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.

高吞吐量阿尔茨海默氏病治疗药的人源化器官板范式 抽象的 由于缺乏足够的临床前，阿尔茨海默氏病（AD）的临床前药物发现研究受到阻碍 尽管几种药物在某种程度上表现出了动物模型中的希望，但许多人类临床 AD疗法的试验失败了。因此，使用人类衍生的细胞系或患者衍生的体外模型 遗传操纵的人类诱导多能干细胞（HIPSC）过表达不同的同工型 β-淀粉样蛋白表现出了关注。这些HIPSC随着完全的细胞功能，微环境的获取 在AD患者中观察到的机械结构提示和模仿血管缺陷正在发育中。 此外，血脑屏障（BBB）的完整性可防止神经毒素进入大脑和双向 中枢神经系统与肠神经系统之间的分子通信对于 实验室模型中的广告疗法策略。这些具有3D灌注工程微型器官的型号 系统可以通过定量和机械数据来帮助昂贵和风险的药物测试。但是，高通量 可以连接多个器官并提供定量药代动力学数据的便携式无源系统，仍然是 要实现。因此，传播系统Inc与UC Irvine团队提出人性化器官板 高吞吐量阿尔茨海默氏病疗法的范式（HOPP），可以准确且可重复地 模仿体内的AD表型，并且可以适合高含量筛选和测定应用。与 来自申请专利的器官平台和测量仪器的初步结果，传记片将利用 现有的药物在临床试验中失败并给出了积极的迹象来表现我们的概念证明 平台。 I期研究的目的是：（i）在体外药理中发展功能性血脑屏障 HOPP系统高吞吐量格式，（ii）整合形态，功能，基因的多孔 表达和代谢标记指标和（iii）使用药代动力学建模验证HOPP系统 体内外推。这些目标的成功完成将为 在第二阶段开发商业器官系统为开发AD治疗剂的客户。传播的 愿景是商业化筛选测定的大规模应用以加速查找过程 改良疾病的疗法。