PreImplantation Factor plus hypothermia to treat neonatal brain injury

植入前因子加低温治疗新生儿脑损伤

• 批准号: 9194271
• 负责人: Michael John Paidas
• 金额: $ 22.34万
• 依托单位: BIOINCEPT, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-16 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9194271
• 关键词: Acute; Adjuvant Therapy; Affect; Animals; Autoimmune Hepatitis; Benchmarking; Biometry; Blood - brain barrier anatomy; Brain; Brain Injuries; Carotid Arteries; Cell Count; Cell Death; Cells; Cerebral Palsy; Clinical; Clinical Trials; Combined Modality Therapy; Control Groups; Data; Demyelinations; Development; Diffusion Magnetic Resonance Imaging; Discipline of obstetrics; Disease model; Dose; Encephalopathies; Epigenetic Process; Epilepsy; Erythropoietin; Gliosis; Glucose; Histology; Hour; Human; Hyperactive behavior; Hypoxia; Hypoxic-Ischemic Brain Injury; Image; Infant; Inflammation; Injury; Ipsilateral; Lead; Length; Ligation; Magnetic Resonance Imaging; Metabolic; Modeling; Multiple Sclerosis; Myelin; National Institute of Child Health and Human Development; Neonatal; Neonatal Brain Injury; Neonatal Mortality; Nervous System Trauma; Neurocognitive Deficit; Neurological outcome; Neuronal Plasticity; Neurons; Oxidative Stress; Oxygen; Pathway interactions; Perinatal Brain Injury; Perinatal anoxic ischemic brain injury; Peripheral; Pharmacology; Phase; Process; Publishing; Rattus; Reporting; Scientist; Signal Transduction; Small Business Technology Transfer Research; Stem cells; Subcutaneous Injections; Survivors; Testing; Toes; Translations; Treatment Factor; Universities; Xenon; adaptive immunity; astrogliosis; axon injury; design; developmental disease; developmental neurobiology; disability; effective therapy; efficacy testing; immunoregulation; improved; macrophage; mortality; motor impairment; natural hypothermia; neonatal hypoxic-ischemic brain injury; neurobehavioral; novel; postnatal; preclinical evaluation; preimplantation; premature; prevent; repaired; targeted treatment

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.

抽象的 每 1000 名新生儿中就有 1 至 3 名婴儿患有围产期缺氧缺血性脑病 (HIE)。死亡 HIE 造成的损失可能高达 20%，大约 25% 的幸存者遭受严重的长期残疾，包括 脑瘫、癫痫和发育障碍。 HIE 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，中学和大学 阶段是造成重大持续损害的原因。初次损伤后，氧化应激增加， 信号级联反应导致细胞死亡。炎症加剧和表观遗传变化可能会持续数月 到初次损伤后数年，表现为髓磷脂缺陷、可塑性降低和细胞数量改变。 最近，低温已被用于显着降低死亡率和发育并发症 患有 HIE 的足月婴儿。然而，这种方法有一些限制。必须开始治疗 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。美国国家儿童健康与人类发展研究所最近报告称 迫切需要开发神经保护联合疗法，在损伤后数小时至数天使用 与低温结合。许多已知的神经保护化合物（促红细胞生成素、干细胞、 氙气等）正在单独或与低温结合进行研究，但迄今为止，还没有出现 作为 HIE 更有效的治疗方法。总体而言，HIE 需要新的辅助疗法。 该项目将测试中度低温加免疫调节化合物的功效， 合成植入前因子 (sPIF)，在 HIE 大鼠模型中相当于发育中的术语 人类婴儿的大脑。 BioIncept 发表的数据表明 PIF 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，并且 在多种疾病模型中防止氧化应激。脑病模型的最新研究 早产表明 PIF 可提供针对神经轴突损伤的保护作用。 在这个项目中，我们将首先使用 sPIF 加低温进行一项短期、剂量范围的研究，以 确定最有效的剂量。然后，我们将对所选 sPIF 进行长期比较 剂量加低温组合并将结果与​​单独低温进行比较。我们将使用组织学， 神经功能测试和磁共振成像（MRI）来比较不同的治疗方法。总的来说，我们 预计 PIF 加低温将影响所有损伤阶段，并产生附加的神经保护作用 因为这些治疗针对不同的途径。 PIF 作为一线 HIE 治疗的临床转化是 如果这些临床前评估成功，我们将充满希望，因为 BioIncept 已获得 FDA 快速通道指定 PIF治疗自身免疫性肝炎（临床试验于2014年开始），耶鲁大学合作者提供 额外的产科和临床专业知识。

项目成果

A Mouse Model of MHV-1 Virus Infection for Study of Acute and Long COVID Infection.

用于研究急性和长期新冠病毒感染的 MHV-1 病毒感染小鼠模型。

• DOI: 10.1002/cpz1.896
• 发表时间: 2023
• 期刊: Current protocols
• 作者: Masciarella,AndrewD;DiGregorio,DibeM;Ramamoorthy,Rajalakshmi;Hussain,Hussain;Jayakumar,ArumugamR;Paidas,MichaelJ
• 通讯作者: Paidas,MichaelJ