LAUSR

Epilepsy is a disturbance in the electrical activity of the brain manifested via countless etiologies. 65 million individuals suffer from epilepsy and one-third of these individuals live with uncontrollable seizures because no known pharmacological treatment works for them. A portion of this population is accounted for by single-gene epilepsy disorders resulting from mutations within sodium, potassium or inhibitory channels. For example, the Slack gene (KCNT1) encodes a sodium-activated potassium channel that is very widely expressed in the brain. Mutations in this KCNT1 gene in humans presents with autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE), a disease marked by brief, but violent, seizures during sleep and devastating effects on intellectual function. Advances in personalized medicine is crucial for these types of diseases. Central to this vision is induced pluripotent stem (iPS) cell technology, which provides a platform to expand our understanding of how single-gene mutations result in disease states. This approach illustrates and leverages the “disease-in-a-dish” iPSC-technology into phenotypic screening and drug development. We have engineered and generated human cortical neurons harboring the KCNT1 {P924L} single-gene mutations, as well as the isogenic wild-type control match. This ability provides unprecedented access to in vitro models of all-types of neurological disorders. Here we present functional data, via patch-clamp and multi-electrode array (MEA) electrophysiological techniques, illustrating the known ‘gain-of-function’ ionotropic cellular-level fingerprint, which has previously been linked to this mutation, along with newly-discovered neural-network level hyper-active phenotypes. We further show multiple examples that selective pharmacology can reverse these observed phenotypes. Collectively, our results illustrate how human iPS cells can be model disease states and be leveraged in the personal medicine space.