GABA靶向治疗癫痫和癫痫的新疗法:II。临床开发中的治疗。

IF 7.4 2区 医学 Q1 CLINICAL NEUROLOGY
CNS drugs Pub Date : 2023-09-01 Epub Date: 2023-08-21 DOI:10.1007/s40263-023-01025-4
Emilio Perucca, H Steve White, Meir Bialer
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引用次数: 1

摘要

抑制性神经递质γ-氨基丁酸(GABA)在调节神经元兴奋性中起着重要作用,GABA能传递的破坏有助于某些癫痫的发病机制。尽管目前许多可用的抗癫痫药物确实至少部分通过增强GABA能传递发挥作用,但仍有机会进行进一步研究,以开发更具创新性的GABA靶向疗法。本文总结了临床发展中一些此类治疗方法的可用证据。这些可以大致分为三组。第一组由GABAA受体的阳性变构调节剂组成,包括Staccato®阿普唑仑(一种已上市的苯二氮卓类药物,被重新用于癫痫,作为长期和重复性癫痫的潜在抢救性吸入治疗)、α2/3/5亚型选择性药物darigabat和ENX-101,以及口服活性神经类固醇ETX155和LPCN 2101。第二组药物包括两种已经上市的非神经适应症药物,它们可以被重新用作癫痫发作障碍的治疗方法。其中包括布美他奈,一种利尿剂,已在苯巴比妥耐药性新生儿癫痫发作中进行临床试验,该适应症进一步发展的理由仍在争论中,以及伊维菌素,一种抗寄生虫药物,目前正在一项针对局灶性癫痫的随机双盲试验中进行研究。最后一组包括一系列高度创新的疗法,即通过立体定向脑植入递送的GABA能中间神经元(NRTX-001),作为内侧颞叶癫痫的治疗,一种旨在上调NaV1.1电流和恢复GABA能中介神经元功能的反义寡核苷酸(STK-001),目前在Dravet综合征患者的试验中进行了测试,以及计划在Dravet综合征中进行研究的基于腺病毒载体的基因治疗(ETX-101)。另一种药物,一种皮下给药的神经活性肽(NRP2945),据报道可上调GABAA受体α和β亚基的表达,目前正在研究中,Lennox-Gastaut综合征和其他癫痫是拟议的适应症。目前管道的多样性突出了人们对GABA系统作为癫痫新治疗开发目标的强烈兴趣。到目前为止,这些研究性治疗的临床数据有限,需要进一步的研究来评估它们在解决癫痫管理中未满足的需求方面的潜在价值。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development.

The inhibitory neurotransmitter γ-aminobutyric acid (GABA) plays an important role in the modulation of neuronal excitability, and a disruption of GABAergic transmission contributes to the pathogenesis of some seizure disorders. Although many currently available antiseizure medications do act at least in part by potentiating GABAergic transmission, there is an opportunity for further research aimed at developing more innovative GABA-targeting therapies. The present article summarises available evidence on a number of such treatments in clinical development. These can be broadly divided into three groups. The first group consists of positive allosteric modulators of GABAA receptors and includes Staccato® alprazolam (an already marketed benzodiazepine being repurposed in epilepsy as a potential rescue inhalation treatment for prolonged and repetitive seizures), the α2/3/5 subtype-selective agents darigabat and ENX-101, and the orally active neurosteroids ETX155 and LPCN 2101. A second group comprises two drugs already marketed for non-neurological indications, which could be repurposed as treatments for seizure disorders. These include bumetanide, a diuretic agent that has undergone clinical trials in phenobarbital-resistant neonatal seizures and for which the rationale for further development in this indication is under debate, and ivermectin, an antiparasitic drug currently investigated in a randomised double-blind trial in focal epilepsy. The last group comprises a series of highly innovative therapies, namely GABAergic interneurons (NRTX-001) delivered via stereotactic cerebral implantation as a treatment for mesial temporal lobe epilepsy, an antisense oligonucleotide (STK-001) aimed at upregulating NaV1.1 currents and restoring the function of GABAergic interneurons, currently tested in a trial in patients with Dravet syndrome, and an adenoviral vector-based gene therapy (ETX-101) scheduled for investigation in Dravet syndrome. Another agent, a subcutaneously administered neuroactive peptide (NRP2945) that reportedly upregulates the expression of GABAA receptor α and β subunits is being investigated, with Lennox-Gastaut syndrome and other epilepsies as proposed indications. The diversity of the current pipeline underscores a strong interest in the GABA system as a target for new treatment development in epilepsy. To date, limited clinical data are available for these investigational treatments and further studies are required to assess their potential value in addressing unmet needs in epilepsy management.

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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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