gs-458967 and Epilepsy

Many epilepsy patients are refractory to conventional antiepileptic drugs. Resurgent and persistent currents can be enhanced by epilepsy mutations in the Nav1.2 channel, but conventional antiepileptic drugs inhibit normal transient currents through these channels, along with aberrant resurgent and persistent currents that are enhanced by Nav1.2 epilepsy mutations. Pharmacotherapies that specifically target aberrant resurgent and/or persistent currents would likely have fewer unwanted side effects and be effective in many patients with refractory epilepsy. This study investigated the effects of cannbidiol (CBD) and GS967 (each at 1 μM) on transient, resurgent, and persistent currents in human embryonic kidney (HEK) cells stably expressing wild-type hNav1.2 channels. We found that CBD preferentially inhibits resurgent currents over transient currents in this paradigm; and that GS967 preferentially inhibits persistent currents over transient currents. Therefore, CBD and GS967 may represent a new class of more targeted and effective antiepileptic drugs.

Topics: Action Potentials; Animals; Anticonvulsants; Cannabidiol; Epilepsy; HEK293 Cells; Humans; Ion Channel Gating; Mice; Mutation; NAV1.2 Voltage-Gated Sodium Channel; Neurons; Protein Isoforms; Pyridines; Triazoles

Pathogenic variants in SCN8A, encoding the voltage-gated sodium (Na+) channel α subunit Nav1.6, is a known cause of epilepsy. Here, we describe clinical and genetic features of all patients with SCN8A epilepsy evaluated at a single-tertiary care center, with biophysical data on identified Nav1.6 variants and pharmacological response to selected Na+ channel blockers.. SCN8A variants were identified via an exome-based panel of epilepsy-associated genes for next generation sequencing (NGS), or via exome sequencing. Biophysical characterization was performed using voltage-clamp recordings of ionic currents in heterologous cells.. We observed a range in age of onset and severity of epilepsy and associated developmental delay/intellectual disability. Na+ channel blockers were highly or partially effective in most patients. Nav1.6 variants exhibited one or more biophysical defects largely consistent with gain of channel function. We found that clinical severity was correlated with the presence of multiple observed biophysical defects and the extent to which pathological Na+ channel activity could be normalized pharmacologically. For variants not previously reported, functional studies enhanced the evidence of pathogenicity.. We present a comprehensive single-center dataset for SCN8A epilepsy that includes clinical, genetic, electrophysiologic, and pharmacologic data. We confirm a spectrum of severity and a variety of biophysical defects of Nav1.6 variants consistent with gain of channel function. Na+ channel blockers in the treatment of SCN8A epilepsy may correlate with the effect of such agents on pathological Na+ current observed in heterologous systems.

Topics: Cell Culture Techniques; Child; Cohort Studies; Epilepsy; Female; HEK293 Cells; Humans; Infant; Infant, Newborn; Male; Mutation; NAV1.6 Voltage-Gated Sodium Channel; Oxcarbazepine; Pyridines; Seizures; Sodium Channels; Triazoles

Familial hemiplegic migraine (FHM) is a group of genetic migraine, associated with hemiparesis and aura. Three causative different genes have been identified, all of which are involved in membrane ion transport. Among these, SCN1A encodes the voltage-gated Na. To obtain a more complete picture, here, we characterized by patch clamp approach the remaining 5 mutations (Q1489H, I1498M, F1499 L, M1500 V, F1661 L) in heterologous expression systems.. In conclusion, late Na

Topics: Action Potentials; Epilepsy; HEK293 Cells; Humans; Migraine Disorders; Migraine with Aura; Mutation; NAV1.1 Voltage-Gated Sodium Channel; Neurons; Pyridines; Sodium; Triazoles

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