Inter-alpha Inhibitors in Hypoxic-Ischemic Brain Injury

围产期脑损伤导致的智力低下和脑瘫是#年最严重的残疾 早产儿为40-148，足月儿为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/治疗战略，以减少围产期脑损伤。 低温疗法是FDA批准的唯一一种减轻婴儿脑损伤的治疗方法。这种疗法只是 部分保护性，治疗窗口狭窄，只能用于治疗缺氧缺血 该药用于足月儿的脑病(HIE)，不被批准用于早产儿。因此，额外的 迫切需要辅助治疗。间α抑制蛋白(IAIP)是一种天然产物 已被证明在调节宿主炎症中发挥重要作用的糖蛋白 通过靶向多种不同的炎症途径进行反应。IAIPs下调细胞因子，抑制丝氨酸 蛋白水解酶，阻断补体的激活，维持中性粒细胞处于静止状态，减少ROS的产生，并结合 死亡细胞释放的核蛋白。我们最近完成的SBIR的令人鼓舞的结果 第二阶段计划显示，IAIPs显著减轻常温条件下的脑体积损失 实验性新生儿缺氧缺血性脑损伤和IAIPs治疗提供了同等的神经保护效果 对新生大鼠的羟色胺作用。核磁共振成像的结果与伤者的脑体积损失有很好的相关性。 小白鼠成年后的大脑，有助于对治疗效果的有效和长期研究。我们 高压氧+高压氧后立即给予IAIPs治疗。在本提案中，我们将修改 我们之前的研究范式是通过提供更长的连续重复剂量来增强IAIPs的效果 暴露在高温下。这一策略专门针对持续数年的延长的继发性炎症阶段 缺氧缺血性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进程 确认和进一步发展有效的治疗策略，使用IAIPs作为替代或辅助治疗 羟色胺可预防和/或减轻新生儿缺氧相关脑损伤。我们还将探讨血液中IAIP的水平 和其他炎症标志物作为潜在的生物标志物，帮助未来的人体试验。具体目标是： 1)优化IAIPs单用和/或后治疗中重度HI的治疗策略 高压氧治疗：我们假设高压氧后多次重复使用IAIP可增加有益效果。 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来治疗高血压 结果：2)确定用于动物毒理学和临床研究的药效学生物标记物 假设IAIPs和相关的靶蛋白(HMGB1和细胞外组蛋白)的水平为 在HIE婴儿中发生改变，除了Apgar/Sarnat评分外，还可以作为有用的预测生物标志物。 AEEG和血气分析指导婴幼儿临床治疗。设计了建议的翻译项目 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.