The novel sodium channel modulator GS-458967 (GS967) is an effective treatment in a mouse model of SCN8A encephalopathy.
The novel sodium channel modulator GS-458967 (GS967) is an effective treatment in a mouse model of SCN8A encephalopathy.
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DOI：
10.1111/epi.14196
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发表时间：
2018-06
期刊：
影响因子：
5.6
通讯作者：
Kearney JA
中科院分区：
文献类型：
--
作者：
Baker EM;Thompson CH;Hawkins NA;Wagnon JL;Wengert ER;Patel MK;George AL Jr;Meisler MH;Kearney JA
编码电压门控钠通道 Nav1.6 的 SCN8A 的新生突变与严重的婴儿发作性癫痫性脑病有关。患有 SCN8A 脑病的个体癫痫发作的平均年龄为 4-5 个月，癫痫发作类型多样，通常用现有药物治疗难以治愈。轶事报告表明，大剂量苯妥英对某些患者有效，但存在相关的不良反应和潜在毒性。几种 SCN8A 脑病变异的功能特征表明，持续升高的钠电流是几种常见的生物物理缺陷之一。因此，在某些情况下，专门针对升高的持续电流可能是一种有用的治疗策略。新型钠通道调节剂 GS967 对持续电流与峰值电流具有更大的偏好，并且效力比苯妥英高出近十倍。我们评估了 GS967 在携带 SCN8A 患者突变（导致持续钠电流升高）的 Scn8a-N1768D/+ 小鼠模型中的治疗效果。我们还进行了膜片钳记录，以评估 GS967 对 Scn8a-N1768D/+ 小鼠海马神经元峰值和持续钠电流以及兴奋性的影响。 GS967 有效阻断持续钠电流，而不影响杂合子 Scn8a-N1768D/+ 小鼠神经元的峰值电流、标准化动作电位形态和减弱的兴奋性。 GS967 的急性治疗为 Scn8a-N1768D/+ 和野生型小鼠提供了针对 MES 诱导的癫痫发作的剂量依赖性保护。用 GS967 对 Scn8a-N1768D/+ 小鼠进行长期治疗，可以降低癫痫发作负担，并完全防止在未经治疗的 Scn8a-N1768D/+ 小鼠中观察到的癫痫相关致死。长期剂量即可实现保护，不会引起明显的行为毒性或镇静作用。
De novo mutations of SCN8A, encoding the voltage-gated sodium channel Nav1.6, have been associated with a severe infant-onset epileptic encephalopathy. Individuals with SCN8A encephalopathy have a mean age of seizure onset of 4–5 months, with multiple seizure types that are often refractory to treatment with available drugs. Anecdotal reports suggest that high-dose phenytoin is effective for some patients, but there are associated adverse effects and potential toxicity. Functional characterization of several SCN8A encephalopathy variants has shown that elevated persistent sodium current is one of several common biophysical defects. Therefore, specifically targeting elevated persistent current may be a useful therapeutic strategy in some cases. The novel sodium channel modulator GS967 has greater preference for persistent versus peak current and nearly ten-fold greater potency than phenytoin. We evaluated the therapeutic effect of GS967 in the Scn8a-N1768D/+ mouse model carrying an SCN8A patient mutation that results in elevated persistent sodium current. We also performed patch clamp recordings to assess the effect of GS967 on peak and persistent sodium current and excitability in hippocampal neurons from Scn8a-N1768D/+ mice. GS967 potently blocked persistent sodium current without affecting peak current, normalized action potential morphology, and attenuated excitability in neurons from heterozygous Scn8a-N1768D/+ mice. Acute treatment with GS967 provided dose-dependent protection against MES-induced seizures in Scn8a-N1768D/+ and wild-type mice. Chronic treatment of Scn8a-N1768D/+ mice with GS967 resulted in lower seizure burden and complete protection from seizure-associated lethality observed in untreated Scn8a-N1768D/+ mice. Protection was achieved at a chronic dose that did not cause overt behavioral toxicity or sedation.
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影响因子：
6.1
作者：
Mistry AM;Thompson CH;Miller AR;Vanoye CG;George AL Jr;Kearney JA
通讯作者：
Kearney JA
影响因子：
5.6
作者：
Anderson LL;Thompson CH;Hawkins NA;Nath RD;Petersohn AA;Rajamani S;Bush WS;Frankel WN;Vanoye CG;Kearney JA;George AL Jr
通讯作者：
George AL Jr
DOI：
10.1007/s13311-015-0372-8
发表时间：
2016-01
期刊：
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
影响因子：
--
作者：
Boerma RS;Braun KP;van den Broek MP;van Berkestijn FM;Swinkels ME;Hagebeuk EO;Lindhout D;van Kempen M;Boon M;Nicolai J;de Kovel CG;Brilstra EH;Koeleman BP
通讯作者：
Koeleman BP
影响因子：
5.6
作者：
Barker BS;Ottolini M;Wagnon JL;Hollander RM;Meisler MH;Patel MK
通讯作者：
Patel MK
影响因子：
4.6
作者：
Anderson, Lyndsey L.;Hawkins, Nicole A.;George, Alfred L., Jr.
通讯作者：
George, Alfred L., Jr.