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

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

Automated summary

Dravet syndrome is a rare but catastrophic genetic epilepsy, with majority of patients carrying a mutation in the SCN1A gene and currently lacking effective antiseizure drugs. Patients with DS often first present with febrile seizures, followed by generalized tonic-clonic seizures that can continue throughout life. The DS mouse model evaluated in this study showed refractoriness to most antiseizure drugs, except for a few that elevated seizure thresholds.