Inter-alpha Inhibitors in Hypoxic-Ischemic Brain Injury

围产期脑损伤导致智力迟钝和脑瘫是最严重的残疾， 影响早产儿40-148例，足月儿1-2/1000。这给社会带来了巨大的负担， 强调迫切需要改进预防/治疗策略以减少围产期脑损伤。 低温（HT）是FDA唯一批准的减轻婴儿脑损伤的治疗方法。这种疗法只是 部分保护，治疗窗窄，只能用于治疗缺氧缺血性 在足月婴儿中，该药物用于治疗新生儿脑病（HIE），并且未被批准用于早产婴儿。因此提供附加 因此，迫切需要治疗。α间抑制蛋白（IAIP）是天然来源的 已被证明在调节宿主炎症反应中起重要作用的糖蛋白 通过靶向多个不同的炎症通路来应对。IAIP下调细胞因子，抑制丝氨酸蛋白酶， 蛋白酶，阻断补体激活，维持中性粒细胞处于静息状态，减少ROS产生，并结合 死亡细胞释放的核蛋白质。我们最近完成的SBIR取得了令人鼓舞的成果 II期研究表明，IAIPs在常温条件下显著减轻脑容量损失， 实验性新生儿HI脑损伤，IAIP治疗提供了等效的神经保护效果 对新生大鼠的HT。MRI检查结果与脑损伤后脑体积的变化有很好的相关性 当他们成为年轻的成年人，促进有效和长期的治疗效果研究。我们 在HI和HT暴露后立即用IAIP处理大鼠。在本提案中，我们将修改 我们先前的研究范式通过在注射后提供更长的连续重复剂量来增强IAIP的效果。 暴露于HT。这种策略特别针对持续时间较长的继发性炎症期， HI脑损伤后数天至数周。该项目的目标是通过以下方式推进药物开发过程： 确认并进一步开发使用IAIP作为替代或替代的有效治疗策略 以预防和/或减轻新生儿中HI相关的脑损伤。我们还将研究血液IAIP水平 和其他炎症标志物作为潜在的生物标志物，以帮助未来的人体试验。具体目标是： 1)优化IAIP单独和/或联合治疗中重度HI的治疗策略， HT治疗：我们假设HT后多次重复IAIP剂量增加了有益效果 HT通过减少继发性炎症阶段和改善长期组织病理学和行为学 结果; 2）为了确定用于动物毒理学和临床研究的药效学生物标志物：我们 假设IAIP和相关靶蛋白（HMGB 1和细胞外组蛋白）的水平是 在患有HIE的婴儿中改变，并且可以作为除了Apgar/Sarnat评分之外的有用的预测生物标志物， aEEG和血气值以指导婴儿的临床治疗。建议的翻译项目设计 获得可靠的关键临床前数据，以支持未来的早期人体安全性和有效性测试。

Perinatal brain injury resulting in mental retardation and cerebral palsy is the most severe disability in children and affects 40-148 in preterm and 1–2/1000 in full term infants. This places a huge burden on society, emphasizing the critical need for improved prevention/treatment strategies to decrease perinatal brain injury. Hypothermia (HT) is the only FDA approved therapy to attenuate brain damage in infants. This therapy is only partially protective, has a narrow therapeutic window, can only be used to treat hypoxic-ischemic encephalopathy (HIE) in full term infants, and is not approved for use in preterm infants. Therefore, additional adjunctive therapies are urgently needed. Inter-alpha Inhibitor Proteins (IAIPs) are naturally derived glycoproteins that have been demonstrated to play an important role in modulating host inflammatory responses by targeting multiple, diverse inflammatory pathways. IAIPs down-regulate cytokines, inhibit serine proteases, block complement activation, maintain neutrophils in a resting state, reduce ROS production, and bind nuclear proteins that are released from dying cells. Our encouraging results from the recently completed SBIR Phase II project showed that IAIPs markedly attenuate brain volume loss under normothermic conditions in experimental neonatal HI brain injury, and that treatment with IAIPs offered equivalent neuroprotective efficacy to HT in neonatal rats. The results of MRI imaging correlated very well with the brain volume loss in the injured rat brains when they became young adults, facilitating efficient and long-term study of treatment effects. We treated the rats with IAIPs immediately after the exposure to HI followed by HT. In this proposal, we will modify our previous study paradigm to enhance IAIPs effect by providing longer sequential repeated doses after exposure to HT. This strategy specifically targets the prolonged secondary inflammatory phase that last for days to weeks after HI brain injury. The goal of this project is to advance the drug development process by confirming and further developing effective therapeutic strategies using IAIPs as an alternative or adjunctive to HT to prevent and/or attenuate HI-related brain damage in neonates. We will also explore blood IAIP levels and other inflammatory markers as potential biomarkers to assist in future human trials. The specific aims are: 1) To optimize the treatment strategy with IAIPs in treating moderate and severe HI alone and/or after treatment with HT: We hypothesize that multiple repeated IAIP doses after HT augments the beneficial effects of HT by reducing the secondary inflammatory phase and improves long term histopathological and behavioral outcomes; 2) To identify pharmacodynamic biomarkers to use in animal toxicology and clinical studies: We hypothesize that the levels of IAIPs and the associated target proteins (HMGB1 and extracellular histones) are altered in infants with HIE and could serve as useful predictive biomarkers in addition to Apgar/Sarnat scores, aEEG and blood gas values to guide clinical therapy in infants. The proposed translational project is designed to obtain robust key preclinical data in support of future early human safety and efficacy testing.