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

基本信息

批准号：
10551783
负责人：
John Collins
金额：
$ 0.47万
依托单位：
BIOPICO
依托单位国家：
美国
项目类别：
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/10551783
关键词：
3-Dimensional Address Albumins Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease diagnostic Alzheimer&apos s disease model Alzheimer&apos s disease test Alzheimer&apos s disease therapeutic Alzheimer&apos 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 diagnostic criteria 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

项目摘要

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.

用于高通量阿尔茨海默病治疗的人源化器官板范例抽象的阿尔茨海默病 (AD) 的临床前药物发现研究因缺乏足够的临床前研究而受到阻碍尽管一些药物在动物模型中显示出一定的前景，但许多药物在人体临床中仍表现出一定的前景。因此，使用人源细胞系或患者来源的细胞系进行的体外模型治疗试验失败了。基因操作的人类诱导多能干细胞（hiPSC），过度表达不同亚型人们对这些具有完整细胞功能和微环境的 hiPSC 表现出了兴趣。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）完整性可防止神经毒素进入大脑和双向中枢神经系统和肠神经系统之间的分子通讯对于实验室模型中的 AD 治疗策略采用 3D 灌注工程微型器官。系统可以通过定量和机械数据帮助进行昂贵且有风险的药物测试，但是吞吐量很高。能够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，仍然是因此，Biopico Systems Inc 与加州大学欧文分校合作提出了人源化器官板。用于高通量阿尔茨海默氏病治疗的范例 (HOPP)，可以准确且可重复地模拟体内 AD 表型并适合高内涵筛选和测定应用。 Biopico 将利用正在申请专利的器官平台和测量仪器的初步结果现有药物在临床试验中失败，并给出了积极的迹象来进行我们的概念验证第一阶段研究的目标是：（i）开发功能性血脑屏障体外药理学。高通量形式的 HOPP 系统，(ii) 整合多器官的形态、功能、基因表达和代谢标志物指标以及 (iii) 使用药代动力学模型验证 HOPP 系统这些目标的成功完成将为体外到体内外推奠定坚实的基础。在第二阶段为开发 AD 治疗药物的客户开发商业器官系统。愿景是将筛选分析的大规模应用商业化，以加速发现的过程疾病缓解疗法。