A physiologically relevant pre-clinical drug screening platform for Alzheimer's Disease and Traumatic Brain Injury with integrated stretchable microelectrodes

具有集成可拉伸微电极的针对阿尔茨海默病和创伤性脑损伤的生理相关临床前药物筛选平台

• 批准号: 10482284
• 负责人: Oliver Graudejus
• 金额: $ 45万
• 依托单位: BMSEED, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10482284
• 关键词: 3-Dimensional; 3xTg-AD mouse; Accounting; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; American; Animal Sources; Astrocytes; Biochemical; Biological Markers; Biomechanics; Brain; Cell Survival; Cells; Clinical Treatment; Clinical Trials; Coculture Techniques; Dementia; Development; Disease; Disease Progression; Drug Screening; Electrodes; Electrophysiology (science); Environment; Epidemiology; Equipment; Evaluation; FDA approved; Genetic; Genetic Predisposition to Disease; Genetically Modified Animals; Goals; Health; Human; Impaired cognition; In Vitro; Injury; Life; Link; Measurement; Mediating; Methodology; Microelectrodes; Microfluidic Microchips; Microfluidics; Microglia; Modeling; Morphologic artifacts; Mus; Neurodegenerative Disorders; Neuronal Injury; Neurons; Noise; Nutrient; Outcome; Oxygen; Parkinson Disease; Pathogenesis; Pathology; Patients; Perfusion; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Physiological; Pre-Clinical Model; Property; Protocols documentation; Recording of previous events; Research; Role; Stretching; Synapses; System; Traumatic Brain Injury; Validation; Vascular Diseases; Wild Type Mouse; Work; base; bioelectricity; cell type; clinical translation; commercialization; cost; density; drug efficacy; drug testing; effective therapy; electric impedance; experimental study; facsimile; high throughput screening; improved; in vivo; induced pluripotent stem cell; innovation; nerve stem cell; neuroinflammation; novel; parallel processing; pre-clinical; prevent; response; screening; simulation; strain injury; symptom management; tau Proteins; theories; therapy development; three dimensional cell culture

Abstract The proposed work aims at the commercialization of a microfluidic chip-based platform for modeling Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD) for preclinical in vitro mechanistic studies and drug testing. AD/ADRD are a growing health concern, accounting for 50-75% of all dementia cases, and currently affecting an estimated 5.8 million Americans. In addition to the human suffering, the annual cost of AD/ADRD is $290 billion. Current FDA approved treatments only help manage the symptoms of the disease. However, there is no treatment to stop or reverse its progression despite hundreds of clinical trials. A major obstacle to successful treatment development is the dearth of suitable preclinical models. In addition, there is substantial epidemiological evidence of an intricate relationship between traumatic brain injury (TBI), longer-term AD/ADRD pathology, and cognitive decline. However, the exact link between AD and TBI is not known. This application aims to solve both of these problems by developing a novel microfluidics- based 3D in vitro AD model, and merging this chip with BMSEED’s existing in vitro TBI model platform, the MicroElectrode Array Stretching Stimulating und Recording Equipment (MEASSuRE), to meet the needs for pre-clinical AD/ADRD research. This new platform presents an efficient and physiologically relevant pre-clinical drug screening platform for AD treatments. The platform is also well-suited to investigate the effects of a TBI on a person with or without a pre-existing genetic disposition to develop AD. The key innovations are the use of a stretchable microelectrode array for functional assessment of neuronal health in a microfluidics drug screening platform, and the capability to investigate the mechanistic links and similarities between AD and TBI using this stretchable microelectrode array in a 3D cell culture matrix (3D-sMEA). This 3D-MEASSuRE platform provides a more realistic in vitro facsimile of the natural in vivo biochemical and biomechanical microenvironment of the cells compared to existing 2D systems. Phase I is focused on demonstrating Proof-of- Concept (PoC) using a single-well (SW) 3D-MEASSuRE platform with cells derived from genetically modified (3xTg, 5xFAD) and wild type mice. Phase II is directed towards (a) improving efficiency by developing a high throughput multi-well (MW) 3D-MEASSuRE platform, and (b) increasing relevance to clinical translation by evaluating the platform using human cells derived from induced-pluripotent stem cells (hiPSCs) from AD patients and age matched controls. The capability of the 3D-MEASSuRE platform for research on the genetic pre-disposition to develop AD and the role of crosstalk between different cell types in the brain in mediating neuronal health after TBI-relevant strain injury will be evaluated and validated. The focus of this proposal is the development of a pre-clinical drug screening platform for AD/ADRD, however, the products developed in this research will also be applicable in drug screening for other neurodegenerative diseases, e.g., Parkinson’s Disease. At the end of Phase II, the 3D-MEASSuRE platform will be ready for the marketplace.

抽象的 拟议的工作旨在商业化基于微流体的芯片平台，用于建模 阿尔茨海默氏病和阿尔茨海默氏病有关的痴呆症（AD/ADRD）用于临床前体外机械 研究和药物测试。 AD/ADRD的健康问题日益严重，占所有痴呆症的50-75％ 案件，目前影响约580万美国人。除了人类的苦难之外 AD/ADRD的年成本为2900亿美元。当前FDA批准的治疗仅有助于管理 疾病。但是，没有治疗方法可以停止或逆转其进展数百个临床 试验。成功治疗发展的主要障碍是合适的临床前模型的死亡。在 此外，还有大量的流行病学证据，表明创伤性大脑之间存在复杂的关系 损伤（TBI），长期AD/ADRD病理和认知能力下降。但是，AD和 TBI尚不清楚。该应用程序旨在通过开发一种新型的微流体 - 基于3D体外广告模型，并将此芯片与BMSEED现有的体外TBI模型平台合并 微电极阵列拉伸刺激和记录设备（测量），以满足需求 临床前广告/ADRD研究。这个新平台提出了一个有效且与身体相关的临床前 广告处理的药物筛查平台。该平台也非常适合研究TBI的影响 对于有或没有先前存在的遗传性牙齿的人。关键创新是用途 可伸缩的微电极阵列用于微流体药物中神经元健康的功能评估 筛选平台以及研究AD和TBI之间的机械链接和相似性的能力 在3D细胞培养基质（3D-S-S-sea）中，使用此可拉伸的微电极阵列。这个3D测量 平台提供了自然体内生物化学和生物力学的更现实的体外传真 与现有的2D系统相比，细胞的微环境。第一阶段专注于证明证明 使用单孔（SW）3D测量平台的概念（POC），并带有源自转基因的细胞 （3XTG，5XFAD）和野生型小鼠。第二阶段针对（a）通过发展高效率来提高效率 吞吐量多孔（MW）3D计量平台，（b）通过 使用源自AD的诱导型干细胞（HIPSC）的人类细胞评估平台 患者和年龄匹配的对照。 3D测量平台的通用研究能力 开发AD的预分解和大脑不同细胞类型之间串扰的作用在介导 与TBI相关的应变损伤后的神经元健康将得到评估和验证。该提议的重点是 但是，开发用于AD/ADRD的临床前药物筛查平台，但是，在此开发的产品 研究还适用于其他神经退行性疾病的药物筛查，例如帕金森氏症 疾病。在第二阶段结束时，3D测量平台将为市场做好准备。