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

项目2-抗白血病药物筛选的临床前模型 在创伤后癫痫中 目前还没有有效的抗癫痫疗法来治疗获得性癫痫，如创伤后癫痫 癫痫。尽管创伤后癫痫造成了巨大的人力成本，但仍在努力进行临床 抗癫痫试验目前是非常困难的，因为费用巨大，随访时间长，而且非常高 需要治疗的受试者数量最终观察到抗癫痫作用。可提供的 生物标志物，在早期阶段预测谁会患上癫痫，谁可能从 一种治疗的抗癫痫作用将显著加快和降低识别 抗癫痫治疗。此外，动物研究报告了几个有希望的发现，这一担忧 并不总是转化为临床相关的发现，这阻碍了资助STRICAL 在有重大失败风险的情况下，在人类进行抗癫痫试验。在这项研究中，项目2 EpiBioS4Rx无墙中心，我们的目标是创建一个严格有效的临床前模型来筛选 创伤后癫痫的抗癫痫治疗试图填补两个重要空白(A)确定和 验证一种创伤后癫痫发生的生物标志物可以预测阿司匹林的抗癫痫作用 治疗和(B)通过创建第一个多中心、双盲、 遵循高标准严格的载体对照、随机临床前抗癫痫研究 由NINDS、AES/ILAE翻译研究工作组和到达指南倡导。我们有 组成了一个由四个国际临床前试验中心组成的合作小组(阿尔伯特·爱因斯坦学院 医学，墨尔本大学，加州大学洛杉矶分校，东芬兰大学)，由 药代动力学模型(明尼苏达大学)，外周电生理学和成像专家 生物标记物的发现，以及神经疗法。临床前数据安全监测委员会将 监督进展，并就策略和未来临床队列的准备工作提出建议 审判。我们选择了5种新的治疗方法，针对不同的机制，使用多模式筛选 创伤后癫痫发生的靶点接触和候选生物标记物的修饰过程 目的确定(A)在这个严格的模型中至少有一种治疗方法可以筛选其抗癫痫潜能，以及 (B)至少有一个创伤后癫痫发生的生物标志物可以早期预测抗癫痫效果。 我们的研究人员与项目1(动物癫痫发生的生物标记物的发现)、项目3密切合作 (人类癫痫发生的生物标记物的发现)，信息学和分析核心，以及公众 接洽核心。

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.