Precision Medicine for Channelopathy-Related Childhood Epilepsies

Ion channels are expressed in multiple tissues and ion channel mutations can lead to a broad range of diseases (channelopathies), including various forms of severe childhood epilepsy. As part of their diagnosis, children with severe epilepsy are often screened for mutations. However, functional consequences of identified pathogenic mutations are in many cases unknown and selecting the appropriate treatment is difficult, often resulting in escalation to polytherapy (administration of multiple drugs simultaneously). For many children, the treatment causes severe side effects and for around 30% of the children the treatment is ineffective. Establishing an appropriate and personalized treatment strategy contributes to improved cognitive and social development and quality of life for children with epilepsy. Patch-clamp recordings are a powerful technology determine the functional consequence of an ion channel mutation. In this project, we will perform such patch-clamp recordings to characterize the interaction of epilepsy drugs with key epilepsy-related ion channels. We will generate a dataset of recordings from genetically manipulated human cells that each express one key ion channel and assess how epilepsy ion channel drugs interact with that channel. Using computational methods, we will establish the mathematical equations that quantitatively capture the key dynamics of these recordings. These equations will be integrated into a model that can simulate how genetically manipulated neuronal cells respond to drug treatments. Uniquely, this model will allow us to predict the efficacy of polytherapy strategies to treat genetic ion channel deficiencies. Finally, the validity of these predictions will be tested in human neuronal cells that are genetically manipulated towards epilepsy. In conclusion, this project will provide a state-of-the-art protein-drug interaction dataset for key ion channel genes as well as a highly innovative simulation model. The results will contribute to the much needed precision treatment of ion channel deficiencies that cause childhood epilepsies and beyond.