The Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) Project 2: Preclinical Model for Antiepileptogenic Therapy Screening in Post-traumatic Epilepsy

摘要-项目2 -抗癫痫治疗筛选的临床前模型 创伤后癫痫 目前还没有有效的抗癫痫治疗获得性癫痫，如创伤后癫痫。 癫痫尽管创伤后癫痫的严重人力成本，进行临床研究的努力， 抗癫痫试验目前是非常困难的，由于显着的成本，随访时间，和非常高的风险。 需要治疗以最终观察抗癫痫作用的受试者数量。的可用性 一种生物标志物，在早期阶段预测谁会患上癫痫，谁可能从癫痫中受益。 治疗的抗癫痫作用将显著加速和降低识别癫痫发作的过程的风险。 抗癫痫治疗此外，动物研究报告了一些有希望的发现， 并不总是转化为临床相关的发现，阻碍了赞助严格的 在人类中进行抗癫痫试验，当有很大的失败风险时。在这项研究中， EpiBioS 4 Rx中心无墙，我们的目标是建立一个严格有效的临床前模型，以筛选 通过尝试填补两个重要的空白（a）识别和 验证创伤后癫痫发生的生物标志物，可以预测抗癫痫作用， 治疗和（B）通过创建第一个多中心，双盲， 按照严格的高标准进行的溶剂对照、随机临床前抗癫痫研究 由NINDS、AES/ILAE转化研究工作组和ARRIVE指南倡导。我们有 成立了一个由四个国际临床前测试中心（阿尔伯特爱因斯坦学院）组成的合作小组。 医学，墨尔本大学，加州大学洛杉矶分校，东芬兰大学），由专家支持， 药代动力学建模（明尼苏达大学）和外周电生理学和成像专家 生物标记物的发现，以及神经治疗学。临床前数据安全性监查委员会将 监督进展情况，并就战略和为未来临床研究准备临床队列提供建议。 审判我们选择了5种针对不同机制的新型治疗方法，并使用多模式筛选 创伤后癫痫发生的候选生物标志物的靶向接合和修饰的过程，我们 目的是确定（a）至少一种治疗，以在该严格模型中筛选其抗癫痫潜力，以及 (b)至少一种创伤后癫痫发生的生物标志物，其可以早期预测抗癫痫作用。 我们的研究人员与项目1（发现动物癫痫发生的生物标志物），项目3 （发现人类癫痫发生的生物标志物），信息学和分析核心，以及公众 订婚的核心。

ABSTRACT– PROJECT 2 – PRECLINICAL MODEL FOR ANTIEPILEPTOGENIC THERAPY SCREENING IN POST-TRAUMATIC EPILEPSY There is currently no validated antiepileptogenic therapy for acquired epilepsies, such as post-traumatic epilepsy. Despite the grave human cost of post-traumatic epilepsy, undertaking the effort to perform a clinical antiepileptogenesis trial is currently hugely difficult, due to the significant cost, time to follow up, and very high numbers of subjects needed to treat to eventually observe antiepileptogenic effect. The availability of a biomarker that predicts, at an early stage, who will develop epilepsy and who might benefit from the antiepileptogenic effect of a treatment would significantly accelerate and de-risk the process of identifying an antiepileptogenic therapy. Furthermore, the concern that animal studies report several promising discoveries that do not always translate into clinically relevant findings has discouraged efforts to sponsor rigorous antiepileptogenesis trials in humans, when there is a significant risk of failure. In this study, Project 2 of the EpiBioS4Rx Center Without Walls, we aim to create a rigorous and effective preclinical model to screen antiepileptogenic therapies for posttraumatic epilepsy by trying to fill two important gaps (a) identify and validate a biomarker of posttraumatic epileptogenesis that can predict the antiepileptogenic effect of a treatment and (b) enhance the reproducibility of the study by creating the first multicenter, double-blinded, vehicle controlled, randomized preclinical antiepileptogenesis study following the high standards of rigor advocated by NINDS, the AES/ILAE Translational Research Task Force and the ARRIVE guidelines. We have formed a collaborative group of four international preclinical testing centers (Albert Einstein College of Medicine, University of Melbourne, UCLA, University of Eastern Finland), supported by experts in pharmacokinetic modeling (University of Minnesota), and experts in peripheral electrophysiology and imaging biomarker discovery, as well as neurotherapeutics. A preclinical Data Safety Monitoring Board will be overseeing the progress and advise on strategies and the preparation of a clinical cohort for the future clinical trial. We have selected 5 novel treatments that target different mechanisms and using a multimodal screening process for target engagement and modification of candidate biomarkers of posttraumatic epileptogenesis, we aim to identify (a) at least one treatment to screen in this rigorous model for its antiepileptogenic potential, and (b) at least one biomarker of posttraumatic epileptogenesis that can predict early the antiepileptogenic effect. Our investigators work closely with Project 1 (discovery of biomarkers of epileptogenesis in animals), Project 3 (discovery of biomarkers of epileptogenesis in humans), the Informatics and Analytics Core, and the Public Engagement Core.