molecule is calcitonin gene-related peptide (CGRP), and early work with animals indicates the approach has promise, although it needs refinement.

Not ready for humans yet

Tests so far have packaged the CGRP gene in an adenovirus, a virus that is a widely used vector, or delivery mechanism for gene therapy work. "It is a standard vector but not a perfect one," Heistad says. "It causes inflammation, so we are very reluctant to try it in humans."

One possible alternative is a "gutted" adenovirus, which has had all its genetic material removed. The gene will still contain CGRP, which is "the most potent cerebral vasodilator known," says Heistad -- so potent that British attempts to give it by injection were abandoned a decade ago because the patients' blood pressure dropped precipitously.

Results have been good in the first experiments on rabbits, Heistad says. They were first injected with a drug to induce vasoconstriction and then were given injections of the gene-carrying virus. The diameter of their cerebral arteries increased up to 25 percent after treatment. Just as important, the gene treatment did not result in a severe decline in blood pressure.

Rabbit studies are continuing. "We are trying to lower the dose of the virus," Heistad says. "We are also doing safety and efficacy tests in experimental models such as dogs and monkeys."

Human tests could follow "in a few years, after we demonstrate safety and efficacy in animals," he says. If it works as hoped, he says gene therapy ultimately could be a routine accompaniment to surgical repair of a stroke.

Dr. Matthew Howard, an associate professor of surgery and neurology at Iowa who is not a member of the research team, says the work "is very important research that is likely to have tremendous impact on clinical neurosurgery. It brings hope that future patients will be spared a devastating stroke."

(From HealthScout)