PreImplantation Factor plus hypothermia to treat neonatal brain injury

摘要 围产期缺氧缺血性脑病(HIE)每1000名新生儿中有1至3名受到影响。死亡率 HIE的致残率可能高达20%，约25%的幸存者患有严重的长期残疾，包括 脑性瘫痪、癫痫和发育障碍。缺氧缺血性脑病急性期的损害是由 大脑中的氧气和葡萄糖缺乏。然而，越来越多的证据表明，第二和第三 各阶段对持续的重大破坏负有责任。在最初的侮辱之后，氧化应激增加和 信号级联导致细胞死亡。炎症加重和表观遗传学改变可能会出现在几个月内 至最初损伤后数年，表现为髓鞘缺失、可塑性降低和细胞数量改变。 最近，低温已被用于显著降低死亡率和发育并发症。 足月新生儿缺氧缺血性脑病。然而，这种方法有几个限制。必须开始治疗 在受伤后6小时内减少代谢损伤和氧化应激，40%-50%的婴儿仍然死亡或 遭受严重残疾。国家儿童健康和人类发展研究所最近报告了一项 迫切需要开发神经保护性联合疗法，以便在受到侮辱后几小时到几天内使用 结合体温过低。一些已知的神经保护化合物(促红细胞生成素、干细胞、 氙气等)正在单独或与体温过低一起进行研究，但到目前为止，还没有出现 作为一种更有效的治疗HIE的方法。总体而言，HIE需要新的辅助治疗。 这个项目将测试亚低温和一种免疫调节化合物的疗效， 合成植入前因子(SPIF)在发育相当于足月的HIE大鼠模型中的作用 人类婴儿的大脑。BioIncept公布的数据表明，PIF同时调节先天和 适应性免疫反应。值得注意的是，PIF逆转了多发性硬化症模型中的神经损伤 在多种疾病模型中保护免受氧化应激。脑病模型的最新研究进展 早产儿表明，PIF对神经轴突损伤具有保护作用。 在这个项目中，我们将首先进行一项短期的、剂量范围的研究，使用SPIF加低温来 确定什么剂量最有效。然后，我们将对选定的SPIF执行长期比较 剂量加亚低温联合治疗，并将结果与单纯亚低温治疗进行比较。我们将使用组织学， 神经功能测试，并进行磁共振成像(MRI)以比较不同的治疗方法。总体而言，我们 预计PIF加低温将影响所有损伤阶段，并将产生额外的神经保护作用 因为这些治疗针对的是不同的途径。PIF作为HIE一线治疗的临床翻译是 如果这些临床前评估成功，BioIncept有望获得FDA的快速通道认证 PIF治疗自身免疫性肝炎(临床试验始于2014年)，耶鲁大学合作者提供 其他产科和临床专业知识。

ABSTRACT Perinatal hypoxic-ischemic encephalopathy (HIE) affects 1 to 3 infants per every 1000 born. Mortality from HIE can be up to 20%, and approximately 25% of survivors suffer significant long-term disability including cerebral palsy, epilepsy, and developmental disorders. Damage during the acute phase of HIE is caused by a deficit in oxygen and glucose in the brain. However, increasing evidence indicates that secondary and tertiary phases are responsible for significant ongoing damage. After an initial insult, oxidative stress increases and signaling cascades lead to cell death. Elevated inflammation and epigenetic changes may be present months to years after initial injury as evidenced by myelin deficits, reduced plasticity, and altered cell number. Recently, hypothermia has been used to significantly reduce mortality and developmental complications in term infants with HIE. However, there are several limitations to this approach. Treatment must be initiated within 6 hours of injury to reduce metabolic damage and oxidative stress, and 40-50% of infants still die or suffer severe disability. The National Institute of Child Health and Human Development recently reported an urgent need to develop neuroprotective combination therapies to be used hours to days after the insult in combination with hypothermia. A number of known neuroprotective compounds (erythropoietin, stem cells, xenon, etc.) are being investigated alone or in combination with hypothermia, but, to date, none have emerged as a more effective treatment for HIE. Overall, there is need for new adjuvant therapies in HIE. This project will test the efficacy of moderate hypothermia plus an immunomodulatory compound, synthetic PreImplantation Factor (sPIF), in a rat model of HIE that is equivalent in development to a term human infant brain. BioIncept has published data demonstrating that PIF regulates both the innate and adaptive immune response. Significantly, PIF reversed neurological damage in a multiple sclerosis model and protected against oxidative stress in multiple disease models. Recent studies in a model of encephalopathy of prematurity showed that PIF provided protection against neuro-axonal injury. In this project, we will first perform a short-term, dose-ranging study with sPIF plus hypothermia to determine what dose is most effective. Then, we will perform a longer-term comparison of the selected sPIF dose plus hypothermia combination and compare the results to hypothermia alone. We will use histology, neurofunctional tests, and magnetic resonance imaging (MRI) to compare the different treatments. Overall, we anticipate PIF plus hypothermia will affect all injury phases and will create an additive neuroprotective effect since these treatments target different pathways. Clinical translation of PIF as a first-line HIE treatment is promising if these preclinical evaluations are successful, as BioIncept received FDA Fast Track designation for PIF treatment of autoimmune hepatitis (clinical trial began in 2014), and Yale University collaborators provide additional obstetric and clinical expertise.