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Release: Oct. 27, 2000

UI researchers study potential gene therapy for preventing certain type of stroke

IOWA CITY, Iowa -- After an aneurysm ruptures during a condition known as subarachnoid hemorrhage, a neurosurgeon typically clips the aneurysm and removes the clot. Usually the patient does well following the procedure but in 30 to 40 percent of cases, people soon develop a post-aneurysm condition known as cerebral vasospasm, which constricts brain arteries and can cause a fatal or debilitating delayed stroke.

Currently, little can be done to prevent this dangerous and frequently lethal condition. However, research in animal models by University of Iowa Health Care investigators suggests that gene therapy to the brain may be key to preventing and treating cerebral vasospasm. The findings appear in the Oct. 27 issue of Circulation Research: Journal of the American Heart Association.

The fact that cerebral vasospasm cannot be treated or prevented using existing drugs was one reason the UI team decided to study the potential of gene therapy, said principal investigator Donald Heistad, M.D., Zahn Professor of Cardiology and deputy director of the UI Cardiovascular Center. Heistad is also a staff physician at the Veterans Affairs Medical Center in Iowa City.

"Even after a subarachnoid hemorrhage is successfully treated with a clip and removal of the clot, vasospasm -- severe constriction of arteries that feed blood to the brain -- can develop a few days to three weeks later in nearly four of every 10 patients treated for the initial rupture," Heistad said.

While the exact causes of vasospasm are not known, researchers do know that a certain neuropeptide called calcitonin gene-related peptide (CGRP) has the potential to alleviate the condition.

"Because the problem in vasospasm is excessive constriction, we wanted a potent dilator to counteract the constriction," Heistad said. "Some dilators don't work in the presence of a subarachnoid hemorrhage, but previous research has shown that CGRP does."

British researchers used the peptide intravenously in patients about 10 years ago to treat the same post-stroke condition but the dilator dropped their blood pressure so precipitously that its use was abandoned.

Using animal models (rabbits), the UI team found that gene transfer of CGRP prevents the dangerous artery constriction without causing severe declines in blood pressure.

"Our ultimate goal using this gene therapy is to be able to administer the peptide locally into the cerebral fluid around the human brain without dangerously lowering blood pressure throughout the body," Heistad said. "Neurosurgeons would insert the gene that codes for the peptide when they go in to clip the aneurysm."

Matthew Howard, M.D., UI associate professor of surgery, and neurology, said such a procedure would be welcomed by neurosurgeons.

"We have highly refined surgical techniques that enable us to safely secure ruptured aneurysms, yet many of our patients survive the surgery only to develop devastating complications from delayed cerebral vasospasms," he said.

Heistad emphasized that potential clinical use may be five to 10 years away.

First, researchers must ensure that the disabled virus that carries the genetic code for the peptide into the brain does not cause harm. The UI team must also show in more extensive experimental models that the CGRP-based gene therapy is both safe and effective.

"This is very important research that will likely have tremendous impact on clinical neurosurgery," Howard said. "The work being carried out in Dr. Heistad's laboratory brings hope that future patients will be spared a deadly or devastating stroke."

Nearly 27,000 Americans die annually of subarachnoid hemorrhage. This type of stroke accounts for only 10 percent of all strokes, but causes 25 percent of all fatal strokes.

"We're trying to treat a currently untreatable disease that has terrible consequences," Heistad said. "Subarachnoid hemorrhage is common and deadly in young people. It's a misconception that stroke is only a disease of the elderly."

This study was supported in part by grants from the National Institutes of Health and from the federal Veterans Affairs Administration.

The research team included investigators from Kyushu University in Fukuoka, Japan. In addition to Heistad, UI research team members were Frank M. Faraci, Ph.D., professor of internal medicine and pharmacology; Jon J. Andresen, graduate student in neuroscience; and Yi Chu, Ph.D., research scientist in internal medicine.

University of Iowa Health Care describes the partnership between the UI College of Medicine and the UI Hospitals and Clinics and the patient care, medical education and research programs and services they provide.