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 目前尚无经过验证的治疗方法来防止开发获得的癫痫病，例如 创伤性癫痫。生物标志物的可用性在早期阶段预测有风险发展癫痫的人 并且从治疗干预措施中受益将显着加速和降低风险的识别过程 抗癫痫病治疗。在这项研究中，这是基于合作和初步数据 Epibios4Rx是一个没有墙的Ninds资助的中心，我们旨在创建一个严格有效的临床前模型 筛选新的候选治疗，以防止外侧流体打击乐模型中创伤后癫痫 以及识别生物标志物来指导治疗实施。我们将遵循一个多中心，双盲， 遵循高标准的高标准，车辆控制的，随机的，随机的抗癫痫发生研究 由Ninds，AES/ILAE转化研究工作组和到达指南提倡。我们有 组成了一个由四个国际临床前测试中心组成的合作小组（阿尔伯特·爱因斯坦医学院， 墨尔本大学，两个UCLA网站），由药代动力学建模专家（大学）支持 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）。我们计划测试去除病理铁的化合物 来自大脑的存储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 识别（a）至少一组多模式生物标志物，可以在对铁的治疗反应后尽早预测 螯合剂，包括创伤后癫痫发生的发展，（b）至少一个生物标志物 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。