Xenon gas treatment to modulate microglia in neurodegenerative diseases

氙气治疗调节神经退行性疾病中的小胶质细胞

• 批准号: 10617078
• 负责人: Oleg Butovsky
• 金额: $ 31.36万
• 依托单位: GENERAL BIOPHYSICS, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10617078
• 关键词: APP-PS1; Acute; Address; Administrative Supplement; Affect; Age-Months; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Alzheimer' s disease therapy; Anesthetics; Biological Markers; Biology; Blood; Blood - brain barrier anatomy; Brain; Brain Injuries; Capital; Cells; Clinical Trials; Data; Disease; Disease Progression; Dose; Gases; Goals; Grant; Hand; Health; Homeostasis; Human; Immune; Immune system; Inhalation; Maintenance; Methods; Microglia; Modeling; Molecular Profiling; Monitor; Mus; Myeloid Cells; Nerve Degeneration; Neurodegenerative Disorders; Neuroprotective Agents; Noble Gases; Onset of illness; Pathogenicity; Pathway interactions; Patients; Phase; Phase I Clinical Trials; Phenotype; Play; Private Sector; Regulation; Role; Sampling; Senile Plaques; Signal Transduction; Technology; Testing; Translating; Transplantation; Work; Xenon; base; brain health; cohort; design; early onset; experimental study; genetic risk factor; induced pluripotent stem cell; meetings; mouse model; neurodegenerative phenotype; neuron apoptosis; novel; parent grant; pharmacokinetics and pharmacodynamics; preclinical development; protective effect; research and development; sensor; technology development; therapeutically effective; tool; translation to humans

Administrative Supplement Application PA-20-272 Xenon gas treatment to modulate microglia in neurodegenerative diseases (R41AG073059) ABSTRACT ABSTRACT FROM ORIGINAL APPLICATION Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder. 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. The microglial function is maintained in healthy brain and is pathogenically dysregulated in AD brain. The prominent genetic risk factors, 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 Aβ-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. The goal of the original proposal was to investigate the Xenon (Xe) gas treatment to modulate microglia in AD mouse models and human iPSCs-derived microglia transplanted in humanized AD mice. 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 original specific aims were as follow: Aim 1: Investigate whether Xe-gas treatment affects phenotype and function of neurodegenerative microglia in APP-PS1 mice. Aim 2: Validate whether Xe-gas treatment affects phenotype and function of neurodegenerative human microglia. SUPPLEMENTAL APPLICATION INFORMATION: To make competitive Phase II application and transition to clinical trial, we are planning to hold a pre-IND meeting with FDA. Developing such pre-IND meeting application was not a part of the original Phase I specific aims, but is closely connected. This new administrative supplement request will increase the likelihood to achieve additional critical R&D milestones in the technology development pathway to make us more competitive for Phase II application and ultimately for raising private-sector capital. The proposed scope of this additional supplement is within the overall scientific scope of the parent grant, which we will be able to complete by end of August 2022. The pre-IND submission package should include results of the originally proposed work and should address the following new specific aims: Aim 1: Determine PK/PD of Xenon inhalation treatment in an acute model of neurodegeneration and in APP/PS1 mice. The primary goal of our current efforts is to translate Xenon technology for testing in human AD patients. To prepare a competitive Phase II application for translation to humans, it is crucial to establish parameters of dosing based on the PK/PD. In this Aim, we will determine PK/PD of Xenon inhalation treatment in acute model of neurodegeneration and in AD mice. Aim 2: Identify blood biomarkers in myeloid cells from healthy and AD patients to monitor Xenon treatment. In this Aim, to monitor the efficacy of the Xe-treatment, we will determine the effect of Xenon treatment on blood immune cells. The results of these new proposed experiments will establish blood biomarkers for Xenon treatment and will be a crucial part for FDA submission and Phase I clinical trial. Feasibility and timeframe: Considering our capabilities and already completed work, we believe that these new important additional aims can be accomplished within the timeframe of the original grant and will take three months. Importantly, the MGnD acute neurodegenerative model, which has been developed in our lab, can be completed within 16hr. A new cohort of APP/PS1 mice has been generated, and the mice will be at 2 months of age (early onset of disease) and will be ready to be tested for PK/PD (Aim 1). All human samples from HC and AD patient are in hand (Aim 2).

行政补充申请PA-20-272 氙气治疗对神经退行性疾病小胶质细胞的调节(R41AG073059) 摘要 从原始应用程序中提取 阿尔茨海默病(AD)是最常见的神经退行性疾病。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 在疾病的发生和发展中起着重要作用。小胶质细胞的功能在健康的大脑中得以维持 在阿尔茨海默病的大脑中处于病理性的失调状态。突出的遗传风险因素，载脂蛋白E，涉及 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A斑块，我们称之为β斑块。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。 最初提案的目标是研究氙气治疗对阿尔茨海默病小胶质细胞的调节作用 小鼠模型和人iPSCs来源的小胶质细胞移植到人源化AD小鼠体内。Xe目前用于 人类患者在脑损伤治疗中作为麻醉剂和神经保护剂。Xe穿透血液 脑屏障，这可以使它有效的治疗。我们最初的具体目标如下： 目的1：探讨氙气治疗是否影响神经退行性变的表型和功能 APP-PS1小鼠的小胶质细胞。 目的2：验证氙气治疗是否影响神经退行性变患者的表型和功能 小胶质细胞。 补充申请信息： 为了进行竞争性的第二阶段应用并过渡到临床试验，我们计划举行IND前会议 与FDA合作。开发这样的IND前会议应用程序不是第一阶段最初特定目标的一部分，但 是紧密相连的。这一新的行政补充请求将增加实现 技术开发道路上的其他关键研发里程碑，使我们在 第二阶段申请，最终用于筹集私营部门资本。这项额外规定的拟议范围 补充是在家长资助的总体科学范围内，我们将能够在#年末完成 2022年8月。IND前提交包应包括最初提议的工作的结果，并应 实现以下新的具体目标： 目的1：测定氙气吸入治疗急性神经变性模型的PK/PD。 APP/PS1小鼠。我们目前努力的主要目标是将氙气技术转化为用于人类AD测试的技术 病人。要准备一个有竞争力的第二阶段应用程序以便翻译给人类，关键是要建立 基于PK/Pd的给药参数。为此，我们将测定氙气吸入治疗的PK/PD 在急性神经退行性变模型和AD小鼠中。 目的2：确定健康和AD患者骨髓细胞中的血液生物标志物以监测氙气 治疗。为此，为了监测氙气治疗的疗效，我们将确定氙气的效果 血液免疫细胞的治疗。这些新提出的实验结果将建立血液生物标记物 用于氙气治疗，并将是FDA提交和I期临床试验的关键部分。 可行性和时间表：考虑到我们的能力和已经完成的工作，我们相信这些新的 重要的额外目标可以在最初拨款的时间框架内完成，并将需要三个 月份。重要的是，我们实验室开发的MGnD急性神经退行性变模型可以 在16小时内完成。一个新的APP/PS1小鼠队列已经产生，这些小鼠将在2个月大小 年龄(早期发病)，并将准备接受PK/PD测试(目标1)。所有来自HC和HC的人类样本 AD患者在手中(目标2)。