Abstracts

Rationale: Dravet syndrome is a catastrophic pediatric epileptic encephalopathy in which patients suffer from severe spontaneous seizures and develop comorbidities including cognitive impairment, gait disturbances and psychomotor dysfunction. Dravet syndrome responds poorly to currently available antiepileptic drugs and exhibits an unfavorable long-term survival. More than 70% of Dravet syndrome patients have de novo heterozygous missense and truncation mutations in SCN1A suggesting haploinsufficiency of SCN1A as the genetic mechanism of Dravet syndrome. Loss-of-function SCN1A mutations have been modeled by Scn1a knockout (Scn1a+/-) mice, which mimic the severe epilepsy phenotype of Dravet syndrome. Studies using Scn1a+/- mice have demonstrated impaired excitability in GABAergic interneurons and have led to the prevailing hypothesis that impaired GABA-mediated inhibition is responsible for epileptogenesis in Dravet syndrome. Clinical observations suggest that conventional sodium channel blocking anticonvulsants are not generally effective in patients with Dravet syndrome and may cause a worsening of the disease. We hypothesized that GS967, an unconventional sodium channel blocker that exhibits anticonvulsant activity in transgenic mice expressing a gain-of-function sodium channel mutation, would likely exacerbate the phenotype of Scn1a+/- mice. GS967 is known to exert preferential inhibition of persistent sodium current in cells transfected with mutant brain sodium channels NaV1.1 and NaV1.2, as well as neurons expressing a gain-of-function NaV1.2 mutation.Methods: We evaluated the effect of GS967 on hyperthermia-induced seizures, spontaneous seizures and survival of Scn1a+/- mice on a mixed genetic background (129.S6/SvEvTac x C57BL/6J). GS967 was administered orally through supplementation in chow (estimated dosage of 1.5 mg/kg/day) beginning at either postnatal day 10 (P10) or postnatal day 18 (P18).Results: GS967 treatment had no effect on temperature threshold of hyperthermia-induced seizures in Scn1a+/- mice assayed at P14-P18. However, unexpectedly, GS967 treated Scn1a+/- mice had no seizures over a 48 hour period compared to a total of 52 seizures in untreated mice (n=10-12, p < 0.01; Figure 1A). Additionally, GS967 treatment significantly improved survival of Scn1a+/- mice, with 88% of mice alive at 8 weeks compared to 20% survival of untreated animals (n=16-18, p < 0.001; Figure 1B).Conclusions: Our findings suggest that the unconventional sodium channel blocker GS967 exerts favorable effects on survival and spontaneous seizure frequency in a mouse model of Dravet syndrome. Whether preferential persistent sodium current inhibition is the molecular basis for this unanticipated benefit of GS967 awaits further study. These findings also suggest that spontaneous seizures and hyperthermia-induced seizures may have different mechanisms in Scn1a+/- mice.