Infant NeuroLUX: A Novel Non-invasive Therapeutic Device for Neonatal Hypoxic Brain Injury

Infant NeuroLUX：一种治疗新生儿缺氧性脑损伤的新型非侵入性治疗装置

基本信息

批准号：
10017347
负责人：
MAIK HUETTEMANN
金额：
$ 76.9万
依托单位：
MITOVATION, INC.
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10017347
关键词：
Achievement Address Affect Animal Model Animals Area Asphyxia Neonatorum Attenuated Back Basic Science Birth Blood flow Brain Brain Diseases Brain Hypoxia Brain Hypoxia-Ischemia Brain Injuries Brain Ischemia Cerebral Palsy Cerebrum Child Clinical Clinical Treatment Combined Modality Therapy Contracts Data Development Developmental Delay Disorders Devices Documentation Dose Engineering Ensure Epilepsy Event Exposure to Family suidae Free Radicals Generations Goals Gold Health Histologic Hospitals Hour Hypoxia Hypoxic Brain Damage Hypoxic-Ischemic Brain Injury Impaired cognition Incidence Infant Infant Mortality Infection Injury Intervention Investigation Laboratories Light Logistics Manufacturer Name Mediating Methods Mitochondria Modeling Molecular Morbidity - disease rate Neonatal Nervous System Physiology Nervous System Trauma Neurocognitive Deficit Neurologic Neurological outcome Newborn Infant Oxidases Oxygen Pathologic Penetration Perinatal Phase Phototherapy Pre-Clinical Model Preclinical Testing Production Reactive Oxygen Species Reperfusion Injury Reperfusion Therapy Research Resources Respiration Resuscitation Safety Scalp structure Survivors Technology Term Birth Testing Therapeutic Time Tissues Translating base brain tissue cytochrome C oxidase subunit II cytochrome c oxidase cytotoxic deprivation design and construction disability early childhood engineering design hypoxia neonatorum improved in utero in vivo in vivo evaluation innovation intrapartum multidisciplinary natural hypothermia neonatal brain neonatal hypoxic-ischemic brain injury neonate neurobehavioral neuromuscular neuroprotection novel premature preterm newborn prevent prototype response restoration standard care standard of care success therapy development

项目摘要

Neonatal hypoxia/ischemia is a known cause of cerebral damage resulting from inadequate blood flow and/or oxygen delivery to the infant brain before, during, or after birth. The occurrence among hospital deliveries is ~2-4 per 1000 full-term births with a drastic increase among premature newborns. The deficit in oxygen delivery to the brain results in extensive damage and severe disabilities. Restoration of blood flow critical for salvage of ischemic tissue, however, also causes significant cerebral damage due in part to cytotoxic reactive oxygen species (ROS) generated upon reintroduction of oxygen. The current standard treatment for neonatal hypoxia/ischemia is therapeutic hypothermia applied on average 4-6 hours after restoration of blood flow/oxygen delivery. A safe and effective neuroprotective intervention that specifically targets reperfusion injury during the early phase of reoxygenation would fill a critical unmet need in the treatment of infants exposed to hypoxia/ischemia. Our molecular studies on mitochondrial function uncovered a novel method to prevent ROS generation during early reoxygenation. Indeed, our studies have, for the first time: (i) identified two wavelengths of infrared light (IRL) that specifically and reversibly reduce mitochondrial respiration by acting on cytochrome c oxidase; and (ii) documented that IRL, applied at the time of reoxygenation, is neuroprotective and limits ROS generation. Based on these data, we propose develop iNeuroLUX, a device that will safely deliver therapeutic IRL to the infant brain. To achieve this goal, Phase I will propose 2 experimental aims: • Conduct ex vivo molecular investigation to define the safe therapeutic IRL dose that can be applied in our large animal studies (Aim 1). • Establish the effect of IRL on HIE in a large animal model of neonatal hypoxia/ischemia (Aim 2). We will determine the effects of IRL on neurologic damage in a neonate swine model of hypoxia/ischemia and investigate safety of IRL in undamaged tissues. Phase II will build upon the findings in the first phase and: • Design and construct a iNeuroLUX light-delivery prototype for testing IRL therapy (Aim 3). • Establish the efficacy of iNeuroLUX and evaluate the concept of iNeuroLUX combination therapy with hypothermia (Aim 4). • Document critical safety parameters of iNeuroLUX to move forward with FDA approval (Aim 5). This proposal combines multi-disciplinary expertise, compelling preliminary data, and state-of-the-art resources available to our research team to address a highly significant health problem.

新生儿缺氧/缺血是血流不足和/或导致脑损伤的已知原因出生前、出生期间或出生后向婴儿大脑输送氧气的情况发生在医院分娩中。每 1000 名足月新生儿中约有 2-4 人缺氧，其中早产儿的缺氧率急剧增加。输送到大脑会导致广泛的损伤和严重的残疾，这对于血流的恢复至关重要。然而，缺血组织的挽救也会导致严重的脑损伤，部分原因是细胞毒性反应重新引入氧气时产生的氧气（ROS）当前新生儿的标准治疗。缺氧/缺血是血液恢复后平均 4-6 小时应用的治疗性低温一种安全有效的神经保护干预措施，专门针对再灌注。再氧合早期阶段的损伤将填补婴儿治疗中未满足的关键需求暴露于缺氧/缺血。我们对线粒体功能的分子研究发现了一种在线粒体过程中防止 ROS 生成的新方法。事实上，我们的研究首次：（i）确定了红外光的两种波长。 (IRL)通过作用于细胞色素c氧化酶来特异性地、可逆地减少线粒体呼吸；和 (ii) 证明在再氧合时应用 IRL 具有神经保护作用并限制 ROS 的产生。基于这些数据，我们建议开发 iNeuroLUX，这是一种能够安全地将治疗性 IRL 传递给患者的设备。为了实现这一目标，第一阶段将提出两个实验目标： • 进行离体分子研究，以确定可应用于我们的安全治疗IRL剂量。大型动物研究（目标 1）。 • 在新生儿缺氧/缺血的大型动物模型中确定IRL 对HIE 的影响（目标2）。确定 IRL 对新生猪缺氧/缺血模型神经损伤的影响研究 IRL 在未受损组织中的安全性。第二阶段将建立在第一阶段的调查结果的基础上，并且： • 设计并构建用于测试IRL 疗法的iNeuroLUX 光传输原型（目标3）。 • 确定 iNeuroLUX 的功效并评估 iNeuroLUX 联合治疗的概念体温过低（目标 4）。 • 记录iNeuroLUX 的关键安全参数，以推动FDA 批准（目标5）。该提案结合了多学科专业知识、令人信服的初步数据和最先进的资源我们的研究团队可以用来解决非常重要的健康问题。