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

• 批准号: 10710031
• 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
• 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/10710031
• 关键词: Acute; Acute Brain Injuries; Adaptive Immune System; Affect; Animal Experiments; Animal Model; Animals; Astrocytes; Behavior Therapy; Behavioral; Biological Markers; Blood; 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; 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; blood-brain barrier crossing; cerebral atrophy; cognitive performance; contact sports; cytokine; effective therapy; experimental study; glial activation; immune activation; improved; inflammatory modulation; injured; mild traumatic brain injury; military veteran; motor deficit; mouse model; neuroinflammation; neuropathology; neuroprotection; novel; novel therapeutics; pre-clinical; preclinical development; prevent; protective effect; response; side effect; suicidal; tau Proteins

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.

本项目研究慢性反复轻度创伤性脑损伤（rmTBI）的治疗。rmTBI是一种 慢性神经退行性疾病，折磨多次脑震荡损伤的个体 例如士兵和接触性运动员。没有已知的治疗这种疾病的方法，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， 痴呆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，长期炎症会导致神经退行性疾病。我们 实验室已经开发出一种新的免疫/炎症调节剂JM 4。JM 4是一种短肽衍生物， 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， 然而，由于其可导致免疫/炎症调节作用，因此其在临床环境中的使用受到限制， 危险的红细胞增多水平。JM 4穿过血脑屏障， 促红细胞生成素的有益作用而没有造血的副作用。初步研究表明， 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 脑脊髓炎和甚至一个短暂的疗程的JM 4诱导长期的改善。它也减少了 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， 对于额颞叶痴呆，它减少了临床体征、小胶质细胞和星形胶质细胞活化以及tau蛋白病。JM 4有 完成了临床前开发，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目前的这项研究检验了这样一种假设， JM 4将通过显著减少慢性rmTBI中的细胞凋亡而在减缓或逆转慢性rmTBI中的缺陷方面具有有益作用。 炎症反应。我们的初步数据表明，即使在以下情况下，JM 4也可以减少慢性rmTBI： 在最初受伤一年后进行的 我们将使用经验证的慢性rmTBI的重复体重下降小鼠模型来评估治疗效果。 在以下实验中显示了JM 4的潜力： SA 1.我们发现10 μ g/天的JM 4剂量在tau蛋白病、MS和MS的动物模型中是有效的治疗。 急性TBI;然而，慢性rmTBI中JM 4的最佳剂量可能不相同。因此，我们将 建立在损伤后12个月开始的长持续时间JM 4剂量反应曲线。动物将 在撞击后1、6、12和18个月测试行为缺陷，并在18个月时处死。 SA 2.我们将研究短期脉冲JM 4治疗是否也可能对慢性rmTBI有效。的 实验设计将与SA 1相同，但JM 4治疗将限于30天。 SA 3.我们认为，突触功能障碍是TBI患者慢性认知功能障碍的主要原因。 为了将受试者的认知表现与电生理测量相关联，突触 在慢性损伤小鼠和对照小鼠中， 电生理学脑切片将用于评估CA 3-CA 1的基础突触传递和LTP 未处理和处理的慢性rmTBI小鼠中的突触。 SA 4.我们将研究JM 4对血液生物标志物，免疫/炎症激活和免疫功能的影响。 在接受短暂JM 4脉冲的动物中，18个月时（终末终点）的神经病理学 治疗1个月后或在处死前接受持续JM 4治疗整整6个月后。 我们预期，晚期慢性rmTBI小鼠中的JM 4治疗将减少炎症， 减少或消除rmTBI的行为和神经病理学体征。如果成功，这将是第一个 为这种疾病开发了潜在的治疗方法。