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/缺血是由于血流不足和/或出生前，期间或之后，向婴儿大脑递送氧气。医院分娩中的发生是〜2-4每1000个完整的出生，早产新生儿的大幅增加。氧气不足传递到大脑会导致广泛的损害和严重的疾病。血流的恢复至关重要但是，挽救缺血组织也会导致明显的脑损伤，部分原因是细胞毒性反应性重新引入氧气后产生的氧（ROS）。新生儿的当前标准治疗缺氧/缺血是血液恢复后4-6小时平均施用的治疗性低温流量/氧递送。一种安全有效的神经保护干预措施，专门针对再灌注在重氧的早期阶段受伤将满足婴儿治疗的关键需求暴露于低氧/缺血。我们对线粒体功能的分子研究发现了一种新的方法，以防止在早期重氧。实际上，我们的研究第一次：（i）确定了两个红外光的波长（IRL）通过作用于细胞色素C氧化酶来特别和可逆地减少线粒体呼吸；和（ii）证明在重氧时应用的IRL是神经保护性的，并限制了ROS的产生。基于这些数据，我们提出了开发Ineurolux，该设备将安全地输送热IRL 婴儿大脑。为了实现这一目标，第一阶段将提出2个实验目标： •进行离体分子投资来定义可以在我们的大型动物研究（目标1）。 •在新生儿缺氧/缺血的大动物模型中建立IRL对HIE的影响（AIM 2）。我们将确定IRL对低氧/缺血的新生猪模型和缺血模型中神经系统损伤的影响研究IRL在未造成的组织中的安全性。第二阶段将基于第一阶段的发现，并且： •设计并构建了用于测试IRL治疗的Ineurolux轻型原型（AIM 3）。 •建立Ineurolux的效率，并评估Ineurolux联合疗法的概念体温过低（目标4）。 •记录Ineurolux的关键安全参数，以通过FDA批准前进（AIM 5）。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研究团队可以解决一个严重的健康问题。