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Promising Gene Therapy Tool May Suppress Epileptic Seizures

For release: Friday, November 14, 2003

A new gene therapy approach may one day stop seizures in people with common forms of epilepsy, according to a new study. Researchers found that the new therapy suppressed focal seizures and seizure induced brain damage in rats.

In partial (or focal) seizures, the most common form of epilepsy, electrical activity goes out of control in one part of the brain. Sometimes this uncontrolled activity occurs repeatedly and spreads to other brain regions. For many epilepsy patients, drug treatment is not successful and may have negative side effects. Surgical removal of the brain tissue where the seizures originate is sometimes the only option, but this approach does not always improve the symptoms. Researchers have been searching for a new therapeutic approach that can reliably prevent seizures on a long-term basis.

A protein called galanin has been found to block seizures in many animal studies of epilepsy. Although it is not clear how galanin prevents seizures, researchers believe it may block the overstimulation of neurons. In the new study, a research team led by Thomas McCown, Ph.D., used a modified virus called adeno-associated virus (AAV) to transfer the gene for galanin into neurons. The study from the University of North Carolina at Chapel Hill was reported in the August 1, 2003 issue of Nature Medicine and was funded by the National Institute of Neurological Disorders and Stroke (NINDS).

To achieve an effective gene therapy approach, not only must the galanin gene be delivered and expressed in the brain, but the galanin must exit the cell to exert its actions. In order to make the cells secrete galanin, the researchers added the secretory signal gene for fibronectin (FIB). This FIB gene gave neurons instructions to pump the galanin out of the cells. When this AAV-FIB-galanin virus was injected into the animals’ brains, the targeted cells pumped the galanin into the surrounding tissue, and the focal seizures were suppressed over a period of 4 weeks. If the AAV-galanin virus did not contain the FIB, the seizures were not suppressed.

An additional property of this AAV-FIB-galanin virus was the ability to control gene expression with doxycycline, a commonly prescribed oral antibiotic. When doxycycline was added to the animals’ drinking water, the gene therapy was shut off and sensitivity to seizures returned. When the drug was taken away, the protection returned, showing that the therapy is highly controllable. This ability to turn the therapy on or off is an important consideration when treating patients. "If the treatment works to fix the problem and is no longer needed, or if the patient develops tolerance or problems with the new protein, doctors need to have a reliable, proven means to shut it down, essentially resetting the system," Dr. McCown says.

The researchers also found that the AAV-FIB-galanin therapy could prevent brain damage caused by generalized seizures. Treatment of a localized brain area with the AAV-FIB galanin virus prevented seizure-induced cell damage in that area, while treatment with the AAV-galanin virus provided no benefit.

"Although the work is still preliminary, this study is consistent with one of the epilepsy research goals of the NINDS, to discover new therapeutic strategies that may cure epilepsy," according to Margaret Jacobs, a program director from the NINDS and an expert in epilepsy and genetics. "One advantage of this treatment is that it can target a small brain area already known to be the source of the problem," Dr. McCown says. Compared to treatment of the whole brain, a localized treatment is much less likely to have adverse side effects. Ultimately, if this gene therapy is used in patients, it could be tested in small brain areas already targeted for surgery. "If this therapy worked, you could reconsider whether to do the surgical procedure."

The next step in the research is to test the procedure for effectiveness and adverse side effects in animal models of temporal lobe epilepsy. Since some brain areas affected in epilepsy are also involved in learning and memory, it will be important to determine whether these functions are affected by the treatment. "Compared to the damage done by repeated seizures, we hope that any side effects of the treatment would be very small," Dr. McCown says.

The NINDS, part of the National Institutes of Health within the U.S. Department of Health and Human Services, is the nation's leading supporter of research on the brain and nervous system.

Haberman, R.P.; Samulski, R.J.; McCown, T.J. "Attenuation of seizures and neuronal death by adeno-associated virus vector galanin expression and secretion." Nature Medicine , August 2003, Vol. 9(8), 1076-1080.

- By Diane Lawrence, Ph.D.


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Last Modified November 3, 2015