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名婴儿。死亡率 新生儿缺氧缺血性脑病的死亡率可高达20%，大约25%的幸存者患有严重的长期残疾，包括 脑瘫癫痫和发育障碍缺氧缺血性脑病急性期的损伤是由 大脑中的氧气和葡萄糖不足。然而，越来越多的证据表明， 阶段是造成重大持续损害的原因。在最初的损伤后，氧化应激增加， 信号级联导致细胞死亡。升高的炎症和表观遗传变化可能存在于数月 到最初损伤后数年，如髓磷脂缺陷、可塑性降低和细胞数量改变所证明的。 最近，低温已被用于显着降低死亡率和发育并发症 在足月新生儿缺氧缺血性脑病中。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说， 迫切需要开发神经保护性联合疗法，在损伤后数小时至数天内使用， 再加上体温过低许多已知的神经保护化合物（促红细胞生成素，干细胞， 氙等）正在单独或与体温过低相结合进行研究，但迄今为止， 作为治疗新生儿缺氧缺血性脑病更有效的方法。总的来说，需要新的辅助治疗HIE。 该项目将测试中度低温加上免疫调节化合物的功效， 合成的植入前因子（sPIF），在HIE大鼠模型中，其在发育上等同于术语 人类婴儿大脑BioIncept发表的数据表明，PIF调节先天性和 适应性免疫反应值得注意的是，PIF逆转了多发性硬化模型中的神经损伤， 在多种疾病模型中保护免受氧化应激。最近对脑病模型的研究 早产表明PIF提供了对神经轴突损伤的保护。 在这个项目中，我们将首先用sPIF加低温进行短期剂量范围研究， 确定什么剂量最有效。然后，我们将对选定的sPIF进行长期比较 剂量加低温组合，并将结果与单独的低温进行比较。我们将使用组织学， 神经功能测试和磁共振成像（MRI）来比较不同的治疗。总的来说，我们 预计PIF加低温将影响所有损伤阶段，并将产生叠加的神经保护作用 因为这些治疗针对不同的途径。PIF作为HIE一线治疗的临床转化是 如果这些临床前评估成功，则前景光明，因为BioIncept获得了FDA快速通道认证， PIF治疗自身免疫性肝炎（2014年开始临床试验），耶鲁大学合作者提供 更多的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.