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.

抽象的阿尔茨海默病 (AD) 的特点是 b-淀粉样蛋白 (Ab) 积累、神经原纤维缠结 (NFT)、神经炎症以及广泛的神经元和突触损失。迄今为止，还没有可用的治疗方法，尽管免疫疗法（即 Lecanemab）有希望。物种差异是困难的根源将动物模型中发现的疗法转化为人类大脑特定疾病，例如 AD 和 AD 相关疾病痴呆症（ADRD）。人类诱导多能干细胞 (hiPSC) 技术的进步使人类能够更好地特定疾病模型，特别是当小鼠或啮齿动物中不存在疾病相关基因突变时模型（例如，许多 AD GWAS 基因），但由于难以模拟体内环境而面临挑战在当前的体外模型中。具有明确细胞组成的微生理系统（MPS）可以提供可扩展、可重复的大脑模型，可以更好地概括体内环境，其中临床前药物发现工作可以转化为已识别目标和化合物的更高成功率。本项目提出使用 AD 开发迷你脑组装类器官（assembloids）微流体平台患者来源的 APOE4 和等基因基因编辑的 APOE3 iPSC，以促进有效且可重复的筛选用于 AD 治疗。 NeuCyte 采用强大的分化方案来生成神经元、星形胶质细胞和大量的小胶质细胞促进神经免疫组合体 (NIA) 的产生，其中 3D 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产生的表型，从而能够改进可翻译的高通量临床前药物发现。虽然是同基因的，但该平台也是模块化的，即可以研究小胶质细胞突变的影响来建模对神经元的影响促进模仿人脑细胞复杂性的机制研究。这 AD/ADRD MPS 微流控平台采用声学技术，能够经济地检查小型化促进了 AD 体外病理学的发展，降低了与细胞数量、试剂和相关的成本药物库数量有利于高通量药物筛选。第一阶段的成功完成将建立 AD/ADRD 药物筛选平台商业化的可行性。