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.

该项目研究了一种慢性重复的轻度脑损伤（RMTBI）的治疗方法。 rmtbi是一个 遭受多发脑震荡的人的慢性神经退行性疾病困扰 例如士兵并联系运动球员。尚无已知治疗这种疾病的治疗方法 进行性神经系统恶化。 rmtbi可以导致记忆丧失，情绪问题，自杀性，并且 失智。该疾病与慢性神经炎症，轴突损伤和脑萎缩有关。 有广泛的证据表明，长期炎症会恶化神经退行性疾病。我们的 实验室已经开发了一种新型的免疫/炎症调节剂JM4。 JM4是衍生的短肽 来自细胞因子红细胞生成素。整个分子红细胞生成素具有良好的神经保护性和 免疫/炎症调节作用，但是，其在临床环境中的使用受到限制，因为它可能导致 危险的红细胞多智能水平。 JM4越过血脑屏障并保留 红细胞生成素的有益作用，没有造血的副作用。初步研究表明 在减少实验自身免疫模型中的免疫/炎症反应方面非常有效 脑脊髓炎，即使是简短的JM4疗程也会引起长期改善。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，在鼠标模型中 额颞痴呆，减少了临床体征，小胶质细胞和星形胶质细胞激活和t​​auopathy。 JM4有 完成了临床前开发，最近被FDA批准为一种调查新药 （IND）治疗急性多发性硬化症的爆发。这项当前的研究探讨了以下假设 JM4通过深刻降低慢性RMTBI的缺陷会产生有益的影响 炎症反应。我们的初步数据表明，即使 最初受伤一年后进行管理。 我们将使用经过验证的慢性RMTBI的重复体重降低鼠标模型来评估治疗性 JM4在以下实验中的潜力： SA1。我们发现，在Tauopathy，MS和 急性TBI;但是，慢性RMTBI中JM4的最佳剂量可能不一样。因此，我们会的 建立在受伤后12个月开始启动的长持续时间JM4剂量响应曲线。动物会 在撞击后1、6、12和18个月的行为赤字测试，并在18个月时牺牲。 SA2。我们将检查短期脉冲JM4治疗是否也可能在慢性RMTBI中有效。这 实验设计将与SA1相同，但是JM4治疗将限于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因素。 为了将认知性能与受试者内的电生理措施相关联 传播和长期增强（LTP）将在慢性受伤和控制小鼠中测量 电生理学。脑切片将用于评估CA3-CA1的基础突触传播和LTP 未治疗和治疗的慢性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 在收到简短JM4脉冲的动物中18个月（终端终点）的神经病理学（终端终点） 治疗1个月或在牺牲前6个月接受持续的JM4治疗后进行治疗。 我们预计晚期慢性rmtbi小鼠中的JM4治疗将减少炎症和 减少或消除RMTBI的行为和神经病理学体征。如果成功的话，这将是第一个 为该疾病开发的潜在治疗方法。