Development and Testing of LUCID: A Therapeutic Device for Brain Injury Following Infant Cardiac Arrest

LUCID 的开发和测试：婴儿心脏骤停后脑损伤的治疗装置

基本信息

批准号：
10708811
负责人：
MAIK HUETTEMANN
金额：
$ 98.66万
依托单位：
MITOVATION, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-21 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10708811
关键词：
1 year old Achievement Address American Heart Association Animal Model Blood flow Brain Brain Injuries Brain Ischemia Cardiac Surgery procedures Cardiopulmonary Resuscitation Cessation of life Child Childhood Circulation Clinical Clinical Engineering Clinical Trials Computer software Coupled Custom Data Development Device or Instrument Development Devices Dose Electroencephalography Enrollment Enzymes Foundations Free Radicals Generations Goals Grant Guidelines Head circumference Health Heart Arrest Hospitals Impairment Infant Institutional Review Boards Interruption Intervention Ischemia Ischemic Brain Injury Laboratories Legal patent Light Measures Mediating Medical Device Medical emergency Methods Mitochondria Molecular Nervous System Physiology Nervous System Trauma Neurocognitive Deficit Neurologic Neurologic Examination Neurological outcome Oxidases Oxygen Patients Phase Phototherapy Pre-Clinical Model Preparation Probability Production Reactive Oxygen Species Recommendation Reperfusion Injury Reperfusion Therapy Research Resources Respiration Resuscitation Rodent Model Safety Scalp structure Small Business Technology Transfer Research Source System Technology Temperature Testing Therapeutic Therapeutic Uses Time Tissues Translating Validation biomaterial compatibility clinical efficacy clinical translation cost cytochrome c oxidase design disability first-in-human improved infant brain injury innovation manufacture multidisciplinary natural hypothermia neurocognitive test neuroprotection novel out-of-hospital cardiac arrest patient population porcine model portability pre-clinical prototype research clinical testing restoration standard care success waveguide wound

项目摘要

Cardiac arrest in infants is a medical emergency requiring rapid resuscitation to restore circulation. However, resuscitation often results in significant brain injury, caused by ischemia/reperfusion injury. Only 36% of infants (<1yr old) treated for out-of-hospital cardiac arrest and 69% of infants that suffer in-hospital cardiac arrest are successfully resuscitated. These infants currently have no therapeutic options to limit brain injury. The current standard treatment for post-cardiac arrest brain injury is therapeutic hypothermia. Unfortunately, recent studies demonstrated that use of therapeutic hypothermia in pediatric cardiac arrest patients does not provide significant benefit beyond what is achieved with controlled normothermia. A safe and effective neuroprotective intervention that specifically targets reperfusion injury would fill a critical unmet need in the treatment of these vulnerable patients. Our molecular studies on mitochondria uncovered a novel method to non-invasively modulate mitochondrial function during reperfusion and reduce brain injury following resuscitation from cardiac arrest. Indeed, our studies have, for the first time: (i) identified two wavelengths of near infrared light (NIR) that specifically and reversibly reduce mitochondrial respiration by acting on cytochrome c oxidase (COX); (ii) documented that NIR, applied at the time of reoxygenation, is neuroprotective in rodent and swine models of infant and pediatric cardiac arrest/resuscitation; and (iii) developed a NIR-delivery system capable of providing therapeutic doses to patients up to 1 year old. Based on these data, we propose to produce the clinical Light Utilizing COX- Inhibitory Device (LUCID), a medical device that will safely deliver therapeutic NIR to the infant brain. To achieve this goal, Phase I will focus on device development and validation of LUCID in 3 experimental aims: • Develop LUCID engineered for clinical use (Aim 1). • Evaluate safety and efficacy of LUCID (Aim 2). • LUCID clinical trial development and HUD and IDE approval (Aim 3). Phase II will utilize the LUCID clinical device and execute the “LUCID Therapy for Infant Cardiac Arrest” (LUTICA) clinical trial (Aim 4). This proposal combines multi-disciplinary expertise, compelling preliminary data, and state-of-the-art resources available to our team to address a significant health problem in a highly vulnerable patient population.

婴儿心脏骤停是一项医疗紧急情况，需要快速复苏才能恢复循环。然而，复苏通常会导致缺血/再灌注损伤引起的严重脑损伤。只有36％的婴儿（<1岁）接受过院外心脏骤停治疗，遭受院内心脏骤停的婴儿中有69％是成功复苏了。这些婴儿目前没有限制脑损伤的治疗选择。电流心脏骤停后脑损伤的标准治疗方法是治疗性体温过低。不幸的是，最近的研究证明在儿科心脏骤停患者中使用热体温过低不提供超出受控的正常热症所取得的重大好处。安全有效的神经保护专门针对再灌注损伤的干预措施将满足对这些治疗的关键需求脆弱的患者。我们对线粒体的分子研究发现了一种新的方法，用于非侵入性调节线粒体再灌注过程中的功能并减少心脏骤停复苏后的脑损伤。确实，我们的研究首次有：（i）确定了两个特定的近感染光（NIR）波长通过作用于细胞色素C氧化酶（COX）来可逆地减少线粒体呼吸；（ii）记录了这一点 NIR在重氧时应用，在婴儿和小儿的啮齿动物和猪模型中具有神经保护作用心脏骤停/复苏；（iii）开发了一种能够提供治疗剂量的NIR交付系统给最多1岁的患者。基于这些数据，我们建议利用Cox-生产临床光抑制装置（Lucid），这是一种可以安全地向婴儿大脑提供热NIR的医疗装置。到实现这一目标，第一阶段将重点介绍3个实验目标中的Lucid的设备开发和验证： •开发供临床使用的清醒工程（AIM 1）。 •评估清醒的安全性和效率（AIM 2）。 •清醒的临床试验开发以及HUD和IDE批准（AIM 3）。第二阶段将利用清晰的临床装置，并执行“婴儿心脏骤停的清醒疗法” （Lutica）临床试验（AIM 4）。该建议结合了多学科专业知识，引人入胜的初步数据和最先进的资源我们的团队可以在高度脆弱的患者人群中解决重大健康问题。