Drug Repurposing to Accelerate Progress in Neonatal Neuroprotection

药物再利用加速新生儿神经保护的进展

基本信息

批准号：
10454287
负责人：
JOHN D BARKS
金额：
$ 19.5万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10454287
关键词：
Acute Brain Injuries Address Adolescent Adverse effects Advocate Age Agonist Animal Model Animals Antibiotics Attenuated Azithromycin Brain Brain Hypoxia-Ischemia Brain Injuries Caffeine Carotid Arteries Cessation of life Childhood Clinical Clinical Trials Cognitive deficits Complex Consultations Contralateral Corpus striatum structure Data Development Dose Ensure Erythropoietin Evaluation Event Experimental Animal Model Exposure to FDA approved Funding Goals Hippocampus (Brain)Histopathology Human Hypoxia Hypoxic-Ischemic Brain Injury Infant Infarction Infection Inflammation Inflammatory Injections Injury Intervention Ipsilateral Ischemia Laboratories Lesion Life Ligation Lipopolysaccharides Mammals Measures Melatonin Memory Methods Modeling Morbidity - disease rate Necrotizing Enterocolitis Neonatal Neonatal Brain Injury Neurologic Neurologic Deficit Neuroprotective Agents Outcome Outcome Measure Oxygen Pathology Perinatal Brain Injury Pharmaceutical Preparations Pharmacotherapy Phase Phase III Clinical Trials Premature Infant Probability Procedures Property Prosencephalon Protocols documentation Publications Rattus Regimen Reperfusion Therapy Reporting Research Research Personnel Risk Rodent Rodent Model Safety Sample Size Sensorimotor functions Severities Side Standardization Stimulus Survivors TLR2 gene TLR4 gene Tetracyclines Therapeutic Time Tissues age group base brain tissue clinical efficacy comparative efficacy design disability drug candidate drug development drug repurposing efficacy study efficacy testing experimental study functional outcomes improved intraamniotic infection intrauterine infection ischemic injury model design natural hypothermia neonatal brain neonatal human neonatal hypoxic-ischemic brain injury neonatal infection neonatal period neonatal resuscitation neonate neuropathology neuroprotection novel strategies novel therapeutics perinatal injury postnatal premature preterm newborn primary outcome protective efficacy response sildenafil stem topiramate white matter white matter injury

项目摘要

Abstract In childhood, the risks of acute brain injury peak in the neonatal period. Major mechanisms of perinatal brain injury include hypoxia-ischemia (HI) and inflammation in response to intrauterine (e.g. chorioamnionitis) or neonatal (e.g. necrotizing enterocolitis) infections. In term infants, antecedent hypoxic-ischemic events can often be discerned; in premature neonates, multifactorial contributing mechanisms are often more difficult to identify. In view of the significant neurologic morbidity associated with perinatal brain injury in both term and preterm infants, effective neuroprotective interventions are greatly needed. Many drugs decrease brain injury and improve functional outcome in neonatal rodent hypoxic-ischemic (HI) brain injury models. A major translational challenge is to select those to prioritize for advancement to complementary larger animal perinatal injury models, and ultimately to early stage human neonatal trials. In view of the time lag from new drug development to clinical trials, our strategy is to prioritize evaluation of potentially neuroprotective drugs that are already approved for other indications i.e. “repurposing”, and utilize an “adaptive platform design model” for comparative efficacy studies. This proposal builds upon our recent findings that treatment with a clinically available antibiotic, azithromycin (AZ), reduces brain damage and improves functional outcomes in multiple neonatal rodent hypoxic-ischemic (HI) brain injury models. Our aims are to compare neuroprotective efficacy among clinically available drugs, including AZ, that are neuroprotective in similar neonatal rodent models, to help prioritize the best candidate(s) to advance to human trials. Efficacy will be compared in well-characterized rat models of hypoxic-ischemic and inflammation-amplified hypoxic-ischemic brain injury. We will incorporate studies in two age groups, post-natal day 7 (P7), to model term brain development, and P3, to model premature neonates. To elicit unilateral forebrain injury, animals undergo unilateral carotid artery ligation and subsequent timed (45-90 min) exposure to 8% oxygen; this results in quantifiable sensorimotor deficits and unilateral brain tissue damage. Pro-inflammatory stimuli, e.g. injections of a TLR-4 (lipopolysaccharide, LPS) or a TLR-2 (Pam3CSK4) agonist prior to lesioning, amplify HI injury. Our preliminary studies showed that treatment with AZ confers dose and time-dependent neuroprotection, at both ages, vs. HI and inflammation- amplified HI injury. Our current goals are to compare the neuroprotective efficacy among multiple clinically available drugs (AZ, erythropoietin, melatonin, sildenafil, caffeine, topiramate) in P7 (Aim 1) and P3 (Aim 2) rat hypoxic-ischemic and inflammation-amplified hypoxic-ischemic brain injury models. We quantify protective efficacy with composite scores that incorporate lateralizing sensorimotor function, memory and neuropathology measures, and also account for death as a possible injury outcome. We hypothesize that these comparative efficacy studies will identify one or two drugs with the highest probability of superiority at each age, and thus accelerate progress towards advancing safe and effective drugs to clinical trials in term and preterm neonates.

