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

阿尔茨海默病治疗的人源化器官板模型 摘要 阿尔茨海默病（AD）的临床前药物发现研究受到缺乏足够的临床前研究的阻碍。 模型虽然几种药物在动物模型中显示出一定程度的前景，但许多人类临床 治疗AD的试验已经失败。因此，使用人源性细胞系或患者源性细胞系的体外模型可用于治疗癌症。 基因操作的人诱导多能干细胞（hiPSC），其过表达不同的 β-淀粉样蛋白已经表现出兴趣。这些hiPSC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）的完整性防止神经毒素进入大脑和双向代谢。 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。这些模型与3D灌注工程微型器官 系统可以帮助昂贵和危险的药物测试与定量和机械数据。然而，高吞吐量 便携式无源系统，可以连接多个器官，并提供定量药代动力学数据，仍然是 才能实现。因此，Biopico系统公司与加州大学欧文分校合作，提出了一种人源化器官板 范式（HOPP）的高通量阿尔茨海默病治疗，可以准确和可重复的 在体内模拟AD表型，并适合高含量筛选和测定应用。与 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 现有的药物在临床试验中失败，并给予积极的适应症，以执行我们的概念验证 平台I期研究的目标是：（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）整合形态，功能，基因 表达和代谢标志物度量和（iii）使用药代动力学建模的CRYSTHOPP系统，以及 体外至体内外推。这些目标的成功实现将为以下方面奠定坚实的基础： 在第二阶段开发商业器官系统，提供给开发AD治疗剂的客户。Biopico's 我们的愿景是将筛选试验的大规模应用商业化，以加速发现过程。 一种改善疾病的疗法

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.