Senior Scientist Xenon Pharmaceuticals, British Columbia, Canada
Rationale: Loss-of-function variants of SCN1A cause Dravet Syndrome (SMEI or EIEE6) and generalized epilepsy with febrile seizures plus (GEFS+), by decreasing NaV1.1 expression or conductance in inhibitory interneurons. Studies of these and other channelopathies in mice reveal that NaV1.1 is the dominant channel in inhibitory circuits while NaV1.6 and NaV1.2 are the dominant channels in excitatory pyramidal neurons. The loss of NaV1.1 function results in hypo-excitability of inhibitory networks that in turn decrease regulation of excitatory neurons leading to epilepsy and developmental delays. A precision medicine therapy for Dravet syndrome would ideally restore NaV1.1 activity specifically without impacting other neuronal conductances or proteins. We have identified brain penetrant small molecule potentiators of NaV1.1 currents that allow oral dosing and titration of interneuron activity. Such activators have the potential to directly address the underlying cause of Dravet syndrome and to provide a safe and effective pharmacotherapy. Methods: We identified small molecule enhancers that selectively target NaV1.1, while sparing other voltage gated sodium channels. Automated patch clamp electrophysiology was used to examine the potency, and selectivity of different compounds. Compounds were also evaluated electrophysiologically in brain slices from SCN1A heterozygous null mice (SCN1A +/-) to assess the effects on inhibitory circuits. The compounds were then tested for efficacy through oral dosing in SCN1A +/- mice in a modified 6Hz seizure assay. Results: Novel and brain penetrant small molecules have been identified that selectively potentiate NaV1.1 channels over NaV1.2, 1.6 and 1.5. In vitro electrophysiological characterization demonstrates these small molecules selectively destabilize the inactivated state of the Nav1.1 channel. In brain slices from SCN1A +/- mice compound increased the maximum firing rate of fast spiking cortical PV+ interneurons and prevented collapse of firing at high stimulus input whilst having no effect on pyramidal cells. In vivo, a representative compound was found to prevent seizures in SCN1A +/- mice in a modified 6 Hz seizure model. Conclusions: Selectively potentiating NaV1.1, the dominant sodium channel isoform expressed in inhibitory interneurons, restores the capability of inhibitory neurons to fire action potentials at high frequency. Efficacy was confirmed in SCN1A +/- mouse seizure model suggesting a small molecule pharmaceutical with this profile could enable reversal of the fundamental defect in Dravet syndrome and may have utility in other neurologic indications where interneuron excitability is impaired. This profile provides a new, mechanistically differentiated, class of voltage-gated sodium channel potentiators with the potential to provide an improved therapeutic profile for Dravet syndrome patients. Funding: Please list any funding that was received in support of this abstract.: Xenon Pharmaceuticals
