Development of an antiseizure drug screening platform for Dravet syndrome at the NINDS contract site for the Epilepsy Therapy Screening Program

• DOI: 10.1111/epi.16925
• Publication Date: 2021-05-18T06:34:58Z
• Authors: Chelsea D. Pernici; Jeffrey A. Mensah; E. Jill Dahle; Kristina J. Johnson; Laura Handy; Lauren Buxton; Misty D. Smith; Peter J. West; Cameron S. Metcalf; Karen S. Wilcox
• Keywords: Clobazam; Dravet syndrome; Tiagabine; Levetiracetam; Valproic Acid; Clonazepam

Abstract Objective Dravet syndrome (DS) is a rare but catastrophic genetic epilepsy, with 80% of patients carrying mutation in the SCN1A gene. Currently, no antiseizure drug (ASD) exists that adequately controls seizures. In clinic, individuals DS often present first febrile seizure and, subsequently, generalized tonic‐clonic seizures can continue throughout life. To facilitate development ASDs for DS, contract site National Institute Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (ETSP) has evaluated mouse model using conditional knock‐in Scn1a A1783V/WT mouse. Methods Survival rates temperature thresholds were determined. Prototype administered via intraperitoneal injections at time‐to‐peak effect, which was previously determined, prior to induction hyperthermia‐induced considered effective if they significantly increased mice had Results Approximately 50% survive adulthood all have The results suggest this are highly refractory battery ASDs. Exceptions clobazam, tiagabine, levetiracetam, combination clobazam valproic acid add‐on stiripentol, elevated thresholds. Significance Overall, data demonstrate proposed suitable screening novel compounds ability block heterozygous be repeatedly over course several weeks, allowing higher throughput screening.