Precision therapies for genetic epilepsies in 2025: Promises and pitfalls.

IF 2.8 3区 医学 Q2 CLINICAL NEUROLOGY
Epilepsia Open Pub Date : 2025-05-24 DOI:10.1002/epi4.70065
Shuyu Wang, Emilio Perucca, Samuel F Berkovic, Piero Perucca
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Abstract

By targeting the underlying etiology, precision therapies offer an exciting paradigm shift to improve the stagnant outcomes of drug-resistant epilepsies, including developmental and epileptic encephalopathies. Unlike conventional antiseizure medications (ASMs) which only treat the symptoms (seizures) but have no effect on the underlying disease, precision therapies have the potential to suppress not only the seizures but also disabling comorbidities, including cognitive and behavioral abnormalities, which share the same causative mechanisms. Monogenic epilepsies are an attractive target for precision therapies because of their well-defined molecular mechanisms which can be tested in vitro and can be counteracted by specific drugs. Unfortunately, however, for the vast majority of proposed precision therapies, the evidence for their clinical efficacy is either non-existent or limited to uncontrolled observational accounts. Everolimus is the sole precision therapy with a seizure-related indication with class I evidence of efficacy, highlighting the practical and ethical challenges in obtaining high-level evidence. Here, we review the evidence landscape for candidate precision therapies, including repurposed and innovative treatments currently in development, discuss lessons learned from their use, and highlight strategies to improve their application and evaluation in the clinical setting. PLAIN LANGUAGE SUMMARY: Precision therapies offer a new approach to treat drug-resistant monogenic epilepsies, that is, epilepsies caused by a defect in a single gene. Unlike traditional antiseizure medications, precision therapies target the cause of the disease and have the potential to improve not only seizure control but also concomitant conditions such as cognitive and behavioral disorders. To date, the evidence derived from the clinical use of most proposed precision therapies is limited. This review explores current evidence and strategies to advance their development.

2025年基因癫痫的精准治疗:希望与陷阱。
通过针对潜在的病因,精确治疗提供了一个令人兴奋的范式转变,以改善耐药癫痫的停滞结果,包括发育性和癫痫性脑病。传统的抗癫痫药物(asm)只治疗症状(癫痫发作),但对潜在疾病没有作用,与之不同的是,精确治疗不仅有可能抑制癫痫发作,还可能抑制致残合并症,包括认知和行为异常,它们具有相同的致病机制。单基因癫痫是精确治疗的一个有吸引力的目标,因为它们具有明确的分子机制,可以在体外测试,并且可以通过特定药物抵消。然而,不幸的是,对于绝大多数提出的精确疗法,其临床疗效的证据要么不存在,要么仅限于不受控制的观察性报道。依维莫司是唯一一种具有癫痫相关适应症和I级疗效证据的精确疗法,这突出了获得高水平证据的实践和伦理挑战。在这里,我们回顾了候选精确疗法的证据景观,包括目前正在开发的重新定位和创新疗法,讨论了从它们的使用中吸取的教训,并强调了在临床环境中改进它们的应用和评估的策略。摘要:精确疗法为治疗耐药单基因癫痫提供了一种新的方法,即由单个基因缺陷引起的癫痫。与传统的抗癫痫药物不同,精准疗法针对疾病的病因,不仅有可能改善癫痫的控制,而且还可能改善伴随疾病,如认知和行为障碍。迄今为止,大多数提出的精确治疗的临床应用证据是有限的。这篇综述探讨了目前的证据和策略,以促进其发展。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Epilepsia Open
Epilepsia Open Medicine-Neurology (clinical)
CiteScore
4.40
自引率
6.70%
发文量
104
审稿时长
8 weeks
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