Academic Journal
NBI-921352, a first-in-class, NaV1.6 selective, sodium channel inhibitor that prevents seizures in Scn8a gain-of-function mice, and wild-type mice and rats
| العنوان: | NBI-921352, a first-in-class, NaV1.6 selective, sodium channel inhibitor that prevents seizures in Scn8a gain-of-function mice, and wild-type mice and rats |
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| المؤلفون: | Johnson, JP, Focken, Thilo, Khakh, Kuldip, Tari, Parisa Karimi, Dube, Celine, Goodchild, Samuel J, Andrez, Jean-Christophe, Bankar, Girish, Bogucki, David, Burford, Kristen, Chang, Elaine, Chowdhury, Sultan, Dean, Richard, de Boer, Gina, Decker, Shannon, Dehnhardt, Christoph, Feng, Mandy, Gong, Wei, Grimwood, Michael, Hasan, Abid, Hussainkhel, Angela, Jia, Qi, Lee, Stephanie, Li, Jenny, Lin, Sophia, Lindgren, Andrea, Lofstrand, Verner, Mezeyova, Janette, Namdari, Rostam, Nelkenbrecher, Karen, Shuart, Noah Gregory, Sojo, Luis, Sun, Shaoyi, Taron, Matthew, Waldbrook, Matthew, Weeratunge, Diana, Wesolowski, Steven, Williams, Aaron, Wilson, Michael, Xie, Zhiwei, Yoo, Rhena, Young, Clint, Zenova, Alla, Zhang, Wei, Cutts, Alison J, Sherrington, Robin P, Pimstone, Simon N, Winquist, Raymond, Cohen, Charles J, Empfield, James R |
| المساهمون: | Xenon Pharmaceuticals, Inc |
| المصدر: | eLife ; volume 11 ; ISSN 2050-084X |
| بيانات النشر: | eLife Sciences Publications, Ltd |
| سنة النشر: | 2022 |
| المجموعة: | eLife (E-Journal - via CrossRef) |
| الوصف: | NBI-921352 (formerly XEN901) is a novel sodium channel inhibitor designed to specifically target Na V 1.6 channels. Such a molecule provides a precision-medicine approach to target SCN8A -related epilepsy syndromes ( SCN8A -RES), where gain-of-function (GoF) mutations lead to excess Na V 1.6 sodium current, or other indications where Na V 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 V 1.6 (IC 50 0.051 µM), with exquisite selectivity over other sodium channel isoforms (selectivity ratios of 756 X for Na V 1.1, 134 X for Na V 1.2, 276 X for Na V 1.7, and >583 Xfor Na V 1.3, Na V 1.4, and Na V 1.5). NBI-921352is a state-dependent inhibitor, preferentially inhibiting inactivatedchannels. The state dependence leads to potent stabilization of inactivation, inhibiting Na V 1.6 currents, including resurgent and persistent Na V 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 V 1.1 predominates. Oral administration of NBI-921352 prevented electrically induced seizures in a Scn8a 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 SCN8A- developmental epileptic encephalopathy ( SCN8A -DEE) and adult focal-onset seizures. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.7554/elife.72468 |
| الاتاحة: | http://dx.doi.org/10.7554/elife.72468 https://cdn.elifesciences.org/articles/72468/elife-72468-v2.pdf https://cdn.elifesciences.org/articles/72468/elife-72468-v2.xml https://elifesciences.org/articles/72468 |
| Rights: | http://creativecommons.org/licenses/by/4.0/ ; http://creativecommons.org/licenses/by/4.0/ ; http://creativecommons.org/licenses/by/4.0/ |
| رقم الانضمام: | edsbas.870F9A5D |
| قاعدة البيانات: | BASE |
| DOI: | 10.7554/elife.72468 |
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