Combined Cardiomyopathy, e.g., of Cancer Chemotherapeutics, and Proarrhythmia for Cardiotoxicity Clinical Trials-in-a-Dish (CTiD) with iPSC-Derived Cardiomyocytes

联合心肌病，例如癌症化疗药物和致心律失常，使用 iPSC 来源的心肌细胞进行心脏毒性临床试验 (CTiD)

• 批准号: 10268102
• 负责人: Jeffrey H. Price
• 金额: $ 29.99万
• 依托单位: VALA SCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10268102
• 关键词: Action Potentials; Address; Aging; American; Animal Experimentation; Animal Model; Animal Testing; Animals; Antineoplastic Agents; Arrhythmia; Artificial Intelligence; Biological Assay; Calcium; Cancer Survivor; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiotoxicity; Cardiovascular system; Cell Membrane Permeability; Cell membrane; Cells; Cellular Structures; Cessation of life; Clinic; Clinical; Clinical Trials; Complex; Contract Services; Contractile Proteins; Dangerousness; Development; Dose; Drug Industry; Female; Fluorescence; Goals; Gold; Growth; Guidelines; Heart; Heart Diseases; Hour; Human; Image; Image Cytometry; Impairment; In Vitro; Kinetics; Label; Lead; Malignant Neoplasms; Measures; Methods; Microscopy; Mitochondria; Motion; Myocardium; Myopathy; Outcome; Pathologic; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Population; Pre-Clinical Model; Production; Protocols documentation; Publications; Publishing; Quality Control; Recording of previous events; Recurrence; Reporting; Research Contracts; Risk Assessment; Robotics; Safety; Sales; Sarcoplasmic Reticulum; Science; Sensitivity and Specificity; Small Business Technology Transfer Research; Source; Specificity; Speed; Structure; System; Technology Transfer; Testing; Time; Tissue Donors; Toxic effect; Treatment Side Effects; anti-cancer therapeutic; base; calcium indicator; cancer recurrence; cancer survival; cancer therapy; cancer type; cardiovascular risk factor; cell injury; cellular imaging; chemotherapy; clinical predictors; compound 30; cost; cytotoxicity; dosage; drug candidate; drug development; drug discovery; drug testing; heart cell; high throughput screening; improved; induced pluripotent stem cell; insight; instrument; lead series; male; novel therapeutics; pre-clinical; pre-clinical research; response; scale up; screening; screening services; side effect; therapeutic candidate; tool; tumor; validation studies; voltage

Cardiotoxicity is a leading cause of drug discovery attrition across all of preclinical and clinical drug discovery. While the FDA and the Comprehensive in vitro Proarrhythmia Assay initiative (CiPA) are focused primarily on predicting proarrhythmic effects, drug attrition due to cardiomyopathy, or primary cardiac cytotoxicity, may be even more prevalent, is typically currently only carried out via animal studies, and limits dosage for many cancer chemotherapeutics. Due to improving cancer survival, it is increasing common for more cancer survivors of some cancer types to die of cardiac diseases due to cancer treatment side effects than cancer recurrence. Cardiac contractions are initiated by electrical depolarizations (action potentials, APs) that propagate through the heart and initiate calcium (Ca2+) transients that activate the contractile apparatus. Importantly, dysregulation of Ca2+ can trigger inappropriate early-after- and delayed-after- depolarizations (EADs and DADs) that initiate arrhythmias, inhibit mitochondrial function, and pathologically alter expression of contractile proteins. Chemotherapy and other drugs can also directly impair mitochondrial function, which is primarily thought to cause cytotoxicity, but can also cause arrhythmias. Cardiomyocytes are also heterogeneous in their voltage, calcium, and contractile functions, and in their responses to therapeutic candidates. Thus, it is highly desirable to simultaneously measure AP, Ca2+ and contractile function on a cell- by-cell basis, in human cardiomyocytes, but this is not possible with current test methods. To address this unmet need we propose to develop a high throughput (robotic) Kinetic Image Cytometry that simultaneously quantifes voltage, calcium, and contractile motion in cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs). The hiPSC-CMs will be labeled with fluorescent indicators of calcium and voltage, and the cells imaged via high-speed automated microscopy during contractile activity. The use of hiPSC-CMs will enable “clinical trials” in a dish, in which test compounds are tested across cells representing several donors. Phase I of this Fast-Track STTR project will develop the basic protocol and perform a proof-of-concept screen of 30 test compounds on hiPSC-CMs representing 5 donors. In Phase II, a large validation study (~350 compounds, 7-concentration dose-response, 30 min and 72 hr exposures) will be performed. Artificial intelligence will be utilized to optimize the sensitivity and specificity of the assay by detecting complex arrhythmia waveforms. This assay represents a human-based preclinical model that will be less expensive and more predictive for cardiotoxicity testing than animal models and will be marketed to the pharmaceutical industry for contract research.

心脏毒性是所有临床前和临床药物发现中药物发现损耗的主要原因。 尽管FDA和全面的体外促肌动脉症分析计划（CIPA）主要集中在 预测心律失常，由于心肌病引起的药物属性或原发性心脏细胞毒性可能是 甚至更普遍，通常仅通过动物研究进行，并且限制了许多剂量 癌症化学治疗药。由于改善了癌症的生存，它增加了更多的癌症 与癌症相比，由于癌症治疗副作用而导致心脏病的某些癌症类型的幸存者 复发。心脏收缩是由去极化（动作电位，AP）引发的 通过心脏传播并启动钙（Ca2+）瞬态，以激活收缩式设备。 重要的是，CA2+的失调会引发不适当的早期和延迟 - 去极化后 （EADS和DADS）启动心律不齐，抑制线粒体功能并在病理上改变表达 收缩蛋白。化学疗法和其他药物也可能直接损害线粒体功能，即 首先认为会引起细胞毒性，但也会引起心律不齐。心肌细胞也是 它们的电压，钙和收缩功能的异质及其对治疗的反应 候选人。这是非常需要同时测量细胞上的AP，Ca2+和收缩功能 在人类心肌细胞中的基础基础，但使用当前的测试方法是不可能的。解决这个问题 未满足的需求我们建议开发出高吞吐量（机器人）动力学图像细胞仪，简单地 量化源自人诱导多能的心肌细胞中的电压，钙和转换器运动 干细胞（HIPSC-CMS）。 HIPSC-CMS将用钙和电压的荧光指标标记 以及收缩活性期间通过高速自动显微镜成像的细胞。 HIPSC-CMS的使用 将在菜肴中启用“临床试验”，其中测试化合物在代表几个的细胞上进行了测试 捐助者。这个快速轨道STTR项目的第一阶段将开发基本协议并执行概念证明 代表5个供体的HIPSC-CMS上的30种测试化合物的屏幕。在第二阶段，一项大型验证研究（〜350 将执行化合物，7-浓度剂量反应，30分钟和72小时暴露）。人造的 智能将通过检测复合物来优化测定的敏感性和特异性 心律不齐波形。该测定法代表了一种基于人类的临床前模型，它将更便宜 并且比动物模型更可预测心脏毒性测试，并将推销到药物 合同研究的行业。