Developing Patient-Specific Stem Cell Models to Inform New Epilepsy Therapies

Epilepsy is a clinical condition characterized by seizures and an associated cognitive impairment. Despite decades of research and the availability of multiple antiepileptic drugs (AEDs), our understanding and treatment of epilepsy remains inadequate. Approximately one third of patients are completely refractory to treatment, while it is hard to predict how a patient will respond to a drug. Clinicians often resort to a trial-and-error approach that can have devastating repercussions for patients, especially those that are diagnosed early in their lives. A subset of early onset childhood epilepsy syndromes known as epileptic encephalopathies (EE), are caused by de novo mutations in ion-channels such as SCN1A and KCNQ2. The specific mechanisms that explain how these ion channel mutations affect different neuronal subtypes in the human cortex, lead to seizure activity and impair neurodevelopment remain undefined. Progress towards more effective treatments has been hampered by patient variability and lack of model systems that mimic the human condition. Children with different mutations in the same gene can have drastically different types and severity of seizures, as well as different responses to AED treatments. While studies of EEs using heterologous expression systems and mouse models have been informative, the functional roles, as well as the tissue and cell type-specific distribution of homologous channels differ between mice and humans. The main goal of our research program is to use iPSC-models for precision medicine in epilepsy. We specifically propose to develop novel cell-based model systems by differentiating patient and isogenic control iPSCs into different subtypes of cortical neurons. Excitatory and inhibitory neurons will be grown in isolation or co-cultured in a functional network, to address three aims. 1) We will elucidate the cell autonomous and non-autonomous neurophysiological alterations resulting from ion channel mutations by analyzing the electrophysiological properties of patient derived and isogenic control cortical neurons. Identifying how patient mutations affect the function of different neuronal subtypes will aid in the design of targeted and effective therapeutic approaches. 2) We will determine whether ion-channel mutations play a role in the development and maturation process of cortical neurons. Establishing a mecha¬nism by which epilepsy-associated channel mutations impair neurodevelopment would advance the channel¬opathy field by shifting the therapeutic focus to neurodevelopment rather than correcting hyperexcitability. 3) We will establish whether the responses of patient neurons to treatments with AEDs can be predictive of the clinical responses of patients. If successful, our model will allow us to diagnose epilepsy in a laboratory dish and select the best drug or combination of drugs for each individual patient.