Department of Brain Sciences, Imperial College London, Room E419, Burlington Danes Building, Hammersmith Hospital Campus 160 Du Cane Road, London, W12 0NN, United Kingdom.
Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse, 124 4070, Basel, Switzerland.
Neuropharmacology. 2020 Jun 15;170:107868. doi: 10.1016/j.neuropharm.2019.107868. Epub 2019 Nov 28.
Modern anti-seizure drug development yielded benefits in terms of improved pharmacokinetics, safety and tolerability profiles, but offered no advances in efficacy compared to previous older generations of anti-seizure drugs. Despite significant advances in our understanding of the genetic bases to epilepsy, and a welcome renewed interest on the severe monogenic epilepsies, modern genetics has yet to directly inform more effective or disease-modifying anti-seizure drugs. Here, we describe a new approach to the identification of novel disease modifying anti-epilepsy drugs. The systems genetics approach aims to first identify pathophysiological mechanisms by integrating polygenic risk with cellular gene expression profiles and then to relate these molecular mechanisms to druggable targets using a gene regulatory (regulome) framework. The approach offers an exciting and flexible framework for future drug discovery in epilepsy, and is applicable to any disease for which appropriate cell-type and disease-context specific data exist. This article is part of the special issue entitled 'New Epilepsy Therapies for the 21st Century - From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy'.
现代抗癫痫药物的发展在改善药代动力学、安全性和耐受性方面带来了益处，但在疗效方面与前几代抗癫痫药物相比并没有进展。尽管我们在癫痫的遗传基础方面有了重大进展，并且严重的单基因癫痫也重新引起了人们的兴趣，但现代遗传学尚未直接为更有效或疾病修饰的抗癫痫药物提供信息。在这里，我们描述了一种鉴定新型疾病修饰抗癫痫药物的新方法。系统遗传学方法旨在首先通过整合多基因风险与细胞基因表达谱来识别病理生理机制，然后使用基因调控（调控组）框架将这些分子机制与可用药靶点联系起来。该方法为癫痫的未来药物发现提供了一个令人兴奋和灵活的框架，并且适用于任何存在适当细胞类型和疾病背景特异性数据的疾病。本文是题为“21 世纪的新型癫痫治疗方法-从抗癫痫药物到癫痫的预防、修饰和治疗”的特刊的一部分。
