Targeting Kv7 Potassium Channels for Epilepsy.

IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY
CNS drugs Pub Date : 2025-03-01 Epub Date: 2025-01-24 DOI:10.1007/s40263-024-01155-3
Emilio Perucca, Maurizio Taglialatela
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引用次数: 0

Abstract

Voltage-gated Kv7 potassium channels, particularly Kv7.2 and Kv.7.3 channels, play a critical role in modulating susceptibility to seizures, and mutations in genes that encode these channels cause heterogeneous epilepsy phenotypes. On the basis of this evidence, activation of Kv7.2 and Kv.7.3 channels has long been considered an attractive target in the search for novel antiseizure medications. Ezogabine (retigabine), the first Kv7.2/3 activator introduced in 2011 for the treatment of focal seizures, was withdrawn from the market in 2017 due to declining use after discovery of its association with pigmentation changes in the retina, skin, and mucosae. A novel formulation of ezogabine for pediatric use (XEN496) has been recently investigated in children with KCNQ2-related developmental and epileptic encephalopathy, but the trial was terminated prematurely for reasons unrelated to safety. Among novel Kv7.2/3 openers in clinical development, azetukalner has shown dose-dependent efficacy against drug-resistant focal seizures with a good tolerability profile and no evidence of pigmentation-related adverse effects in early clinical studies, and it is now under investigation in phase III trials for the treatment of focal seizures, generalized tonic-clonic seizures, and major depressive disorder. Another Kv7.2/3 activator, BHV-7000, has completed phase I studies in healthy subjects, with excellent tolerability at plasma drug concentrations that exceed the median effective concentrations in a preclinical model of anticonvulsant activity, but no efficacy data in patients with epilepsy are available to date. Among other Kv7.2/3 activators in clinical development as potential antiseizure medications, pynegabine and CB-003 have completed phase I safety and pharmacokinetic studies, but results have not been yet reported. Overall, interest in targeting Kv7 channels for the treatment of epilepsy and for other indications remains strong. Future breakthroughs in this area could come from exploitation of mechanistic differences in the action of Kv7 activators, and from the development of molecules that combine Kv7 activation with other mechanisms of action.

靶向Kv7钾通道治疗癫痫
电压门控的Kv7钾通道,特别是Kv7.2和kv7.3通道,在调节癫痫易感性中起着关键作用,编码这些通道的基因突变导致异质性癫痫表型。基于这一证据,Kv7.2和Kv.7.3通道的激活一直被认为是寻找新型抗癫痫药物的一个有吸引力的靶点。Ezogabine(瑞加滨)是2011年推出的第一种用于治疗局灶性癫痫发作的Kv7.2/3激活剂,在发现其与视网膜、皮肤和粘膜色素沉着变化相关后,由于使用量下降,于2017年退出市场。最近研究了一种新的儿童用ezogabine (XEN496)配方,用于kcnq2相关的发展性和癫痫性脑病儿童,但由于与安全性无关的原因,该试验过早终止。在临床开发的新型Kv7.2/3开放剂中,azetukalner在早期临床研究中显示出对耐药局灶性癫痫的剂量依赖性疗效,具有良好的耐受性,无色素相关不良反应的证据,目前正在进行III期试验,用于治疗局灶性癫痫、全身性强直-阵挛性癫痫和重度抑郁症。另一种Kv7.2/3激活剂BHV-7000已经在健康受试者中完成了I期研究,在抗惊痫活性临床前模型中,当血浆药物浓度超过中位有效浓度时,BHV-7000具有出色的耐受性,但迄今尚无癫痫患者的疗效数据。在其他作为潜在抗癫痫药物临床开发的Kv7.2/3激活剂中,pynegabine和CB-003已经完成了I期安全性和药代动力学研究,但结果尚未报道。总的来说,针对Kv7通道治疗癫痫和其他适应症的兴趣仍然很强。这一领域未来的突破可能来自对Kv7激活剂作用机制差异的利用,以及将Kv7激活与其他作用机制结合起来的分子的开发。
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来源期刊
CNS drugs
CNS drugs 医学-精神病学
CiteScore
12.00
自引率
3.30%
发文量
82
审稿时长
6-12 weeks
期刊介绍: CNS Drugs promotes rational pharmacotherapy within the disciplines of clinical psychiatry and neurology. The Journal includes: - Overviews of contentious or emerging issues. - Comprehensive narrative reviews that provide an authoritative source of information on pharmacological approaches to managing neurological and psychiatric illnesses. - Systematic reviews that collate empirical evidence to answer a specific research question, using explicit, systematic methods as outlined by the PRISMA statement. - Adis Drug Reviews of the properties and place in therapy of both newer and established drugs in neurology and psychiatry. - Original research articles reporting the results of well-designed studies with a strong link to clinical practice, such as clinical pharmacodynamic and pharmacokinetic studies, clinical trials, meta-analyses, outcomes research, and pharmacoeconomic and pharmacoepidemiological studies. Additional digital features (including animated abstracts, video abstracts, slide decks, audio slides, instructional videos, infographics, podcasts and animations) can be published with articles; these are designed to increase the visibility, readership and educational value of the journal’s content. In addition, articles published in CNS Drugs may be accompanied by plain language summaries to assist readers who have some knowledge of, but not in-depth expertise in, the area to understand important medical advances.
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