Novel EPO peptide therapy for chronic rmTBI dependent neurodegeneration and neuroinflammation

本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 患有多发性脑震荡头部损伤的慢性神经退行性疾病 例如士兵和接触运动的运动员。目前还没有已知的治疗这种疾病的方法，这种疾病通常以 神经功能进行性恶化。RmTBI可导致记忆丧失、情绪问题、自杀和 痴呆症。这种疾病与慢性神经炎、轴突损伤和脑萎缩有关。 有大量证据表明，长期炎症会加重神经退行性疾病。我们的 实验室已经开发出JM4，一种新型的免疫/炎症调节剂。JM4是一种来源于 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和 然而，免疫/炎症调节作用在临床环境中的使用受到限制，因为它可能导致 危险的红细胞增多症水平。JM4跨越血脑屏障，保留了 促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，它 能有效降低实验性自身免疫模型的免疫/炎症反应 脑脊髓炎，即使是短暂的JM4疗程也能带来长期的改善。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， 额颞叶痴呆患者的临床体征、小胶质细胞和星形胶质细胞的激活和功能障碍均有所减轻。JM4有 完成临床前开发，最近被FDA批准为研究新药 (IND)用于治疗急性多发性硬化症发作。这项目前的研究检验了这样的假设 JM4在减缓或逆转慢性rmTBI的缺陷方面将具有有益的效果，因为它将显著减少 炎症反应。我们的初步数据显示，JM4可以减少慢性rmTBI，即使在 在最初受伤一年后进行治疗。 我们将使用一种经过验证的慢性rmTBI重复体重下降小鼠模型来评估治疗 JM4在以下实验中的潜力： SA1.我们发现，JM4剂量为10ug/天是治疗多发性硬化症和多发性硬化症动物模型的有效方法。 然而，JM4治疗慢性rmTBI的最佳剂量可能不同。因此，我们将 建立损伤后12个月开始的长时间JM4剂量反应曲线。动物将会是 在撞击后1、6、12和18个月检测行为缺陷，并在18个月时处死。 SA2.我们将研究短期脉冲JM4疗法是否对慢性rmTBI也有效。这个 试验设计将与SA1相同，但JM4治疗将被限制在30天内。 SA3.我们认为，突触功能障碍是脑外伤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指标联系起来，突触 慢性损伤小鼠和对照小鼠的传递和长时程增强(LTP)将通过以下方法测量 电生理学。脑片将被用来评估CA3-CA1区的基础突触传递和LTP 未经治疗和治疗的慢性rmTBI小鼠的突触。 SA4.我们将检查JM4对血液生物标记物、免疫/炎症激活和 18个月(终点)接受JM4脉冲或短暂脉冲的动物的神经病理学 治疗1个月或在牺牲前接受持续JM4治疗整整6个月后。 我们预计JM4对晚期慢性rmTBI小鼠的治疗将减少炎症和 减少或消除rmTBI的行为和神经病理体征。如果成功，这将是第一次 为这种疾病开发了潜在的治疗方法。

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.