Abstracts

Rationale: Epilepsy is a common neurological disorders that affects 1% of the population worldwide. Although many epilepsy patients achieve adequate seizure control with currently available antiepileptic drugs (AEDs), 30% of patients are refractory to treatment, highlighting the need for novel AEDs. The development of AEDs has relied predominantly on screening test compounds in acute seizure models, namely MES and PTZ. A limitation of these models is that they are induced, acute seizure models, and may not be etiologically relevant to the approximately two-thirds of epilepsies that have a genetic basis. Mutations in voltage-gated sodium channel genes are the most frequent causes of monogenic epilepsy. SCN1A mutations result in a spectrum of epilepsy phenotypes ranging from simple febrile seizures to Dravet Syndrome (DS), a severe epileptic encephalopathy. DS typically begins during the first year of life with febrile seizures and then progresses to afebrile seizures. Affected children respond poorly to currently available AEDs and have increased mortality risk. Scn1a+/- heterozygous knockout mice recapitulate features of DS, including spontaneous seizures, thermally-induced seizures and premature death. The Scn1a+/- mouse model of DS provides an ideal platform to test therapeutic agents. We sought to conduct a comprehensive AED screen in Scn1a+/- mice to determine which phenotypic measure(s) (spontaneous seizures, hyperthermia-induced seizures or survival) correlate best with human therapeutic response, and to demonstrate more generally the utility of a genetic epilepsy model in AED screening. Methods: We screened 12 drugs (10 conventional AEDs and 2 investigational compounds) in Scn1a+/- mice, evaluating effects on hyperthermia-induced seizures, spontaneous seizures and survival. Conventional AEDs were administered at therapeutically relevant doses, producing plasma drug concentrations within the human therapeutic range. Results: Scn1a+/- mice model DS by mimicking phenotypic hallmarks of the disease and exhibiting a similar response to AED treatment to that which is observed clinically. Conventional sodium channel inhibitors were not effective in Scn1a+/- mice and the phenotype was exacerbated by lamotrigine treatment. Overall, clobazam was the most effective anticonvulsant in Scn1a+/- mice, consistent with its effect in patients. Conclusions: The advent of genetic models that recapitulate spontaneous epilepsy provides alternative screening platforms and an opportunity to augment the AED development process. Here we validated the Scn1a+/- mouse model of DS for screening AEDs. We developed an AED screening pipeline that evaluates effects on hyperthermia-induced seizures and spontaneous seizures, and incorporates pharmacokinetic monitoring. This unique phenotyping package provides a foundation to predict the efficacy of novel compounds in the treatment of DS. Funding: NIH R01 NS084959 PhRMA Foundation Post Doctoral Fellowship in Pharmacology/Toxicology