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

• 批准号: 10515831
• 负责人: MAIK HUETTEMANN
• 金额: $ 99.93万
• 依托单位: MITOVATION, INC.
• 依托单位国家: 美国
• 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/10515831
• 关键词: 1 year old; Achievement; Address; American Heart Association; Animal Model; Blood Circulation; Blood flow; Brain; Brain Injuries; Brain Ischemia; Cardiac Surgery procedures; Cardiopulmonary Resuscitation; Cessation of life; Child; Childhood; 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; Investigation; 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; Production; Reactive Oxygen Species; 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; base; biomaterial compatibility; clinical efficacy; clinical translation; cost; cytochrome C oxidase subunit II; cytochrome c oxidase; design; disability; first-in-human; improved; infant brain injury; innovation; 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; verification and validation; waveguide; wound

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.

婴儿心脏骤停是一种需要快速复苏以恢复循环的医疗紧急情况。但是，在这方面， 复苏通常导致由缺血/再灌注损伤引起的严重脑损伤。只有36%的婴儿 （<1岁）因院外心脏骤停接受治疗，69%的院内心脏骤停婴儿 成功复苏。这些婴儿目前没有治疗选择来限制脑损伤。当前 心脏骤停后脑损伤的标准治疗是治疗性低温。不幸的是，最近的研究 证明在儿童心脏骤停患者中使用治疗性低温不能提供 比控制正常体温所获得的益处更显著。安全有效的神经保护剂 专门针对再灌注损伤的干预将填补这些治疗中关键的未满足的需求， 脆弱的病人。 我们对线粒体的分子研究揭示了一种新的方法，可以非侵入性地调节线粒体 在再灌注过程中发挥作用，并减少心脏骤停复苏后的脑损伤。的确，我们的 研究首次：（i）确定了两种波长的近红外光（NIR）， 通过作用于细胞色素c氧化酶（考克斯）可逆地减少线粒体呼吸;（ii）记录了 在复氧时应用的NIR在婴儿和儿童的啮齿动物和猪模型中具有神经保护作用 心脏骤停/复苏;以及（iii）开发了能够提供治疗剂量的NIR递送系统 1岁以下的患者。基于这些数据，我们提出利用考克斯- 抑制装置（LUCID），一种将治疗性NIR安全输送到婴儿大脑的医疗装置。到 为了实现这一目标，第一阶段将重点关注LUCID的设备开发和验证，有3个实验目标： ·开发用于临床的LUCID（目标1）。 ·评估LUCID的安全性和有效性（目标2）。 · LUCID临床试验开发和HUD和IDE批准（目标3）。 第二阶段将使用LUCID临床设备，并执行“婴儿心脏骤停的LUCID治疗” （LUTICA）临床试验（目标4）。 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 我们的团队可以解决高度脆弱患者群体的重大健康问题。