Monogenic Epilepsy Disease Modeling and Drug Screening in iPSC Neurons

The study of dysfunctional human neuronal network development is a challenging topic, made more approachable with advances in the combination of human iPSC neurons and HD-MEA technology. This cutting edge combination allows our lab to investigate the neurodevelopmental role of KCNQ2, a gene encoding a potassium channel crucial for regulating the resting membrane potential and modulating neuronal excitability. Pathogenic variants in KCNQ2 cause a range of developmental and epileptic encephalopathies, often featuring seizures and lifelong intellectual disability with no treatment options available apart from general antiseizure medication.

In this webinar, I will present findings from two-month longitudinal recordings of networks harboring loss-of-function (LOF) and gain-of-function (GOF) and KCNQ2 variants, highlighting distinct network characteristics associated with each. Leveraging these dysfunctional network phenotypes, I will showcase how this model supports novel drug screening efforts highlighted by A) acute treatment with channel modulators in a KCNQ2-LOF background and B)chronic treatment with a novel antisense oligonucleotide targeting gene expression knockdown in KCNQ2-GOF networks. Insights gained from these HD-MEA recordings, particularly chronic drug testing in a human in vitro model, represents an important expansion of our toolkit for screening novel treatments of monogenic neurodevelopmental disorders.