Using patient specific iPSC-derived neurons to identify molecular biomarkers of drug treatment responsiveness in Dravet Syndrome

Dravet Syndrome is a devastating type of epilepsy that strikes newborns and severely impedes their normal development and quality of life. The epileptic seizures are caused by an imbalance in the electrical communication between the cells of the brain. It remains particularly difficult to treat, with one third of all patients failing to respond to any of the currently available medication. In all cases it is hard to predict how a patient will respond to a drug and clinicians often have to resolve to a trail-and-error approach. This can have devastating repercussions for infants diagnosed early in their lives due to: (a) the extended time between diagnosis and effective treatment, and (b) the potentially severe effects of seizures as well as the effects of inappropriate antiepileptic medication on normal neurodevelopment. The main problem in the fight against Dravet Syndrome has been the fact that we cannot easily access the brains of suffering patients to isolate their cells and understand how the disease develops or why some patients respond well to a treatment whereas others don’t. Therefore, we have relied on using non-human cells or animal models of the disease. However, fundamental differences exist between humans and animals in the biology of the molecules that are implicated in epilepsy. To solve these problems we propose to generate patient-specific stem cells and differentiate these into patient-specific brain cells. We aim to carefully examine brain cells from Dravet patients that have shown good seizure control after drug treatment as well as patients that have been completely refractory to drug treatment. By studying the electrical patterns, the molecular properties and the responses to drugs of these brain cells grown in a dish we aim to: a) understand what makes brain cells respond well to drugs, and b) determine whether we can predict what drug would work best for each patient simply by studying their cells. If successful, our approach will have a major impact in how we diagnose and treat Dravet as well as patients suffering with other kinds of epilepsies.