Novel EPO peptide therapy for chronic rmTBI dependent neurodegeneration and neuroinflammation

用于治疗慢性 rmTBI 依赖性神经变性和神经炎症的新型 EPO 肽疗法

基本信息

批准号：
10375442
负责人：
Yun-Beom Choi
金额：
--
依托单位：
VA NEW JERSEY HEALTH CARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-10-01 至 2026-09-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10375442
关键词：
Acute Acute Brain Injuries Adaptive Immune System Affect Animal Model Animals Astrocytes Behavior Therapy Behavioral Biological Markers Blood Blood - brain barrier anatomy Brain Brain Concussion Chronic Clinical Clinical Trials Cognitive deficits Craniocerebral Trauma Cyclic Peptides Dangerousness Data Dementia Deposition Deterioration Development Disease Disease remission Dose Down-Regulation Drops Electrophysiology (science)Elements Emotional Erythrocytes Erythropoietin Event Experimental Autoimmune Encephalomyelitis Experimental Designs Experimental Models Exposure to FDA approved Flare Frequencies Frontotemporal Dementia Functional disorder Funding Hematopoiesis Hematopoietic Immune Impairment Individual Inflammation Inflammatory Inflammatory Response Injury Innate Immune System Investigational Drugs Laboratories Lead Learning Length Link Long-Term Potentiation Measures Memory Memory Loss Memory impairment Mild Concussions Modeling Moods Multiple Sclerosis Mus Neoadjuvant Therapy Nerve Degeneration Neurodegenerative Disorders Neurologic Neurologic Deficit Peptides Pharmaceutical Preparations Physiologic pulse Process Production Reporting Research Series Slice Soldier Suicide Symptoms Synapses Synaptic Transmission TBI Patients Tauopathies Testing Therapeutic Time Tissues Traumatic Brain Injury United States National Institutes of Health Weight axon injury behavior test behavioral outcome cerebral atrophy cognitive performance contact sports cytokine effective therapy experimental study immune activation injured mild traumatic brain injury military veteran motor deficit mouse model neuroinflammation neuropathology novel novel therapeutics pre-clinical preclinical development prevent protective effect response side effect tau Proteins

项目摘要

This project examines a treatment for chronic repeated mild traumatic brain injury (rmTBI). rmTBI is a chronic neurodegenerative disease afflicting individuals who have received multiple concussive head injuries such as soldiers and contact sport players. There is no known cure for this disease that is often marked by progressive neurological deterioration. rmTBI can lead to memory loss, mood problems, suicidality, and dementia. The disease is associated with chronic neuroinflammation, axonal injury and brain atrophy. There is extensive evidence that long-term inflammation worsens neurodegenerative disease. Our laboratory has developed JM4, a novel immune/inflammatory regulatory agent. JM4 is a short peptide derived from the cytokine erythropoietin. Whole molecule erythropoietin has well established neuroprotective and immune/inflammatory modulating effects, however, its use in clinical settings is limited since it can lead to dangerous polycythemic levels of red blood cells. JM4 crosses the blood-brain barrier and retains erythropoietin's beneficial effects without the side effect of hematopoiesis. Preliminary studies showed that it was highly effective in reducing the immune/inflammatory responses in models of experimental autoimmune encephalomyelitis and that even a brief course of JM4 induced long term improvement. It also decreased neuropathology and clinical deficit in acute traumatic brain injury. Furthermore, in a mouse model of frontotemporal dementia, it reduced clinical signs, microglial and astrocytic activation and tauopathy. JM4 has completed preclinical development and was recently approved by the FDA as an Investigational New Drug (IND) for the treatment of acute multiple sclerosis flare-ups. This current study examines the hypothesis that JM4 will have beneficial effects in slowing or reversing deficits in chronic rmTBI by profoundly reducing the inflammatory response. Our preliminary data showed that JM4 can reduce chronic rmTBI even when administered a year after the initial injuries. We will use a validated repeat weight drop mouse model of chronic rmTBI to evaluate the therapeutic potential of JM4 in the following experiments: SA1. We found that a JM4 dose of 10ug/day was effective therapy in animal models of tauopathy, MS, and acute TBI; however, the optimal dose of JM4 in chronic rmTBI may not be the same. Accordingly, we will establish a long duration JM4 dose response curve initiated at 12 months after injury. Animals will be tested for behavioral deficit at 1, 6, 12, and 18 months after impact and sacrificed at 18 months. SA2. We will examine whether short-term pulse JM4 therapy may also be effective in chronic rmTBI. The experimental design will be identical to SA1, but JM4 therapy will be restricted to 30 days. SA3. We believe that synaptic dysfunction is a major contributor to chronic cognitive deficit in TBI patients. To correlate cognitive performance with electrophysiological measures within subjects, synaptic transmission and long-term potentiation (LTP) will be measured in chronic injured and control mice by electrophysiology. Brain slices will be used to assess basal synaptic transmission and LTP at the CA3-CA1 synapses in untreated and treated chronic rmTBI mice. SA4. We will examine JM4 effects on blood biomarkers, immuno/inflammatory activation and neuropathology at 18 months (terminal endpoint) within animals who received either brief JM4 pulse therapy for 1 month or after receiving sustained JM4 treatment for a full 6 months prior to sacrifice. We anticipate that JM4 treatment in advanced chronic rmTBI mice will reduce inflammation and decrease or eliminate both behavioral and neuropathological signs of rmTBI. If successful this will be the first potential treatment developed for this disease.

