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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.

摘要