Inter-alpha Inhibitors in Hypoxic-Ischemic Brain Injury

缺氧缺血性脑损伤中的α间抑制剂

• 批准号: 10761207
• 负责人: YOW-PIN LIM
• 金额: $ 277.69万
• 依托单位: PROTHERA BIOLOGICS, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10761207
• 关键词: Adult; Affect; Aftercare; Animals; Anti-Inflammatory Agents; Attenuated; Binding; Binding Proteins; Blood; Blood gas; Blood specimen; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Cells; Cerebral Ischemia-Hypoxia; Cerebral Palsy; Child; Chromatography; Clinical; Clinical Research; Clinical Trials; Complement; Complement Activation; Data; Dose; Exposure to; FDA approved; Family; Future; Glycoproteins; Goals; HMGB1 gene; Health; Histones; Human; Hypoxic-Ischemic Brain Injury; Image; Infant; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Ischemia; Longitudinal Studies; Magnetic Resonance Imaging; Matrix Metalloproteinases; Mental Retardation; Modeling; Motor; Neonatal; Neurologic; Neuroprotective Agents; Newborn Animals; Newborn Infant; Nuclear Proteins; Pathway interactions; Perinatal Brain Injury; Phase; Plasma; Play; Premature Infant; Prevention; Process; Production; Property; Proteins; Public Health; Rattus; Recovery; Reperfusion Therapy; Replacement Therapy; Resolution; Rest; Role; Serine Protease; Small Business Innovation Research Grant; Societies; Therapeutic; Therapeutic Agents; Toxicology; behavior test; behavioral outcome; brain volume; cognitive function; cytokine; design; disability; drug development; efficacy testing; extracellular; high risk infant; immunoregulation; improved; inflammatory marker; injured; inter-alpha-inhibitor; natural hypothermia; neonatal hypoxic-ischemic brain injury; neonate; neuroprotection; neutrophil; novel; pharmacodynamic biomarker; pharmacologic; potential biomarker; pre-clinical; preclinical study; predictive marker; preterm newborn; prevent; protein complex; safety testing; sex; standard of care; therapeutically effective; tissue repair; treatment effect; treatment optimization; treatment strategy; young adult

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.

围产期脑损伤导致智力低下和脑瘫是最严重的残疾 儿童，影响 40-148 名早产儿和 1-2/1000 名足月婴儿。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 批准的唯一一种减轻婴儿脑损伤的疗法。此疗法仅 部分保护，治疗窗窄，只能用于治疗缺氧缺血 足月婴儿脑病（HIE），未获批准用于早产儿。因此，额外 迫切需要辅助治疗。 Inter-α 抑制剂蛋白 (IAIP) 是天然衍生的 糖蛋白已被证明在调节宿主炎症中发挥重要作用 通过针对多种不同的炎症途径来做出反应。 IAIPs 下调细胞因子，抑制丝氨酸 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 垂死细胞释放的核蛋白。最近完成的 SBIR 取得了令人鼓舞的结果 II 期项目表明，IAIP 可以显着减轻常温条件下的脑容量损失 实验性新生儿 HI 脑损伤，并且 IAIP 治疗具有同等的神经保护功效 新生大鼠中的 HT。 MRI 成像结果与受伤者的脑容量损失密切相关 大鼠年轻时的大脑，促进有效和长期的治疗效果研究。我们 在暴露于 HI 和 HT 后立即用 IAIP 治疗大鼠。在这个提案中，我们将修改 我们之前的研究范式通过在治疗后提供更长的连续重复剂量来增强 IAIP 的效果 暴露于HT。该策略专门针对持续时间较长的继发性炎症阶段 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进程 使用 IAIP 作为替代或辅助手段确认并进一步开发有效的治疗策略 HT 可预防和/或减轻新生儿 HI 相关的脑损伤。我们还将探讨血液 IAIP 水平 和其他炎症标志物作为潜在的生物标志物，以协助未来的人体试验。具体目标是： 1) 优化 IAIPs 单独治疗中度和重度 HI 和/或治疗后的治疗策略 HT 治疗：我们假设 HT 后多次重复 IAIP 剂量可增强有益效果 通过减少继发炎症阶段并改善长期组织病理学和行为来治疗 HT 结果； 2) 确定用于动物毒理学和临床研究的药效生物标志物：我们 假设 IAIP 和相关靶蛋白（HMGB1 和细胞外组蛋白）的水平 患有 HIE 的婴儿发生了改变，除了 Apgar/Sarnat 评分之外，还可以作为有用的预测生物标志物， aEEG 和血气值指导婴儿的临床治疗。拟议的转化项目设计 获得可靠的关键临床前数据，以支持未来早期的人体安全性和有效性测试。

项目成果

Effects of Three Different Doses of Inter-Alpha Inhibitor Proteins on Severe Hypoxia-Ischemia-Related Brain Injury in Neonatal Rats.

• DOI: 10.3390/ijms232113473
• 发表时间: 2022-11-03
• 期刊: International journal of molecular sciences
• 影响因子: 5.6

Changes in Cellular Localization of Inter-Alpha Inhibitor Proteins after Cerebral Ischemia in the Near-Term Ovine Fetus.

• DOI: 10.3390/ijms221910751
• 发表时间: 2021-10-04
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Hatayama K;Kim B;Chen X;Lim YP;Davidson JO;Bennet L;Gunn AJ;Stonestreet BS
• 通讯作者: Stonestreet BS

Time Course of Changes in the Neurovascular Unit after Hypoxic-Ischemic Injury in Neonatal Rats.

新生大鼠缺氧 - 缺血性损伤后神经血管单元的变化时间。

• DOI: 10.3390/ijms23084180
• 发表时间: 2022-04-10
• 期刊: International journal of molecular sciences
• 影响因子: 5.6

Inter-Alpha Inhibitor Proteins Modify the Microvasculature after Exposure to Hypoxia-Ischemia and Hypoxia in Neonatal Rats.

• DOI: 10.3390/ijms24076743
• 发表时间: 2023-04-04
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Girolamo, Francesco;Lim, Yow-Pin;Virgintino, Daniela;Stonestreet, Barbara S. S.;Chen, Xiaodi F. F.
• 通讯作者: Chen, Xiaodi F. F.

Effects of inter-alpha inhibitor proteins on brain injury after exposure of neonatal rats to severe hypoxia-ischemia.

• DOI: 10.1016/j.expneurol.2020.113442
• 发表时间: 2020-12
• 期刊: Experimental neurology
• 影响因子: 5.3
• 作者: Schuffels S;Nakada S;Wu Y;Lim YP;Chen X;Stonestreet BS
• 通讯作者: Stonestreet BS