Predictive assessment of acute and chronic cardiotoxicity using combinatorially matured hPSC-CMs

使用组合成熟的 hPSC-CM 对急性和慢性心脏毒性进行预测评估

• 批准号: 10505634
• 负责人: Nicholas Andrew Geisse
• 金额: $ 12.31万
• 依托单位: CURI BIO INC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10505634
• 关键词: Acute; Animal Experimentation; Biological Assay; Biological Models; Biomedical Engineering; Cardiac; Cardiotoxicity; Cells; Chronic; Clinical; Clinical Trials; Cues; Data; Detection; Development; Disease; Dose; Drug Costs; Drug toxicity; Early Diagnosis; Exhibits; Exposure to; Failure; Fetal Tissues; Heart; Human; In Vitro; Industry; Laboratories; Mechanics; Methods; Outcome; Patients; Pharmaceutical Preparations; Phase; Phenotype; Physiological; Play; Process; Production; Role; Source; Stimulus; Technology; Testing; Tissues; Toxic effect; Toxicity Tests; Validation; acute toxicity; base; combinatorial; cost; drug development; drug discovery; falls; human tissue; improved; in vitro Model; in vivo; induced pluripotent stem cell derived cardiomyocytes; patient population; pre-clinical; preclinical toxicity; predictive modeling; response; screening; stem cells; tool; wasting

PROJECT SUMMARY Nearly 90% of drugs under development fail to reach the market. Many of these failures occur due to cardiotoxicity. In a few notable cases, some drugs pass pre-clinical screens and clinical trials, only to be removed from the market once toxic effects are discovered in large patient populations. These failures represent a tremendous source of waste and constitute a significant part of the ~$2 billion cost of bringing a single drug to market. Consequently, the FDA now mandates that all drugs undergo in vitro cardiotoxicity testing before being tested in humans. This has led to a significant and growing market for tools and technologies that enable earlier detection of toxic effects before exposure to patients. However, current screening methods fall short of predicting how a drug will behave in the body; indeed there is a pressing need for more predictive model systems. Further, most screens focus on acute toxicity and do not test for longer-term structural toxicity which is typically only caught after a patient is exposed to the drug over long treatments. Human induced pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are an attractive model for in vitro preclinical toxicity screening; they are relatively easy to maintain, are derived from human tissue, and have the potential to reduce the need for animal experimentation. However, at present, hPSC-CM based assays do not properly replicate the function of the human heart. These cells exhibit phenotypes similar to that of fetal tissue and do not respond as expected to drugs of known effect; in some cases, known bad-actor drugs fail to induce toxicity in hPSC-CMs, while others only show effects when exposed to supra-physiological doses of the drug in question. The drug discovery industry and its regulators realize the potential of hPSC-CMs for early cardiotoxicity screening, but also understand that—at present—there are significant limitations to their use in the drug development process. Thus, it is clear that the production of mature cardiac tissues that accurately recapitulate in vivo drug responses represents a significant opportunity for reducing cost and waste in drug development. NanoSurface Biomedical, Inc., aims to apply bioengineering approaches to enhance the maturity and predictive power of hPSC-CM cells for highly predictive drug-induced cardiotoxicity screening. We hypothesize that these cells will give more predictive results in in vitro cardiotoxicity detection for both acute and chronic toxicity mechanisms. We will first focus on applying these stimuli and validating their ability to predict toxicity (Phase 1). After this validation, we will characterize the phenotypes of these cells and use them in a variety of assays targeted toward understanding a wide variety of specific toxicity mechanisms that are very difficult to screen in the laboratory (Phase 2). We will use these data to understand the role that cell maturity plays in toxicity detection and create a roadmap for a comprehensive cardiotoxicity screening framework.

项目摘要 近90％的正在开发的药物未能进入市场。这些失败中有许多是由于 心脏毒性。在少数值得注意的情况下，一些药物通过了临床前筛查和临床试验，只能去除 从市场中发现有毒作用的大量患者人群。这些失败代表 浪费的巨大来源，构成了将一种药物带到约20亿美元的重要成本中 市场。因此，FDA现在要求所有药物在进行之前进行体外心脏毒性测试 在人类中测试。这导致了工具和技术的巨大市场，使得能够较早 暴露于患者之前检测有毒作用。但是，当前的筛选方法缺乏预测 药物在体内如何表现；确实，需要更需要更重要的模型系统。更远， 大多数筛查都专注于急性毒性，并且不测试长期结构毒性，通常仅是 患者在长期治疗中暴露于药物后捕获。人类诱导的多能干细胞衍生 心肌细胞（HPSC-CMS）是体外临床前毒性筛查的有吸引力的模型；他们相对 易于维护，源自人体组织，并具有减少动物需求的潜力 实验。但是，目前，基于HPSC-CM的测定不能正确复制该功能 人心。这些细胞表现出与胎儿组织相似的表型，并且没有预期的反应 已知作用的药物；在某些情况下，已知的坏动物药物无法在HPSC-CM中诱导毒性，而其他药物则无法诱导 仅在暴露于相关药物的上生物生理剂量时才显示影响。药物发现 行业及其监管机构意识到HPSC-CMS对早期心脏毒性筛查的潜力，但也 理解，在目前的情况下，它们在药物开发过程中的使用有重大局限性。那， 显然，精确概括体内药物反应的成熟心脏组织的产生 代表了降低药物开发成本和浪费的重要机会。纳米表面生物医学， Inc.，旨在采用生物工程方法来增强HPSC-CM细胞的成熟和预测能力 用于高度预测的药物诱导的心脏毒性筛查。我们假设这些细胞将提供更多 预测性导致急性和慢性毒性机制的体外心脏毒性检测。我们将首先 专注于应用这些刺激并验证其预测毒性的能力（第1阶段）。验证后，我们 将表征这些细胞的表型，并将它们用于针对理解的各种测定法 在实验室中很难筛选的多种特异性毒性机制（第2阶段）。我们将 使用这些数据了解细胞成熟在毒性检测中的作用，并为A创建路线图 全面的心脏毒性筛查框架。