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.

摘要 拟议的工作旨在将基于微流控芯片的建模平台商业化 阿尔茨海默病和阿尔茨海默病相关痴呆(AD/ADRD)临床前的体外机制 研究和药物测试。AD/ADRD是一个日益严重的健康问题，占所有痴呆症的50%-75% 病例，目前估计有580万美国人受到影响。除了人类的苦难之外， AD/ADRD的年成本为2900亿美元。目前FDA批准的治疗方法仅有助于控制 这种疾病。然而，尽管有数百例临床病例，但没有治疗方法来阻止或逆转其进展。 审判。成功开发治疗的一个主要障碍是缺乏合适的临床前模型。在……里面 此外，有大量流行病学证据表明，创伤性脑损伤之间存在复杂的关系 损伤(TBI)，较长期的AD/ADRD病理，以及认知能力下降。然而，AD和AD之间的确切联系 TBI尚不清楚。本申请旨在通过开发一种新型的微流体来解决这两个问题- 基于3D体外AD模型，并将该芯片与BMSEED现有的体外脑损伤模型平台相融合， 微电极阵列拉伸刺激和记录设备(MEASSuRE)，以满足 临床前AD/ADRD研究。这一新平台提供了高效和生理上相关的临床前 AD治疗药物筛选平台。该平台也非常适合于研究TBI的影响 对有或没有预先存在的阿尔茨海默病遗传倾向的人。关键的创新是使用 用于微流控药物中神经元健康功能评估的可伸缩微电极阵列 筛选平台，以及调查AD和TBI之间的机制联系和相似性的能力 在3D细胞培养基质(3D-sMEA)中使用该可伸展微电极阵列。本3D-MEASSuRE 平台提供了更逼真的体内自然生物化学和生物力学的传真 细胞的微环境与现有的2D系统相比。第一阶段的重点是展示 概念(PoC)使用单孔(SW)3D-MEASSuRE平台，细胞来自转基因 (3xTg、5xFAD)和野生型小鼠。第二阶段的目标是：(A)通过开发高效率的 吞吐量多井(MW)3D-MEASSuRE平台，以及(B)通过以下方式提高与临床翻译的相关性 使用AD诱导多能干细胞(HiPSCs)来源的人类细胞评估该平台 患者和年龄匹配的对照组。3D-MEASSuRE平台用于遗传学研究的能力 阿尔茨海默病的易感性和脑内不同细胞类型之间的串扰在调节中的作用 将评估和验证脑损伤相关应变损伤后的神经元健康状况。这项提案的重点是 AD/ADRD临床前药物筛选平台的开发，然而，在该平台中开发的产品 这项研究也将适用于其他神经退行性疾病的药物筛选，例如帕金森氏症 疾病。在第二阶段结束时，3D-MEASSuRE平台将投放市场。