Gene Therapy may help to control seizures

US researchers have shown through a study on mice, that using gene therapy to modify signalling pathways in the brain, can help bring significant reduction in the development of epileptic seizures. "We have shown that there is a window to intervene after a brain insult to reduce the risk that epilepsy will develop," said one of the lead researchers, Amy R Brooks-Kayal, MD, a paediatric neurologist at the Children''s Hospital of Philadelphia and associate professor of Neurology and Paediatrics at the University of Pennsylvania School of Medicine.

"This provides a ''proof of concept'' that altering specific signalling pathways in nerve cells after a brain insult or injury could provide a scientific basis for treating patients to prevent epilepsy," he added. The researchers focused their study, published in the Journal of Neuroscience, on a type of cell receptor that 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 of epilepsy in children and adults.

They say that when GABA (A) receptors are activated, they inhibit the repetitive, excessive firing of brain cells that characterizes a seizure. Seizures are thought to occur, at least in part, because of an imbalance between two types of neurotransmitters – the glutamate system that stimulates neurons to fire, and the GABA system that inhibits that brain activity. The researchers say that GABA (A) receptors are made up of five subunits, proteins that play important roles in brain development and in controlling brain activity.

In their previous research, Dr Brooks-Kayal’s team had found that rats with epilepsy had lower levels of the alpha1 subunits of these receptors, and higher levels of alpha4 subunits. In the latest study, they used gene delivery to alter the expression of the alpha1 subunit to see if this would have an effect on later seizure development. To carry the gene that alters the expression of the protein, they used an adeno-associated virus vector, injected into the rats'' brains. They later injected the rats with pilocarpine, a drug that causes status epilepticus (SE), a convulsive seizure, shortly after injection, and then evaluated the rats for later development of spontaneous seizures or epilepsy.

The researchers found that rats that had received the gene therapy had elevated levels of alpha1 proteins, and either did not develop spontaneous seizures, or took three times as long to experience a spontaneous seizure, compared to their controlled counterparts. Dr Brooks-Kayal said that during the study it was impossible for the researchers to tell whether the increased alpha1 subunit levels were only suppressing seizures, or whether they would permanently prevent epilepsy from developing.

"In people, an initial episode of SE 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 signalling pathways in the brain after such an insult may help prevent epilepsy," said Dr Brooks-Kayal. "The approach would likely be different than in this proof-of-concept animal study that involved injecting agents directly into the brain. This study, does, however, lay the foundation for a potential drug therapy that might act on the same signalling pathways, to prevent epilepsy after a brain insult such as an episode of SE," he added.