Grant: Project Grant

Infantile spasms is a rare but devastating epilepsy for which treatment oftentimes do not work. Because of this, children with infantile spasms frequently develop other seizure types and do not learn to talk, walk or care for themselves. Moreover one third of children with infantile spasms will die due to the uncontrolled seizures. A high fat low carbohydrate diet known as the ketogenic diet is emerging as an effective treatment for infantile spasms even in those patients who do not respond to current first-line treatments. The diet however is fraught with side effects and difficult for patients tolerate. It is important to determine how the diet works in infantile spasms so that safe, effective and tolerable treatments can be developed. This timely proposal is directed at uncovering precisely how the ketogenic diet works in infantile spasms. We've discovered in a model of infantile spasms that the ketogenic diet works by making the brain acidic. Correcting this acidity significantly attenuated the antiseizure effects of the ketogenic diet. We hypothesized that the acidity in the brain induced by the ketogenic diet works to control seizures by activating acid sensing ion channels. Our preliminary results show that deleting these channels in the brain using advanced gene editing techniques abolished the antiseizure effects of the ketogenic diet. This proposal describes important experiments to 1) determine how acid sensing ion channels are involved in the anti-seizure effects of the ketogenic diet, 2) determine whether acid sensing ion channels in all brain cells are involved in the ketogenic diet's antiseizure effects or a subtype thereof 3) to test new treatments that will strengthen the ability of acidosis to activate acid sensing ion channels for the treatment of infantile spasms. The goal is to identify a treatment strategy for infantile spasms that will bring us one step closer to eliminating this catastrophic form of epilepsy from the pediatric population.