Melissa Barker-Haliski

Using a newly developed translational scoring matrix, we provide novel insights into the clinical validity of common preclinical seizure models for FOS. The PAC-FOS framework identifies mouse MES, audiogenic, and 6 Hz (32 mA) as the three acute models with the greatest predictive validity and versatility for FOS drug discovery. We present a pragmatic approach and decision tree to support efficient use of drug discovery resources and in consideration of the 3R's of animal ethics.

Abstract Objective: Central to the development of novel antiseizure medications (ASMs) is testing of anticonvulsant activity in preclinical models. While various well-established models exist, their predictive validity across the spectrum of clinical epilepsies has been less clear. We sought to establish the translational concordance of commonly used preclinical models to define models with the highest predictive clinical validity for focal onset seizures (FOS).

ENX-101 is a α2,α3,α5-selective γ-aminobutyric acid type A (GABAA) receptor partial positive allosteric modulator (PAM). ENX-101 showed dose-related antiseizure effects in clinically validated rodent seizure models at doses not causing motor impairment. ENX-101 was most potent at suppressing spike-and-wave discharges (SWDs) in Genetic Absence Epilepsy Rat from Strasbourg (GAERS), a model of generalized absence epilepsy.