EMBARGOED UNTIL 3 P.M. E.D.T
THURSDAY, JULY 22, 1999
Contact: Carolyn Conway
Columbia University
212-305-3900
Joan E. Kureczka
Avant Immunotherapeutics
415-821-2413
INJURED NEURONS SAVED AFTER STROKE
Researchers at Columbia University's College of Physicians & Surgeons have shown that a hybrid molecule can mount a potent, double-sided defense to prevent the death of brain cells following a stroke. The strategy takes advantage of a surprising discovery that injured neurons flag themselves for destruction. The findings, reported in the July 23 issue of Science, demonstrate in mice that the hybrid molecule, known as sCR1sLex, could reduce by as much as elevenfold the amount of brain tissue damaged by an ischemic stroke.
"This was a combination of ideas," says Dr. David Pinsky, assistant professor of medicine at the College of Physicians & Surgeons and principal investigator on the study. "By protecting neurons from attack by the complement system, and preventing the blockage of tiny blood vessels in the brain, we get two benefits."
An ischemic stroke results from a blood clot or other blockage of blood flow to the brain. Some brain cells, those in the ischemic core, are irreparably damaged by the lack of oxygen and glucose normally delivered in the blood. Other cells, in the penumbral area, are injured, but not killed, by the original insult. But even if blood flow is restored to the brain they often die later.
"Any new stroke therapy aims to rescue these cells," says Dr. Judy Huang, a neurological surgery resident at the College of Physicians & Surgeons and first author of the study.
The cellular damage is caused by two mechanisms. Complement, which consists of immune-system proteins that lyse cells, is activated by fragments of dead cells. Scientists had thought that these "little cluster bombs" inadvertently destroyed neurons in the penumbral region as a sort of collateral damage. Drs. Huang and Pinsky and their colleagues showed that neurons in the penumbral region of the stroke express a protein on their surface, C1q, that directly targets them for destruction or consumption by adjacent cells.
"We were surprised to see neurons express C1q, which flags them as injured cells," says Dr. Pinsky. C1q activates the complement proteins, leading to the destruction of the injured neurons. Dr. Pinsky believes the discovery may have relevance for the treatment of neurodegenerative diseases, such as Alzheimer's disease, that also destroy neurons.
Cells in the penumbral area of the stroke also die when tiny blood vessels become clogged with immune system cells even after blood supply has been restored to the brain. Previous research by Dr. Pinsky and his colleagues showed that sugar molecules known as P-selectins are expressed on the inner surface of blood vessels of the brain following stroke.
"These P-selectins are sticky," says Dr. Pinsky. They are especially sticky to immune system cells known as leukocytes, which clog the blood vessels and kill brain cells by blocking their blood supply and releasing toxic substances.
Researchers at Avant Immunotherapeutics developed a molecule that blocked both of these deleterious post-stroke effects. They took a known inhibitor of complement activation and attached numerous sugar molecules to it. The plan was to prevent complement from attacking injured neurons and to also use the sugars to bind the leukocytes that would otherwise clog the tiny blood vessels in the brain. The sugar-coated protein, referred to as sCR1sLex in the Science paper, is also called TP20 by Avant.
In mice models of ischemic stroke, TP20 reduced the amount of brain tissue killed by the stroke by as much as elevenfold when administered before the stroke. When administered 45 minutes after the stroke began, TP20 cut the amount of damaged brain tissue in half.
"This demonstrates the functional contributions of these two pathways to the pathophysiology of this injury," says co-author Dr. Andrea Tenner, professor of molecular biology and biochemistry at the University of California at Irvine. "In addition, this chimeric protein is unlikely to have deleterious effects because its target is the inhibition of an overzealous response to injury by the body."
The researchers plan to next study the effects of TP20 in non-human primates and expect to progress to clinical trials if those tests prove successful.
Additional authors on the study were Louis J. Kim, Yuan Zhang and E. Sander Connolly at the College of Physicians & Surgeons; and Richard Mealey and Henry C. March Jr. of Avant Immunotherapeutics. The research was supported by grants from the American Heart Association and the National Institutes of Health. Louis Kim also received an Alpha Omega Alpha scholarship supporting work on this project.
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