Translational platform for epilepsy therapy and biomarker discovery

癫痫治疗和生物标志物发现的转化平台

• 批准号: 10467726
• 负责人: Denes V. Agoston
• 金额: $ 222.91万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10467726
• 关键词: Acute; Address; Advisory Committees; Advocate; Anatomy; Animal Model; Animals; Antiepileptogenic; Autophagocytosis; Axon; Bioinformatics; Biological Markers; Blood; Blood Vessels; Brain; Brain Pathology; Calcium-Binding Proteins; California; Caring; Cell Death; Cessation of life; Clinical; Collaborations; Corpus Callosum; Data; Deposition; Development; Discriminant Analysis; Disease; Double-Blind Method; Early Post-Traumatic Seizures; Early treatment; Electroencephalography; Epilepsy; Epileptogenesis; External Capsule; Free Radicals; Funding; Future; Glial Fibrillary Acidic Protein; Guidelines; HMGB1 Protein; Hemorrhage; High Frequency Oscillation; Image; Inflammatory; Injury; Interferon Type II; Interferons; Interleukin-1; International; Intervention; Investigation; Iron; Iron Chelating Agents; Isoenzymes; Laboratories; Lateral; Learning; Levetiracetam; Link; Machine Learning; Magnetic Resonance Imaging; Medicine; Memory; Metabolic; Minnesota; Modeling; Modification; Molecular; Monitor; Motor; National Institute of Neurological Disorders and Stroke; Neuroglia; Neurons; Oxidative Stress; Pathologic; Pathology; Patients; Peripheral; Persons; Pharmaceutical Preparations; Physiological; Plasma; Post-Traumatic Epilepsy; Pre-Clinical Model; Preclinical Testing; Predictive Value; Process; Randomized; Rattus; Recovery of Function; Research; Risk; Risk Factors; Seizures; Site; Testing; Therapeutic; Time; Tissues; Translational Research; Traumatic Brain Injury; Universities; University Health Services; Visuospatial; acquired epilepsy; base; biomarker discovery; biomarker panel; brain magnetic resonance imaging; candidate marker; clinical practice; college; design; early detection biomarkers; efficacy testing; experience; fluid percussion injury; functional outcomes; high standard; histological stains; in vivo; multimodality; neuroimaging; novel; novel marker; pharmacokinetic model; pre-clinical; predictive marker; prevent; primary endpoint; prophylactic; protein biomarkers; standard of care; synergism; tau Proteins; tau-1; treatment response; ubiquitin C-terminal hydrolase

PROJECT SUMMARY There is currently no validated treatment to prevent the development of acquired epilepsies, such as post- traumatic epilepsy. The availability of biomarker that predicts, at an early stage, people at risk to develop epilepsy and benefit from treatment interventions would significantly accelerate and de-risk the process of identifying an antiepileptogenic therapy. In this study, that is based on collaborations and preliminary data derived from EpiBioS4Rx, an NINDS funded Center without Walls, we aim to create a rigorous and effective preclinical model to screen a new candidate treatment to prevent posttraumatic epilepsy in the lateral fluid percussion injury model as well as identify biomarkers to guide treatment implementation. We will follow a 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, two UCLA sites), supported by experts in pharmacokinetic modeling (University of Minnesota), protein biomarker research (Uniformed Services University of the Health Services) and bioinformatics (University of Southern California). We plan to test a compound that removes pathological iron stores from the brain and test whether it can modify early biomarkers of epileptogenesis and injury. We aim to identify (a) at least one panel of multimodal biomarkers that can predict early on treatment response to the iron chelator, including the development of post-traumatic epileptogenesis, (b) at least one biomarker of epileptogenesis, (c) and determine whether iron chelator treatment can prevent post-traumatic epilepsy development.

项目摘要 目前还没有有效的治疗方法来预防获得性癫痫的发展，例如癫痫后癫痫。 外伤性癫痫在早期阶段预测有癫痫风险的人的生物标志物的可用性 并从治疗干预中获益将大大加快和降低识别 抗癫痫治疗在这项研究中，这是基于合作和初步数据来自 EpiBioS 4 Rx是NINDS资助的无墙中心，我们的目标是创建一个严格有效的临床前模型 筛选一种新的候选治疗方法，以预防侧向液压冲击损伤模型中的创伤后癫痫 以及识别生物标志物以指导治疗实施。我们将遵循多中心，双盲， 一项遵循高标准严格性的溶剂对照、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（阿尔伯特爱因斯坦医学院， 墨尔本大学，两个UCLA研究中心），由药代动力学建模专家（墨尔本大学 明尼苏达州），蛋白质生物标志物研究（卫生服务统一服务大学）和 生物信息学（南加州大学）。我们计划测试一种化合物， 并测试它是否可以改变癫痫发生和损伤的早期生物标志物。我们的目标是 鉴定（a）至少一组多模式生物标志物，其可以早期预测对铁的治疗反应 螯合剂，包括创伤后癫痫发生的发展，（B）至少一种生物标志物， 癫痫发生，（c）并确定铁螯合剂治疗是否可以预防创伤后癫痫 发展