Tackling intractable epilepsies with parallel in vitro and in vivo preclinical platforms

Project Leader: Wayne Frankel, Ph.D.

Co-Investigators: David Goldstein, PhD (Columbia Univ.); Stephen F. Traynelis, Ph.D. (Emory University); Dan Lowenstein, M.D. (UCSF)

The objective of this project is to generate new models for intractable pediatric epilepsy, based on recent exome sequence discovery of de novo gene variants, and by examining neuronal excitability phenotypes in vitro and in vivo, to design and implement drug screens with the potential to deliver new therapies to the clinic.

Background & Rationale

Epilepsy, the common disorder defined by recurrent seizures, affects 1% of the U.S. population (3.8% lifetime incidence). Drug and other therapies such as vagal nerve stimulation, ketogenic diet or surgery are effective in many, but 30%, or ~1 million, patients are refractory to these treatments; and many drugs also have intolerable side effects. About half of all epilepsies likely have a genetic basis, but due to genetic complexity progress in gene discovery has been modest. However, various recent efforts have significantly accelerated discovery and findings suggest many exciting new genetic targets.

This project focuses on recently identified gene variants found in patients with pediatric epileptic encephalopathies (EE). EE is a severe, largely intractable disorder where cognitive decline is comorbid and often worse than recurrent seizures.

Using the patient-derived data we select genetic variants to be evaluated for new model development. Selected mutations are introduced into neuronal cell cultures and screened for an in vitro disease phenotype that can then be used to test drugs that might block or reverse the functional effects of the mutations. Parallel introduction of the same mutations into mice then allows comprehensive, clinically-relevant, in vivo testing to establish the models for pre-clinical testing.