该项目研究慢性反复轻度创伤性脑损伤 (rmTBI) 的治疗方法。 rmTBI 是一种慢性神经退行性疾病，困扰多次头部脑震荡的人例如士兵和接触运动运动员。这种疾病尚无已知的治疗方法，通常以进行性神经功能恶化。 rmTBI 可导致记忆丧失、情绪问题、自杀倾向和失智。该疾病与慢性神经炎症、轴突损伤和脑萎缩有关。有大量证据表明，长期炎症会使神经退行性疾病恶化。我们的实验室开发了JM4，一种新型免疫/炎症调节剂。 JM4 是一种短肽衍生的来自细胞因子促红细胞生成素。全分子促红细胞生成素具有良好的神经保护作用和免疫/炎症调节作用，然而，其在临床环境中的使用受到限制，因为它可能导致红细胞的危险红细胞增多水平。 JM4 穿过血脑屏障并保留促红细胞生成素的有益作用而无造血的副作用。初步研究表明，它在减少实验性自身免疫模型中的免疫/炎症反应方面非常有效脑脊髓炎，即使是短暂的 JM4 疗程也能带来长期的改善。也减少了急性创伤性脑损伤的神经病理学和临床缺陷。此外，在小鼠模型中额颞叶痴呆，它减少了临床症状、小胶质细胞和星形细胞的激活以及 tau 蛋白病变。 JM4有完成临床前开发，最近被 FDA 批准为研究性新药（IND）用于治疗急性多发性硬化症发作。目前的研究检验了以下假设： JM4 将通过大幅减少炎症反应。我们的初步数据表明，JM4 可以减少慢性 rmTBI，即使最初受伤一年后进行。我们将使用经过验证的慢性 rmTBI 重复体重下降小鼠模型来评估治疗效果 JM4 在以下实验中的潜力： SA1。我们发现，10ug/天的 JM4 剂量对于 tau 蛋白病、MS 和急性创伤性脑损伤；然而，JM4 在慢性 rmTBI 中的最佳剂量可能并不相同。据此，我们将建立受伤后 12 个月开始的长期 JM4 剂量反应曲线。动物将会在撞击后 1、6、12 和 18 个月进行行为缺陷测试，并在 18 个月时处死。 SA2。我们将研究短期 JM4 脉冲疗法是否也可能对慢性 rmTBI 有效。这实验设计将与 SA1 相同，但 JM4 治疗将被限制为 30 天。 SA3。我们认为突触功能障碍是 TBI 患者慢性认知缺陷的主要原因。为了将受试者的认知表现与电生理测量相关联，突触将通过以下方法在慢性损伤和对照小鼠中测量传输和长时程增强（LTP）电生理学。脑切片将用于评估 CA3-CA1 的基础突触传递和 LTP 未经治疗和治疗的慢性 rmTBI 小鼠的突触。 SA4。我们将检查 JM4 对血液生物标志物、免疫/炎症激活和接受短暂 JM4 脉冲的动物 18 个月（终点）的神经病理学治疗 1 个月或在处死前接受持续 JM4 治疗整整 6 个月后。我们预计 JM4 治疗晚期慢性 rmTBI 小鼠将减少炎症和减少或消除 rmTBI 的行为和神经病理学症状。如果成功的话这将是第一个针对这种疾病开发了潜在的治疗方法。