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PHILADELPHIA—For the first time, by using gene therapy to modify signaling pathways in the brain, neurology researchers have found that they can significantly reduce the development of epileptic seizures in rats.
 
"We have shown that there is a window to intervene after a brain insult to reduce the risk that epilepsy will develop," says one of the lead researchers, Dr. Amy R. Brooks-Kayal, a pedi­atric neurologist at The Children's Hospital of Philadelphia (CHOP) and associate professor of Neurology and Pediatrics at the University of Pennsylvania School of Medicine. "This pro­vides a proof of concept that altering specific signaling pathways in nerve cells after a brain insult or injury could provide a scientific basis for treating patients to prevent epilepsy." About 180,000 people are diagnosed with new onset epilepsy every year, Dr. Brooks-Kayal notes.
 
Working in a portion of the brain called the dentate gyrus (DG), the research team headed by Brooks-Kayal and Dr. Shelley J. Russek of the Boston University School of Medicine, focused on the alpha1 subunit of type A receptors for the neurotransmitter gamma-amino­butyric acid (GABA). Their pre­vious research determined that rats with epilepsy have lower lev­els of the alpha1 subunit. When GABA(A) receptors are activated, they inhibit the repetitive, exces­sive firing of brain cells that char­acterizes a seizure.
 
GABA's inhibitory role is con­sidered particularly important in the DG because it acts as a gateway for brain activity into the hippocampus, an area that is critical to generating seizures in temporal lobe epilepsy, the most common type in both children and adults.
 
To carry the gene that alters the expression of the protein, they used an adeno-associated virus vector, AAV—alpha 1, injected into the rats' brains. The researchers later injected the rats with pilocar­pine, a drug that causes status epi­lepticus (SE), a convulsive seizure, shortly after injection.
 
Although a small-scale study, all rats in the control group experienced SE after pilocarpine injection. Injection with the AAV—alpha 1 resulted in elevated levels of alpha1 proteins and reduced the occurrence of seizures to 39 percent of the ani­mals in the treatment group. The time to onset for the animals that did experience seizures was three times as long compared to rats that did not receive the delivered gene.
 
"In people, febrile convulsions or an injury such as severe head trauma is known to raise the risk of later developing epilepsy. So this study suggests that strate­gies aimed at modifying signaling pathways in the brain after such an insult may help prevent epilepsy," Brooks-Kayal concludes. "Our goal is to understand how alpha 1 is turned down and then to prevent down regulation with an effective drug that is safe to administer and exhibits benign side effects."
 
The doctor notes that a similar treat­ment strategy might extend to anxiety disorders and alcoholism which exhibit similar patterns of alpha 1 activity in the DG.

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