CONTACT: BECKY SOGLIN
Iowa City IA 52242
(319) 335-6660; fax (319) 335-8034
Release: Oct. 27, 2000
UI researchers study potential gene therapy for preventing certain type
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,"
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,"
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
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