抽象的在儿童时期，急性脑损伤的风险在新生儿期达到顶峰。围产期大脑的主要机制。损伤包括缺氧缺血 (HI) 和宫内反应炎症（例如绒毛膜羊膜炎）或新生儿（例如坏死性小肠结肠炎）感染对于足月婴儿，先前发生的缺氧缺血事件可能导致。在早产儿中，多因素的影响机制通常更难以识别。鉴于与足月和围产期脑损伤相关的显着神经系统发病率。对于早产儿，非常需要有效的神经保护干预措施，许多药物可以减少脑损伤。并改善新生儿啮齿类缺氧缺血（HI）脑损伤模型的功能结果。转化挑战是选择那些优先发展到补充大型动物围产期的动物鉴于新药的时间滞后，最终进入早期人类新生儿试验。从开发到临床试验，我们的策略是优先评估潜在的神经保护药物已经批准用于其他适应症，即“重新利用”，并利用“自适应平台设计模型” 该建议基于我们最近的研究结果，即临床治疗。可用的抗生素阿奇霉素 (AZ) 可减少脑损伤并改善多种疾病的功能结果我们的目的是比较新生儿啮齿类缺氧缺血（HI）脑损伤模型的神经保护功效。在临床上可用的药物（包括 AZ）中，对类似的新生啮齿动物模型具有神经保护作用，帮助优先考虑进入人体试验的最佳候选者，并在充分表征的情况下比较功效。我们将纳入缺氧缺血性和炎症放大性缺氧缺血性脑损伤的大鼠模型。在两个年龄组中进行的研究，即出生后第 7 天（P7），以模拟足月大脑发育，以及 P3，以模拟为了引起单侧前脑损伤，对早产儿进行单侧颈动脉结扎和随后定时（45-90 分钟）暴露于 8% 的氧气；这会导致可量化的感觉运动缺陷和单侧脑组织损伤。促炎性刺激，例如注射 TLR-4（脂多糖，LPS）。或在损伤前使用 TLR-2 (Pam3CSK4) 激动剂，会放大 HI 损伤。我们的初步研究表明，与 HI 和炎症相比，AZ 治疗在两个年龄段均具有剂量和时间依赖性神经保护作用我们当前的目标是比较多种临床方法的神经保护功效。 P7（目标 1）和 P3（目标 2）大鼠可用药物（AZ、促红细胞生成素、褪黑激素、西地那非、咖啡因、托吡酯）我们量化了缺氧缺血性脑损伤和炎症放大的缺氧缺血性脑损伤模型。综合评分的功效，包括偏侧感觉运动功能、记忆和神经病理学措施，并将死亡视为可能的伤害结果。功效研究将确定一种或两种药物在每个年龄段具有最高的优越性，从而加快将安全有效的药物用于足月和早产儿临床试验的进程。