PRECLINICAL CYCLOSPORIN A THERAPY TRIALS FOR PEDIATRIC TBI

描述（由申请人提供）：我们建议使用我们的未成熟的创伤性脑损伤（TBI）大型动物模型来加速基础科学治疗发现到儿童TBI的临床试验。由于线粒体在TBI的许多原发性和继发性病理通路中起着关键作用，我们将使用环孢素a （cyclosporin a, CsA）来挽救线粒体功能，减少细胞死亡和改善神经功能。由于其在人体中的安全性、多效性以及在多种临床前成年啮齿动物TBI模型中的成功，CsA （CsA）作为儿科TBI的治疗方法具有令人兴奋的潜力。由于CsA也处于非专利状态，并且已经用于儿童的其他适应症，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。我们使用已建立的未成熟猪TBI模型，确定CsA治疗儿童中度TBI的最佳剂量：可控皮质撞击引起的局灶性病变和快速非撞击性头部旋转引起的弥漫性脑损伤。此外，我们还包括在脑外伤后1小时的优化，以确定现场的给药策略，以及在脑外伤后6小时的优化，以确定医院的给药策略。为了加强翻译，我们纳入了临床相关的生理监测和当前的重症监护管理策略。此外，我们使用组织学和神经功能终点来确定急性减少脑损伤的药物，并具有持续的认知益处。在目标1中，我们将使用短期终末结果评估短期剂量反应。对于每一个开始时间和损伤类型，最有效和最低的有显著效果的剂量将持续到Aim 2。在目标2中，我们测试了这些给药策略对神经认知结果的疗效，在损伤后6天测量，以确定在儿科TBI临床试验中评估的最佳给药策略。在目标3中，我们将确定性别特异性认知恢复和最佳剂量CsA的毒理学反应。在Aim 4中，我们根据猪的数据和已发表的人类研究设计临床试验，并向FDA提交IND申请。这种最先进的、创新的临床前研究设计可以应用于其他治疗方法的未来评估，更长的治疗窗口，其他年龄，其他脑损伤，以及其他促进神经恢复或修复的药物。

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.