NBI-921352, a first-in-class, Na<sub>V</sub>1.6 selective, sodium channel inhibitor that prevents seizures in <i>Scn8a</i> gain-of-function mice, and wild-type mice and rats.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 35234610.
- Also identified by DOI 10.7554/eLife.72468 and PMC identifier 8903829.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
NBI-921352 (formerly XEN901) is a novel sodium channel inhibitor designed to specifically target Na<sub>V</sub>1.6 channels. Such a molecule provides a precision-medicine approach to target <i>SCN8A</i>-related epilepsy syndromes (<i>SCN8A</i>-RES), where gain-of-function (GoF) mutations lead to excess Na<sub>V</sub>1.6 sodium current, or other indications where Na<sub>V</sub>1.6 mediated hyper-excitability contributes to disease (Gardella and Møller, 2019; Johannesen et al., 2019; Veeramah et al., 2012). NBI-921352 is a potent inhibitor of Na<sub>V</sub>1.6 (IC<sub>50</sub>0.051 µM), with exquisite selectivity over other sodium channel isoforms (selectivity ratios of 756 X for Na<sub>V</sub>1.1, 134 X for Na<sub>V</sub>1.2, 276 X for Na<sub>V</sub>1.7, and >583 Xfor Na<sub>V</sub>1.3, Na<sub>V</sub>1.4, and Na<sub>V</sub>1.5). NBI-921352is a state-dependent inhibitor, preferentially inhibiting inactivatedchannels. The state dependence leads to potent stabilization of inactivation, inhibiting Na<sub>V</sub>1.6 currents, including resurgent and persistent Na<sub>V</sub>1.6 currents, while sparing the closed/rested channels. The isoform-selective profile of NBI-921352 led to a robust inhibition of action-potential firing in glutamatergic excitatory pyramidal neurons, while sparing fast-spiking inhibitory interneurons, where Na<sub>V</sub>1.1 predominates. Oral administration of NBI-921352 prevented electrically induced seizures in a <i>Scn8a</i> GoF mouse,as well as in wild-type mouse and ratseizure models. NBI-921352 was effective in preventing seizures at lower brain and plasma concentrations than commonly prescribed sodium channel inhibitor anti-seizure medicines (ASMs) carbamazepine, phenytoin, and lacosamide. NBI-921352 waswell tolerated at higher multiples of the effective plasma and brain concentrations than those ASMs. NBI-921352 is entering phase II proof-of-concept trials for the treatment of <i>SCN8A-</i>developmental epileptic encephalopathy (<i>SCN8A</i>-DEE) and adult focal-onset seizures.
Medical subject headings
- Epilepsy
- NAV1.6 Voltage-Gated Sodium Channel