gs-458967 and Brain-Diseases

De novo mutations of SCN8A, encoding the voltage-gated sodium channel Na. The novel sodium channel modulator GS967 has greater preference for persistent as opposed to peak current and nearly 10-fold greater potency than phenytoin. We evaluated the therapeutic effect of GS967 in the Scn8a. GS967 potently blocked persistent sodium current without affecting peak current, normalized action potential morphology, and attenuated excitability in neurons from heterozygous Scn8a. Persistent sodium current modulators like GS967 may be an effective precision targeting strategy for SCN8A encephalopathy and other functionally similar channelopathies when elevated persistent sodium current is the primary dysfunction.

Topics: Action Potentials; Animals; Anticonvulsants; Brain Diseases; Disease Models, Animal; Drug Administration Schedule; Electroshock; Epilepsy; Female; Hippocampus; Humans; Male; Mice; Mice, Transgenic; Mutation; NAV1.6 Voltage-Gated Sodium Channel; Neurons; Off-Label Use; Phenytoin; Pyridines; Triazoles