A Humanized Organ Plate Paradigm for High Throughput Alzheimer's disease Therapeutics

用于高通量阿尔茨海默病治疗的人源化器官板范例

• 批准号: 10259088
• 负责人: John Collins
• 金额: $ 45.48万
• 依托单位: BIOPICO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10259088
• 关键词: 3-Dimensional; Address; Albumins; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease diagnostic; Alzheimer' s disease model; Alzheimer' s disease test; Alzheimer' s disease therapeutic; Alzheimer' s disease therapy; Amyloid beta-Protein; Animal Model; Astrocytes; Behavior; Biological Assay; Biological Availability; Biological Markers; Biological Sciences; Blood - brain barrier anatomy; Blood Vessels; Brain; Cause of Death; Cell Line; Cell physiology; Cells; Clinic; Clinical; Clinical Data; Clinical Trials; Collagen; Communication; Coupling; Cues; Data; Defect; Development; Disease; Dose; Drug Kinetics; Drug Targeting; Early Diagnosis; Electrical Resistance; Electrodes; Endothelium; Engineering; Enteric Nervous System; Excretory function; Force of Gravity; Foundations; Gel; Gene Expression; Gene Expression Regulation; Glucose; Goals; Gold; Human; Immune; In Vitro; Individual; Kidney; Laboratories; Legal patent; Letters; Liquid substance; Literature; Liver; Malignant Neoplasms; Measurement; Measures; Metabolic Marker; Metabolism; Microelectrodes; Modeling; Molecular; Morphology; Mutation; Neuraxis; Neurons; Neurotoxins; Oral; Organ; Organ Size; Oxidative Stress; Patients; Pericytes; Permeability; Pharmaceutical Preparations; Pharmacology; Phase; Physiological; Physiology; Pre-Clinical Model; Process; Protein Isoforms; Proximal Kidney Tubules; Reproducibility; Research; Rodent Model; Safety; Stains; Structure; System; Therapeutic; Therapeutic Agents; Therapy Clinical Trials; Tight Junctions; Time; Tissues; Toxic effect; Transgenic Organisms; Translating; Up-Regulation; Vascular Endothelium; Vision; Visualization; absorption; base; beta-site APP cleaving enzyme 1; body on a chip; body system; brain endothelial cell; calcein AM; cost; disease phenotype; drug development; drug discovery; drug efficacy; drug testing; effective therapy; genetic manipulation; high throughput screening; high-throughput drug screening; human model; improved; in vitro Model; in vivo; induced pluripotent stem cell; instrumentation; interest; intestinal barrier; intestinal epithelium; liver metabolism; nephrotoxicity; nerve damage; nervous system disorder; neuroinflammation; neuropathology; novel; novel strategies; novel therapeutics; overexpression; pharmacokinetic characteristic; pharmacokinetic model; physiologically based pharmacokinetics; portability; pre-clinical; prevent; prototype; response; screening; small molecule; stem cells; success; tau Proteins; therapeutic target

A Humanized Organ Plate Paradigm for High Throughput Alzheimer's disease Therapeutics Abstract Preclinical drug discovery research for Alzheimer's Disease (AD) is hampered by the lack of sufficient preclinical models. Although several drugs have shown promise in animal models to some extent, many human clinical trials of therapies for AD have failed. Therefore in vitro models using human-derived cell lines or patient-derived genetically-manipulated human induced pluripotent stem cells (hiPSC) that overexpress the different isoforms of β-amyloid have shown interest. These hiPSCs with the acquisition of full cellular functionality, microenvironment mechanostructural cues and mimicking vascular defects observed in patients with AD are in development. Further, blood-brain-barrier (BBB) integrity that prevents neurotoxins from entering the brain and bidirectional molecular communications between the central nervous system and the enteric nervous system, are critical for AD therapeutic strategy in the laboratory models. These models with 3D perfused engineered micro-sized organ systems can help costly and risky drug testing with quantitative and mechanistic data. However, high throughput portable passive system that can connect multiple organs and provide quantitative pharmacokinetics data, is still to be realized. Therefore, Biopico Systems Inc teams with UC Irvine to propose a Humanized Organ Plate Paradigm (HOPP) for high throughput Alzheimer's disease therapeutics that can accurately and reproducibly mimic the AD phenotype in vivo and be amenable to high-content screening and assay applications. With the preliminary results from the patent-pending organ platform and measurement instrumentation, Biopico will utilize existing drugs that have failed in clinical trials and given positive indications to perform proof-of-concept of our platform. The Phase I research aims are to: (i) Develop functional blood-brain-barrier in vitro pharmacological HOPP system in high throughput format, (ii) Integrate multi-organs for morphological, functional, gene expression & metabolic markers metrics and (iii) Validate HOPP system using pharmacokinetic modeling and in vitro to in vivo extrapolation. The successful completion of these aims will provide a strong foundation for developing a commercial organ system in Phase II to customers developing therapeutic agents for AD. Biopico's vision is to commercialize the largescale application of the screening assay to accelerate the process of finding a disease-modifying therapy.

一种用于阿尔茨海默病高通量治疗的人性化器官模板范式 摘要 阿尔茨海默病(AD)的临床前药物发现研究因缺乏足够的临床前药物而受阻 模特们。尽管有几种药物在动物模型上显示出了一定的前景，但许多人类临床 治疗阿尔茨海默病的试验已经失败。因此，在体外模型中使用人类来源的细胞系或患者来源的细胞 基因操纵的人诱导多能干细胞(HiPSC)过表达不同亚型的 β-淀粉样蛋白已经表现出兴趣。这些HiPSCs获得了完整的细胞功能、微环境 在AD患者中观察到的机械结构线索和模拟血管缺陷正在开发中。 此外，血脑屏障(BBB)的完整性可以防止神经毒素进入大脑和双向 中枢神经系统和肠道神经系统之间的分子通讯对于 AD治疗策略在实验室模型中的应用。这些模型带有3D灌流的工程化微型器官 系统可以用定量和机械数据来帮助昂贵和有风险的药物测试。然而，高吞吐量 可连接多个器官并提供定量药代动力学数据的便携式被动系统仍在进行中 有待实现。因此，Biopico Systems Inc与加州大学欧文分校合作提出了一种人性化的器官盘 用于高通量阿尔茨海默病治疗的范例(Hopp)，可以准确和可重复性 在体内模拟AD的表型，并适应高含量的筛选和检测应用。与 来自正在申请专利的器官平台和测量仪器的初步结果，Biopico将利用 已在临床试验中失败并给出阳性适应症以执行我们的概念验证的现有药物 站台。第一阶段的研究目标是：(I)开发体外药理功能的血脑屏障 高通量的Hopp系统，(Ii)集成了多器官的形态、功能、基因 表达和代谢标记物指标和(Iii)使用药代动力学模型和 从体外到体内的外推。这些目标的成功实现将为 在第二阶段为客户开发商业器官系统，开发AD治疗剂。Biopico‘s 愿景是将筛查试验的大规模应用商业化，以加速发现 一种治病疗法。