PRECLINICAL CYCLOSPORIN A THERAPY TRIALS FOR PEDIATRIC TBI

环孢菌素 A 治疗儿童 TBI 的临床前试验

基本信息

批准号：
8042851
负责人：
Ann-Christine Duhaime
金额：
$ 148.22万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8042851
关键词：
Abbreviations Adult Age Animal Model Animals Basic Science Behavioral Biological Markers Blood Brain Brain Injuries Caring Cause of Death Cell Death Child Childhood Childhood Injury Clinical Research Clinical Trials Clinical Trials Design Clinical trial protocol document Cognitive Continuous Infusion Core-Binding Factor Critical Care Cyclosporine Data Development Development Plans Diffuse Diffuse Brain Injury Dose Drug Kinetics Effectiveness Ensure Environmental air flow Evaluation Exposure to Family suidae Female Future Goals Head Histology Hospitals Hour Human IV Fluid Impaired cognition Incidence Injury Institutional Review Boards Intensive Care Investigational Drugs Kidney Laboratories Learning Legal patent Lesion Measures Memory Metabolic Metric Microdialysis Mitochondria Modeling Monitor National Institute of Neurological Disorders and Stroke Neurocognitive Outcome Outcome Measure Pathologic Pathway interactions Pediatric Hospitals Philadelphia Physiologic Monitoring Play Procedures Process Protocols documentation Publishing Randomized Controlled Trials Reducing Agents Relative (related person)Research Design Rodent Rotation Safety Saline Sampling Sedation procedure Serum Sex Characteristics Spectrin Testing Therapeutic Time Toddler Toxic effect Toxicology Translating Translational Research Translations Traumatic Brain Injury United States Weaning base clinically relevant cognitive recovery controlled cortical impact disability functional outcomes improved in vivo inclusion criteria injured innovation male meetings neuroprotection pre-clinical pre-clinical therapy preclinical study programs repaired respiratory response sex success therapy development treatment strategy

项目摘要

DESCRIPTION (provided by applicant): We propose to use our immature large animal models of traumatic brain injury (TBI) to accelerate basic science therapeutic discoveries to clinical trials for TBI in children. Because mitochondria play a key role in many primary and secondary pathologic pathways in TBI, we will use cyclosporin A (CsA) to rescue mitochondrial function, reduce cell death and improve neurofunction. Due to its safety profile in humans, pleiotropic effects, and success in multiple preclinical adult rodent TBI models, CsA (CsA) has exciting potential as a therapy for pediatric TBI. Because CsA is also off-patent and already in use in children for other indications, the results of the proposed preclinical therapy development plan can be translated rapidly to clinical trial. We determine the optimal dose of CsA for the spectrum of moderate TBI in the child, using our established immature porcine TBI models: focal lesions from controlled cortical impact and diffuse brain injury from rapid nonimpact head rotation. In addition, we include optimization at 1 hr after TBI to determine dosing strategies in the field, and at 6 hrs after TBI for hospital-based strategies. To enhance translation, we include clinically relevant physiological monitoring and current critical care management strategies. Furthermore, we use both histological and neurofunctional endpoints to identify agents that reduce brain injury acutely, and have sustained cognitive benefits. In Aim 1, we will evaluate short-term dose response using short term terminal outcomes. For each start time and injury type, the most effective and the lowest dose with significant effect will continue to Aim 2. In Aim 2 we test these dosing strategies for efficacy in neurocognitive outcomes, measured 6 days after injury, to identify the optimal dosing strategy to evaluate in pediatric TBI clinical trials. In Aim 3 we will identify sex-specific cognitive recovery and toxicology responses to the optimal dose of CsA. In Aim 4 we design the clinical trial from the porcine data and published human studies, and submit an IND application to the FDA. This state-of-the-art, innovative preclinical study design can be applied to future evaluations of other therapies longer treatment windows, other ages, other brain injuries, and to other agents that promote neurorecovery or repair.

描述（由申请人提供）：我们建议使用未成熟的大型脑损伤（TBI）大型动物模型，以加快基础科学的治疗发现，以便儿童的TBI临床试验。由于线粒体在TBI的许多原发性和继发性病理途径中起关键作用，因此我们将使用环孢菌素A（CSA）来挽救线粒体功能，减少细胞死亡并改善神经功能。由于其在人类中的安全性，多效性效应以及在多个临床前成年啮齿动物TBI模型中的成功，因此CSA（CSA）具有令人兴奋的潜力作为儿科TBI的疗法。由于CSA也是非适当的，并且已经在儿童中用于其他适应症，因此拟议的临床前治疗开发计划的结果可以迅速转化为临床试验。我们使用我们已建立的未成熟猪TBI模型来确定儿童中等TBI谱的CSA的最佳剂量：受控皮质影响的局灶性病变和快速非冲击头部旋转的弥漫性脑损伤。此外，我们在TBI后1小时还包括优化，以确定该领域的给药策略，以及在TBI之后进行基于医院策略的6小时。为了增强翻译，我们包括临床相关的生理监测和当前的重症监护管理策略。此外，我们同时使用组织学和神经功能端点来识别急性减少脑损伤并具有持续认知益处的药物。在AIM 1中，我们将使用短期终端结果评估短期剂量反应。对于每种开始时间和伤害类型，最有效和最低剂量具有显着效果的目标2。在AIM 2中，我们测试了在受伤后6天测量神经认知结果的这些给药策略，以确定在儿科TBI临床试验中评估的最佳给药策略。在AIM 3中，我们将确定性别特异性的认知恢复和毒理学对CSA最佳剂量的反应。在AIM 4中，我们从猪数据中设计了临床试验并发布了人类研究，并向FDA提交了IND应用程序。这种最先进的创新临床前研究设计可以应用于对其他疗法的未来评估，其他治疗窗口，其他年龄，其他脑损伤以及促进神经记录或修复的其他药物。