Intranasal Treatment of Stem Cell-derived Extracellular Vesicles for Alzheimer's Disease

干细胞来源的细胞外囊泡鼻内治疗阿尔茨海默病

基本信息

批准号：
10455945
负责人：
ASHOK K SHETTY
金额：
$ 221.27万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10455945
关键词：
Affect Age Age-Months Allogenic Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease therapy Amyloid Amyloid beta-Protein Amyloid deposition Animals Anti-Inflammatory Agents Brain Brain Injuries Brain region Cells Clinical Cognitive Data Dementia Deposition Diet Disease Dose Exhibits Female Gene Expression Goals Hippocampus (Brain)Human Impaired cognition Impairment Inflammation Injury Intervention Intranasal Administration Investigation Knock-in Mouse Life Medial Mediating Membrane MicroRNAs Microglia Midbrain structure Molecular Moods Morphology Mus Nerve Degeneration Neurons Nucleic Acids Oxidative Stress Patients Persons Prefrontal Cortex Property Prosencephalon Proteins Regimen Research Role Signal Pathway Synapses Testing Therapeutic Time Translating Translational Research Treatment Efficacy affective disturbance astrogliosis base behavior test brain tissue clinical translation efficacy evaluation efficacy testing efficacy validation extracellular extracellular vesicles functional improvement hindbrain improved improved functioning in vivo induced pluripotent stem cell inhibitor knock-down male mouse model nerve stem cell neurogenesis neuroinflammation neuropathology novel strategies overexpression research study stem cell therapy stem cells tau-1 virtual

项目摘要

Project Summary This project's principal goal is to develop a non-invasive, extracellular vesicle (EV) based therapeutic strategy for improving brain function in Alzheimer's disease (AD). A novel approach that investigates the efficacy of intranasal (IN) administration of therapeutic EVs generated from human induced pluripotent stem cell (hiPSC)- derived neural stem cells (NSCs) in mouse models of AD are proposed. The scientific premise is that hNSC- derived EVs (hNSC-EVs) carrying a cargo of beneficial miRNAs and neuroprotective proteins can activate advantageous signaling pathways in target cells, positively modulate the brain microenvironment, microglia, and neurogenesis in the brain, and improve brain function after injury or disease. Notably, preliminary studies have shown that IN administration of hNSC-EVs results in their incorporation by neurons and microglia in virtually all brain regions in 5XFAD mice and leads to better cognitive and mood function, higher levels of hippocampal neurogenesis, and reductions in oxidative stress, neuroinflammation, and amyloid deposits. This project, using mouse models of AD, will test the hypothesis that IN administration of hNSC derived EVs: (i) in the early stage of AD will maintain better cognitive and mood function; and (ii) in the advanced stage of AD will reverse cognitive and mood dysfunction with significant modulation of neuropathology. Studies in Specific Aim 1 will employ 5XFAD mice and investigate whether intervention with hNSC-EVs in the early stage of AD would maintain better cognitive and mood function and whether such positive effects persist for prolonged periods. Investigations in Specific Aim 2, using both 5XFAD and A-beta-Knock-in mice, will test whether IN administration of hNSC-EVs in the advanced stage of AD would reverse cognitive and mood dysfunction. Specific Aim 3 studies will ascertain the role of microglial modulation in hNSC-EV mediated improvements in cognitive and mood function in 5XFAD mice through selective microglia depletion using PLX5622 introduced through diet. Studies in Specific Aim 4 will first examine changes in the antiinflammatory property of hNSC-EVs with knock-down or overexpression of specific miRNAs and proteins, using hiPSC-derived microglia cultures. Next, the effects of IN administration of hNSC-EVs overexpressing the select miRNA and/or protein having robust antiinflammatory activity will be tested in 6 months old 5XFAD mice to determine whether such a strategy would improve the therapeutic benefits of hNSC-EVs in the advanced stage of AD. Both male and female mice will be employed. The hippocampus and the medial prefrontal cortex will be rigorously examined for the various cellular and molecular changes mediated by hNSC-EVs in all Aims. Particularly whether functional improvements with hNSC-EV treatment would comprise the suppression of oxidative stress and neuroinflammation, a higher level of hippocampal neurogenesis, and reductions in amyloid-beta deposits, p-tau, synapse loss, and neurodegeneration will be ascertained. The proposed translational research studies are highly conducive to developing an allogeneic hNSC-EV therapy for AD.

项目概要该项目的主要目标是开发一种非侵入性、基于细胞外囊泡 (EV) 的治疗策略用于改善阿尔茨海默氏病 (AD) 的大脑功能。一种研究功效的新颖方法鼻内 (IN) 施用由人诱导多能干细胞 (hiPSC) 产生的治疗性 EV 提出了在 AD 小鼠模型中衍生的神经干细胞（NSC）。科学前提是 hNSC- 携带有益 miRNA 和神经保护蛋白的衍生 EV（hNSC-EV）可以激活靶细胞中有利的信号通路，积极调节大脑微环境，小胶质细胞，和大脑中的神经发生，并改善受伤或疾病后的大脑功能。值得注意的是，初步研究已经表明，hNSC-EV 的 IN 给药会导致它们被神经元和小胶质细胞掺入 5XFAD 小鼠的几乎所有大脑区域都会产生更好的认知和情绪功能，更高水平的海马神经发生，以及氧化应激、神经炎症和淀粉样蛋白沉积的减少。这该项目使用 AD 小鼠模型，将测试以下假设：(i) 在 hNSC 衍生的 EV 的 IN 管理中： AD早期会保持较好的认知和情绪功能； (ii) 在 AD 的高级阶段将通过显着调节神经病理学来逆转认知和情绪功能障碍。特定目标的研究 1 将采用 5XFAD 小鼠并研究在 AD 早期阶段使用 hNSC-EV 进行干预是否会保持更好的认知和情绪功能，以及这种积极影响是否持续较长时间。使用 5XFAD 和 A-beta-Knock-in 小鼠对特定目标 2 进行的研究将测试 IN 是否在 AD 晚期给予 hNSC-EV 可以逆转认知和情绪功能障碍。具体目标 3 研究将确定小胶质细胞调节在 hNSC-EV 介导的改善中的作用通过使用 PLX5622 选择性去除小胶质细胞来观察 5XFAD 小鼠的认知和情绪功能通过饮食。具体目标 4 的研究将首先检查 hNSC-EV 抗炎特性的变化使用 hiPSC 衍生的小胶质细胞培养物敲低或过度表达特定 miRNA 和蛋白质。接下来，IN 施用 hNSC-EV 的效果，hNSC-EV 过表达具有以下特征的选定 miRNA 和/或蛋白质：将在 6 个月大的 5XFAD 小鼠中测试强大的抗炎活性，以确定这种该策略将提高 hNSC-EV 在 AD 晚期的治疗效果。无论是男性还是将使用雌性小鼠。海马体和内侧前额叶皮层将受到严格检查用于所有目标中 hNSC-EV 介导的各种细胞和分子变化。特别 hNSC-EV 治疗的功能改善是否包括抑制氧化应激和神经炎症、海马神经发生水平升高以及淀粉样蛋白沉积物减少，将确定 p-tau、突触损失和神经变性。拟议的转化研究非常有利于开发针对 AD 的同种异体 hNSC-EV 疗法。