GS967(PRAX-330) improves survival and reduces persistent current in SCN8A encephalopathy

De novo mutations in SCN8A, encoding NaV1.6, have been associated with early infantile epileptic encephalopathy type 13 (EIEE13). Over 100 mutations have been found in patients with multiple seizure types, delays in cognitive and motor development, and increased risk of sudden unexpected death in epilepsy (SUDEP). Functional characterization of mutations demonstrated that elevated persistent current is a common defect. TALEN technology was used to generate a mouse model carrying the N1768D gain-of-function mutation that exhibits elevated levels of persistent sodium current. This mouse model recapitulates many features of the patient phenotype, including spontaneous seizures and reduced lifespan in heterozygous mutant mice. These features are exacerbated in homozygous mutant mice. High-dose phenytoin has been reported as beneficial for seizure control in some patients with SCN8A mutations, but the narrow therapeutic window of phenytoin is a concern. Additional drugs that preferentially block persistent current could benefit this patient population. GS967 is a sodium channel blocker with greater potency for suppressing persistent current compared to phenytoin. It has been found to be effective at reducing seizures and improving survival in the Scn2aQ54 mouse model with epilepsy caused by elevated persistent sodium current. We hypothesized that suppressing persistent sodium current with GS967 would improve survival of heterozygous and homozygous Scn8a-N1768D mutant mice. Chronic treatment with GS967 rescued the premature lethality observed in Scn8a-N1768D/+ mice, with 100% surviving to 6 months of age compared to 20% of untreated. The beneficial effect was lost upon withdrawal of the GS967 chow. Treatment with GS967 extended survival of homozygous Scn8a-N1768D/N1768D mice by one week compared to untreated homozygotes, with 50% of treated mice surviving for 4 weeks. Electrophysiology studies demonstrated that elevated persistent current in neurons from untreated Scn8a-N1768D/+ mice was attenuated by acute application of GS967. Chronic GS967 administration prolonged the survival of Scn8a-N1768D mice, which is best explained by suppression of aberrant persistent sodium current in neurons. This work demonstrates a beneficial effect of GS967 in a mouse model of SCN8A encephalopathy and provides further support for GS967 as a novel anticonvulsant for refractory epilepsies.