Miniaturized AD/ADRD Microphysiological Systems Platform for High-throughput Screening

用于高通量筛选的小型化 AD/ADRD 微生理系统平台

基本信息

批准号：
10761587
负责人：
Wayne W Poon
金额：
$ 50万
依托单位：
NEUCYTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10761587
关键词：
3-Dimensional AD transgenic mice Acoustics Address Aging Alzheimer disease screening 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 related dementia Alzheimer&apos s disease therapeutic Alzheimer&apos s disease therapy Amyloid Animal Model Animal Testing Astrocytes Biological Assay Brain Cell Count Cells Clinical Trials Communities Cryopreservation DNA Sequence Alteration Development Disease Disease associated microglia Disease model Drug Screening Drug Targeting Environment Enzymes Exhibits Face Failure Future Generations Genes Glutamates Goals Healthcare Human Immunotherapy In Vitro Induced pluripotent stem cell derived neurons Late Onset Alzheimer Disease Lead Libraries Microfluidics Microglia Miniaturization Modeling Mus Mutation Nature Nerve Degeneration Neurofibrillary Tangles Neuroimmune Neurons Organoids Patients Pharmaceutical Preparations Phase Phenotype Physiologic pulse Pluripotent Stem Cells Population Production Property Reagent Reproducibility Rodent Model Screening procedure Site Societies Somatic Cell Synapses Technology Testing Therapeutic Time Translating age related neurodegeneration apolipoprotein E-3 apolipoprotein E-4 care burden cell type commercialization cost cost effective differentiation protocol drug discovery excitatory neuron familial Alzheimer disease genome wide association study high throughput screening high-throughput drug screening improved in vitro Model in vivo induced pluripotent stem cell induced pluripotent stem cell technology microphysiology system miniaturize mouse model neuroinflammation neuropathology novel therapeutics patient population pre-clinical screening species difference stem cell model success tau mutation

项目摘要

Abstract Alzheimer Disease (AD) is characterized by b-amyloid (Ab) accumulation, neurofibrillary tangles (NFTs), neuroinflammation, and widespread neuronal and synaptic loss. To date, there are no therapies available, although immunotherapies i.e., Lecanemab hold promise. Species differences underlie the difficulties in translating therapeutics uncovered in animal models for human brain-specific diseases, e.g., AD and AD-related dementia (ADRD). Human induced pluripotent stem cell (hiPSC) technological advances enable better human- specific disease modeling, particularly when disease-related genetic mutations are absent in murine or rodent models (e.g., many AD GWAS genes), but face challenges due to the difficulty in mimicking the in vivo context in current in vitro models. Microphysiological systems (MPS) with defined cellular compositions can provide scalable, reproducible brain models that better recapitulate the in vivo environment, in which preclinical drug discovery efforts can translate to a higher success rate for identified targets and compounds. This project proposes the development of a mini-brain assembled organoids (assembloids) microfluidics platform using AD patient-derived APOE4 and isogenic gene-edited APOE3 iPSCs to facilitate effective and reproducible screening for AD therapeutics. NeuCyte employs robust differentiation protocols to generate neurons, astrocytes, and microglia in large quantities facilitating the generation of NeuroImmune Assembloids (NIA) in which the 3D microenvironment recapitulates salient ex vivo brain phenotypes, e.g., neurodegenerative and cell-type specific phenotypes due to a genetic mutation, enabling improved translatable high-throughput preclinical drug discovery. While isogenic, this platform is also modular, i.e., the impact of a mutation in microglia can be studied to model effects on neurons facilitating mechanistic studies mimicking the cellular complexity of the human brain. The AD/ADRD MPS microfluidic platform incorporates acoustic technology and enables economical examination of AD pathology in vitro facilitated by miniaturization, reducing costs associated with cell numbers, reagents, and drug library quantities to facilitate high-throughput drug screening. Successful completion of Phase I will establish the feasibility for commercialization of an AD/ADRD drug screening platform.

抽象的阿尔茨海默氏病（AD）的特征是B-淀粉样蛋白（AB）积累，神经原纤维缠结（NFTS），神经炎症，以及广泛的神经元和突触损失。迄今为止，没有可用的疗法尽管免疫疗法，即lecanemab保持诺言。物种差异是困难在人脑特异性疾病的动物模型中发现的翻译治疗剂，例如AD和AD相关痴呆症（ADRD）。人类诱导的多能干细胞（HIPSC）技术进步使得更好的人类特定的疾病模型，特别是在鼠或啮齿动物中不存在与疾病相关的遗传突变时模型（例如，许多AD GWAS基因），但是由于难以模仿体内环境而面临挑战在当前的体外模型中。具有定义的细胞组成的微生物生理系统（MPS）可以提供可扩展的，可再现的大脑模型，可以更好地概括体内环境，其中临床前药物发现努力可以转化为确定的靶标和化合物的更高成功率。这个项目提出了使用AD的微型脑组装的类器官（组装）微流体平台的开发患者衍生的APOE4和同基因基因编辑的APOE3 IPSC，以促进有效且可重复的筛选用于广告疗法。 Neucyte采用强大的分化方案来产生神经元，星形胶质细胞和大量的小胶质细胞促进了3D的神经免疫性组合物（NIA）微环境概括了显着的离体脑表型，例如神经退行性和细胞类型特异性由于基因突变而引起的表型，从而可以改善可翻译的高通量临床前药物发现。虽然等源性，但该平台也是模块化的，即，可以研究小胶质细胞中突变的影响以建模对神经元的影响，促进了模仿人脑细胞复杂性的机理研究。这 AD/ADRD MPS微流体平台结合了声学技术，并可以经济检查小型化的体外病理学促进，降低与细胞数，试剂和药物文库的数量以促进高通量药物筛查。成功完成第一阶段将建立 AD/ADRD药物筛查平台商业化的可行性。