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，并用于儿童脑损伤的临床试验。由于线粒体在颅脑损伤的许多原发和继发病理途径中起关键作用，我们将使用环孢素A(CsA)来挽救线粒体功能，减少细胞死亡，改善神经功能。由于环孢素A(CsA，CsA)在人类中的安全性，多效性，以及在多种临床前成年啮齿动物脑损伤模型上的成功，CsA(CsA)在治疗儿童脑外伤方面具有令人兴奋的潜力。由于CsA也是非专利的，已经在儿童中用于其他适应症，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。我们使用我们建立的未成熟猪脑损伤模型：受控皮质撞击造成的局灶性损伤和快速非撞击头部旋转造成的弥漫性脑损伤，确定了儿童中度脑损伤的CsA最佳剂量。此外，我们还包括在TBI后1小时优化以确定现场给药策略，以及在TBI后6小时优化以医院为基础的策略。为了加强翻译，我们包括临床相关的生理监测和当前的危重护理管理策略。此外，我们使用组织学和神经功能终点来确定显著减少脑损伤并具有持续认知益处的药物。在目标1中，我们将使用短期最终结果来评估短期剂量反应。对于每个开始时间和损伤类型，最有效和最低剂量且有显著效果的剂量将继续目标2。在目标2中，我们测试这些剂量策略在损伤后6天测量的神经认知结果的疗效，以确定在儿童脑外伤临床试验中评估的最佳剂量策略。在目标3中，我们将确定特定性别的认知康复和对最佳剂量CsA的毒理学反应。在目标4中，我们根据猪数据和已发表的人体研究设计临床试验，并向FDA提交IND申请。这一最先进的创新临床前研究设计可应用于未来对其他治疗方法的评估，包括更长的治疗窗口、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.