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.

项目摘要该项目的主要目标是开发基于细胞外囊泡（EV）的治疗策略用于改善阿尔茨海默氏病（AD）中的大脑功能。一种研究的新方法，调查了由人类诱导的多能干细胞（HIPSC）产生的治疗EV的鼻内（IN） - 提出了AD小鼠模型中的衍生神经干细胞（NSC）。科学的前提是HNSC- 带有有益miRNA和神经保护蛋白的货物的衍生电动汽车（HNSC-EVS）可以激活靶细胞中有优势的信号通路，积极调节脑微环境，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，在施用HNSC-EVS时会导致神经元和小胶质细胞掺入它们实际上，5XFAD小鼠的所有大脑区域都可以提高认知和情绪功能，更高水平海马神经发生，氧化应激，神经炎症和淀粉样蛋白沉积物的减少。这项目使用AD的鼠标模型，将检验以下假设：在HNSC的给药中，EVS的给药：（i）广告的早期阶段将保持更好的认知和情绪功能；（ii）在广告的高级阶段将反向认知和情绪功能障碍，具有明显的神经病理学调节。特定目的的研究 1将采用5xFAD小鼠，并调查在AD早期对HNSC-EVS的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长时间。使用5xFAD和A-BETA-KNOCK-IN小鼠进行的特定AIM 2的调查将测试是否在在AD的高级阶段，HNSC-EV的给药会逆转认知和情绪功能障碍。特定目标3研究将确定小胶质调制在HNSC-eV介导的改进中的作用使用PLX5622引入的选择性小胶质细胞耗竭，在5xFAD小鼠中的认知和情绪功能通过饮食。特定目标4的研究将首先检查HNSC-EVS抗炎特性的变化使用hipsc衍生的小胶质细胞培养物对特定的miRNA和蛋白质进行敲低或过表达。接下来，在施用HNSC-eV中过表达的hnsc-evs的影响，其具有选择的miRNA和/或蛋白质具有强大的抗炎活性将在6个月大的5XFAD小鼠中进行测试，以确定是否是这样策略将在AD的高级阶段提高HNSC-EV的治疗益处。男性和雌性小鼠将被雇用。海马和内侧前额叶皮层将进行严格检查对于由HNSC-EV介导的所有目的，各种细胞和分子变化。特别 HNSC-EV处理的功能改进是否包括抑制氧化应激和神经炎症，海马神经发生水平较高，淀粉样蛋白β沉积物的减少， P-TAU，突触损失和神经退行性将得到确定。拟议的翻译研究高度利用为AD开发同种异体HNSC-EV疗法。