High-throughput Human Micro-Heart Muscle for Drug Discovery

用于药物发现的高通量人体微心肌

• 批准号: 10682473
• 负责人: Samuel Wall
• 金额: $ 35.13万
• 依托单位: ORGANOS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10682473
• 关键词: 3-Dimensional; Automation; Back; Belief; Biological Assay; Calcium; Cardiac; Cause of Death; Complex; Computer software; Computing Methodologies; Cycloparaffins; Data; Development; Devices; Drug Industry; Electrophysiology (science); Exclusion; Feeds; Fostering; Goals; Heart; Heart Diseases; Heart failure; Human; In Vitro; Libraries; Licensing; Mediation; Microfluidics; Muscle Contraction; Muscle Fibers; Myocardial dysfunction; Myocardium; Outcome; Pharmaceutical Preparations; Physiological; Polymers; Pre-Clinical Model; Productivity; Reproducibility; Sarcomeres; Speed; Structure; System; Testing; Therapeutic; Tissue Model; Tissues; Validation; Work; assay development; copolymer; deep learning model; drug candidate; drug development; drug discovery; drug mechanism; drug testing; fabrication; high throughput screening; human disease; improved; in silico; induced pluripotent stem cell derived cardiomyocytes; innovation; medication safety; microphysiology system; miniaturize; monolayer; novel; novel therapeutic intervention; predictive tools; prognostic; research and development; response; screening; software systems; success; technology platform; tool; two-dimensional; virtual

Although heart failure is the leading cause of death in the U.S., therapeutic treatments remain suboptimal as the pharmaceutical industry has proven incapable of generating more predictive human-relevant preclinical models of the human heart that are amenable to high-throughput screening (HTS) assays. Thus, vast compound libraries remain virtually unexplored in an effective manner, hindering the speedy development of new therapeutic approaches to treat heart disease. Organos, Inc. proposes a solution to this problem in the commercial development of an in vitro miniaturized array of “Micro-Heart Muscle” (µHM) amenable to HTS. Organos’ innovation is that our HTS capable assay is based on heart muscle contraction metrics, which to date has neither been achieved nor is attainable in two-dimensional (2D) platforms. A main focus of this proposal is to create an HTS assay, using µHMs that fit a 384 microplate form factor, amenable to use with pre-existing automation. In the µHM, elongated muscle fibers are formed from induced pluripotent stem cell-derived cardiomyocytes (hiPSC- CMs) in polymer templates that promote uniaxial alignment and contraction, robust sarcomere assembly, and physiologically relevant drug responsiveness. The µHM 384 HTS platform and assay will lead the front end of Organos’ discovery pipeline and feed data into our computational and deep learning models for compound discovery, target identification, and repurposing. The Specific Aims focus first on the fabrication of the HTS µHM platform, microtissue characterization, and assay development, then on validation and its use in HTS to identify compounds that improve cardiac contractility. The main outcome will be a robust HTS assay employing human heart muscle suitable for use in large screening campaigns for de novo drug discovery.

虽然心力衰竭是美国的主要死因，治疗仍然是次优的， 制药行业已被证明无法生成更具预测性的人类相关临床前模型 适合于高通量筛选（HTS）测定的人心脏的。因此，庞大的化合物库 实际上仍然没有以有效的方式进行探索，阻碍了新的治疗方法的快速发展。 治疗心脏病的方法。Organos公司提出了一个解决这个问题的商业 开发了一种适用于HTS的体外小型化“微心肌”（µHM）阵列。有机物 创新之处在于，我们的HTS能力测定是基于心肌收缩指标，迄今为止， 在二维（2D）平台中也不能实现。该提案的一个主要重点是建立一个 HTS检测试剂盒，使用适合384微孔板外形的µ HM，适合与预先存在的自动化一起使用。在 µHM，细长的肌纤维由诱导多能干细胞衍生的心肌细胞（hiPSC-1）形成。 CM），其促进单轴排列和收缩、稳健的肌节组装，以及 生理学相关的药物反应性。µHM 384 HTS平台和检测将引领 Organos的发现管道，并将数据输入我们的计算和深度学习模型， 发现目标识别和再利用具体目标首先关注HTS µHM的制造 平台，微组织表征和检测开发，然后验证及其在HTS中的使用，以确定 改善心脏收缩力的化合物。主要结果将是采用人类的稳定HTS测定。 心肌适合用于从头药物发现的大规模筛选活动。