Grant: Operating Grant

Epilepsy is one of the most common and severe neurological conditions, characterized by frequent seizures due to abnormal excessive electrical activity in the brain. Although many drugs are currently available for the management of epileptic seizures, a surprisingly large number patients fail to respond to these treatments. As many as 30% of patients with epilepsy are refractory to current treatments, and many others suffer significant side effects from these drugs. Also, many of the drugs used to treat epilepsy are decades (or even centuries) old. Taken together, these observations suggest that new approaches are needed. A principal reason for the unmet need in seizure therapy that many existing drugs are redundant - they act on similar ion targets in the brain. However, genetic studies have identified dozens of proteins in the brain that may regulate electrical activity and seizures. Our study will focus on a recently introduced anti-epileptic drug named retigabine (also known as Ezogabine, Trobalt, or Potiga). This drug was approved for use in Canada in 2012, and is unique because it is the only anti-epileptic drug that targets a class of protein called voltage-gated potassium channels in the brain. These voltage-gated channels alter their activity when the drug binds, helping to suppress seizures. Our study applies several cutting edge approaches to study the specific chemical forces that allow retigabine to interact with its target, and to unravel the changes in protein function that take place after retigabine binds. Since retigabine is the first drug of its class that has been developed to treat epilepsy, we anticipate that our research project will identify changes that can be made to improve the potency and effectiveness of the drug.