Phase 1 Trial to Assess Safety and Immune Effects of Xenon Gas in Healthy Human Subjects

第二阶段申请 (STTR计划PAS-22-197) “评估氙气对健康受试者的安全性和免疫效果的第一阶段试验” 摘要 阿尔茨海默病(AD)是最常见的神经退行性疾病之一。新出现的证据 表明大脑免疫系统的动态平衡失调，特别是由小胶质细胞协调的免疫系统， 在疾病的发生和发展中起着重要作用。健康人的小胶质细胞功能得以维持 在阿尔茨海默病的大脑中存在病理性的异常调节。显著的遗传风险因素apoE参与了 小胶质细胞功能。我们最近发现了一个独特的动态平衡小胶质细胞的分子特征，并已经 开发了强大的工具来研究健康和疾病中的小胶质生物学。我们还确定了 APOE信号在调节与神经退行性变相关的新的小胶质细胞亚群和小胶质细胞中的作用 人AD脑内神经炎性抗体斑块周围，我们称之为MGnD。主要问题涉及 以小胶质细胞为基础的治疗AD的方法是如何调节小胶质细胞的表型和功能。保存 Aβ诱导神经细胞凋亡以及恢复驻留小胶质细胞的稳态功能 对恢复大脑功能至关重要。 这项建议的目标是进行第一阶段临床试验，以评估Xe吸入的安全性 健康的正常志愿者以递增的暴露时间给予：20、40、60和90分钟。XE目前 在人类患者中用作麻醉剂，并在治疗脑损伤时用作神经保护剂。Xe穿透 血脑屏障，这可以使它有效的治疗。我们的初步数据显示Xe提供了 通过吸入：1)将小胶质细胞从MGnD调节为动态平衡表型 神经退行性变模型和AD小鼠；2)改善AD样病理与降低的抗体- APP/PS1小鼠的斑块；3)减轻APOE4诱导的神经变性和减轻脑萎缩 P301S小鼠和4)减少单核细胞的渗透和抑制其促炎反应。 从机制上讲，我们发现Xe处理使动态平衡的小胶质细胞极化成中间态。 (MGiS)，通过诱导小胶质细胞对IFNG信号的反应。重要的是，我们确定了最优PK/PD 氙气吸入治疗急性神经变性模型和AD小鼠。成功完成这项工作 临床试验提案将是评估氙气吸入疗法在人体上的第一步，并将允许 转向对AD患者进行安全性和有效性评估，从而筹集私营部门资金并启动 AD的第二阶段临床试验。因此，我们提出以下具体目标： 目的：评价健康健康志愿者雾化吸入氙气的安全性。 曝光时间：20、40、60和90分钟。

PHASE II APPLICATION (STTR Program PAS-22-197) “Phase 1 Trial to Assess Safety and Immune Effects of Xenon Gas in Healthy Human Subjects” ABSTRACT Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative disorders. Emerging evidence shows that homeostatic dysregulation of the brain immune system, especially that orchestrated by microglia, plays a significant role in the onset and progression of the disease. Microglial function is maintained in healthy brain and is pathogenically dysregulated in AD brain. The prominent genetic risk factor, APOE, is involved in microglial function. We have recently identified a unique molecular signature for homeostatic microglia and have developed robust tools to investigate microglial biology in health and disease. We also identified a role for the APOE-signaling in the regulation of a new microglial subset associated with neurodegeneration and in microglia surrounding neuritic Ab-plaques in human AD brain, which we have termed MGnD. The major question relates to microglia-based approach to treat AD is how to modulate microglia phenotype and function. Preservation of neuronal cells from Aβ-induced apoptosis as well as restoration of resident microglial homeostatic function is critical for the restoration of brain function. The goal of this proposal is to perform Phase 1 clinical trial to evaluate the safety of Xe inhalation in healthy normal volunteers given at increasing durations of exposure: 20, 40, 60, and 90 minutes. Xe is currently used in human patients as an anesthetic and as a neuroprotectant in treatment of brain injuries. Xe penetrates blood brain barrier, which can make it effective therapeutic. Our preliminary data demonstrated that Xe delivered through inhalation: 1) modulates microglia from an MGnD to homeostatic phenotype in an acute neurodegeneration model and in AD mice; 2) ameliorates AD-like pathology associated with decreased Ab- plaques in APP/PS1 mice; 3) reduces APOE4-induced neurodegeneration and decreases brain atrophy in P301S mice and 4) decreases monocyte infiltration and suppresses their proinflammatory response. Mechanistically, we found that Xe treatment polarizes homeostatic microglia toward an intermediate state (MGiS), via induction of microglial responses to IFNg signaling. Importantly, we identified the optimal PK/PD of Xe inhalation treatment in an acute model of neurodegeneration and in AD mice. Successful completion of this clinical trial proposal will be the first step of evaluation of xenon inhalational therapy in humans and will allow to move to its evaluation in AD patients for safety and efficacy, leading to raising private-sector capital and initiation of Phase 2 clinical trials in AD. Thus, we propose the following specific aim: Aim: To evaluate the safety of Xe inhalation in healthy normal volunteers given at increasing durations of exposure: 20, 40, 60, and 90 minutes.