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

评估氙气对健康人体受试者的安全性和免疫影响的第一阶段试验

基本信息

批准号：
10758938
负责人：
Ilya Ilin
金额：
$ 131.84万
依托单位：
GENERAL BIOPHYSICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-10-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10758938
关键词：
APP-PS1 Acute Alzheimer like pathology Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease therapy Amyloid beta-Protein Anesthesia procedures Anesthetics Behavior Biology Blood Blood Cells Brain Brain Injuries Capital Capital Financing Cells Certification Clinical Clinical Research Clinical Trials Data Development Disease Disease Progression Disease associated microglia Dose Drug Kinetics Evaluation Feedback Funding Gases Glaucoma Goals Health Hospitals Human Immune Immune system Impairment In Vitro Induction of Apoptosis Infiltration Inflammatory Inflammatory Response Inhalation Inhalation Therapy Late Onset Alzheimer Disease Legal patent Microglia Modeling Molecular Profiling Mus Myeloid Cells Nerve Degeneration Neurodegenerative Disorders Neurons Neuroprotective Agents Pathogenicity Patients Peripheral Phagocytes Phase Phase I Clinical Trials Phase II Clinical Trials Phase Ia Clinical Trial Phenotype Play Preparation Private Sector Published Comment Regulation Role Safety Senile Plaques Signal Transduction Small Business Technology Transfer Research Tauopathies Testing Transplantation Woman Work Xenon apolipoprotein E-4 blood-brain barrier penetration cerebral atrophy clinical development commercialization efficacy clinical trial efficacy study efficacy trial genetic risk factor healthy volunteer human subject improved in vivo induced pluripotent stem cell interest lipid biosynthesis monocyte mouse model neuroprotection neutrophil novel novel strategies patient safety pharmacokinetics and pharmacodynamics pharmacologic phase 1 study phase I trial pre-Investigational New Drug meeting pre-clinical preservation programs response restoration safety assessment safety study therapeutically effective timeline tool volunteer

项目摘要

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.

二期申请（STTR 计划 PAS-22-197） “评估氙气对健康人类受试者的安全性和免疫影响的第一阶段试验” 抽象的阿尔茨海默病（AD）是最常见的神经退行性疾病之一。表明大脑免疫系统的稳态失调，尤其是由小胶质细胞精心策划的失调，小胶质细胞功能在健康状态下得以维持 AD 脑中的致病性失调主要涉及 APOE 遗传危险因素。我们最近发现了稳态小胶质细胞的独特分子特征，并已研究出小胶质细胞的功能。我们开发了强大的工具来研究小胶质细胞生物学在健康和疾病中的作用。 APOE 信号传导在与神经变性相关的新小胶质细胞亚群和小胶质细胞中的调节人类 AD 大脑中神经质 Ab 斑块周围，我们称之为 MGnD。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的保存。 Aβ 诱导的神经元细胞凋亡以及常驻小胶质细胞稳态功能的恢复对于大脑功能的恢复至关重要。该提案的目标是进行一期临床试验，以评估吸入氙气的安全性健康正常志愿者的暴露时间逐渐增加：20、40、60 和 90 分钟。用于人类患者作为麻醉剂和治疗脑损伤的神经保护剂。血脑屏障，这可以使其有效治疗。我们的初步数据表明，Xe 具有治疗作用。通过吸入：1) 在急性发作中将小胶质细胞从 MGnD 调节为稳态表型神经退行性疾病模型和 AD 小鼠；2) 改善与 Ab- 减少相关的 AD 样病理学 APP/PS1 小鼠中的斑块；3) 减少 APOE4 诱导的神经变性并减少脑萎缩 P301S 小鼠和 4) 减少单核细胞浸润并抑制其促炎反应。从机制上讲，我们发现 Xe 处理使稳态小胶质细胞极化至中间状态 (MGiS)，通过诱导小胶质细胞对 IFNg 信号传导的反应，重要的是，我们确定了最佳 PK/PD。氙气吸入治疗急性神经变性模型和 AD 小鼠的成功完成。临床试验提案将是评估人类氙吸入疗法的第一步，并将允许转向对 AD 患者的安全性和有效性进行评估，从而筹集私营部门资本并启动 AD 2 期临床试验因此，我们提出以下具体目标：目的：评估健康正常志愿者增加吸入氙气的安全性曝光时间：20、40、60 和 90 分钟。