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High-throughput Human Micro-Heart Muscle for Drug Discovery

用于药物发现的高通量人体微心肌

基本信息

批准号：
10484494
负责人：
Samuel Wall
金额：
$ 62.29万
依托单位：
ORGANOS, INC.
依托单位国家：
美国
项目类别：
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/10484494
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)Feeds Fostering Goals Heart Heart Diseases Heart failure Human In Vitro Lead Libraries Licensing Mediation Microfluidics Muscle Contraction Muscle Fibers Myocardial dysfunction Myocardium Outcome Pharmaceutical Preparations Physiological Polymers Pre-Clinical Model Productivity Reproducibility Sarcomeres Structure System Technology Testing Therapeutic Tissue Model Tissues Validation Work assay development base copolymer deep learning model drug candidate drug development drug discovery drug mechanism drug testing 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 tool two-dimensional virtual

项目摘要

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.

尽管心力衰竭在美国是主要的死亡原因，但治疗方法仍然不是最理想的，因为制药行业已被证明无法产生更具预测性的与人类相关的临床前模型适用于高通量筛查(HTS)分析的人的心脏。因此，庞大的复合库几乎没有以有效的方式进行探索，阻碍了新疗法的快速发展治疗心脏病的方法。Organos，Inc.在商业广告中提出了一个解决方案体外微型化HTS“微心肌”阵列的研制奥古诺斯创新之处在于，我们的HTS分析是基于心肌收缩指标的，到目前为止，这一指标既没有在二维(2D)平台上也无法实现。这项提案的一个主要焦点是创建一个 HTS分析，使用适合384微板外形因数的µHMS，可与预先存在的自动化一起使用。在……里面微细肌纤维由诱导多能干细胞来源的心肌细胞(hiPSC- CMS)在聚合物模板中，促进单轴排列和收缩，坚固的肌节组装，以及生理上相关的药物反应性。µHM 384 HTS平台和分析将引领 Organos的发现流程，并将数据输入我们的化合物计算和深度学习模型发现、目标识别和再利用。具体目标首先集中在HTSµHM的制造上平台、微组织表征和分析开发，然后是验证及其在HTS中的使用，以确定改善心脏收缩能力的化合物。主要结果将是一个强大的HTS测试，使用人类适合用于新药发现的大型筛选活动的心肌。