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.

项目概要 近 90% 的正在开发的药物未能进入市场，其中许多失败的原因是。 在一些值得注意的案例中，一些药物通过了临床前筛选和临床试验，但最终被移除。 一旦在大量患者群体中发现毒性作用，这些失败就代表着一种失败。 浪费的巨大来源，并且构成了将单一药物运送到全球约 20 亿美元成本的重要组成部分。 经过市场测试，FDA 现在要求所有药物在上市前都要经过体外心脏毒性测试。 这导致了一个重要且不断增长的工具和技术市场，这些工具和技术能够实现更早的发展。 在接触患者之前检测毒性作用然而，目前的筛查方法不足以预测。 药物在体内的表现如何；确实迫切需要更具预测性的模型系统。 大多数筛选侧重于急性毒性，而不测试长期结构毒性，这通常只是 患者长期接触人类诱导多能干细胞衍生的药物后发现。 心肌细胞（hPSC-CM）是体外临床前毒性筛选的一个有吸引力的模型； 易于维护，源自人体组织，并有可能减少对动物的需求 然而，目前，基于 hPSC-CM 的检测无法正确复制该功能。 这些细胞表现出与胎儿组织相似的表型，并且不会按预期做出反应。 已知的作用；在某些情况下，已知的不良药物无法在 hPSC-CM 中引起毒性，而其他情况下 仅当暴露于超生理剂量的相关药物时才显示出效果。 行业及其监管机构认识到 hPSC-CM 在早期心脏毒性筛查方面的潜力，但也 了解目前它们在药物开发过程中的使用存在重大限制。 很明显，能够准确再现体内药物反应的成熟心脏组织的产生 NanoSurface 生物医学是降低成本和浪费的重要机会， Inc.，旨在应用生物工程方法来增强 hPSC-CM 细胞的成熟度和预测能力 我们发现这些细胞将提供更多的预测性药物诱导的心脏毒性筛选。 我们将首先对急性和慢性毒性机制进行体外心脏毒性检测的预测结果。 重点是应用这些刺激并验证它们预测毒性的能力（第一阶段）。 将表征这些细胞的表型，并将它们用于各种旨在了解的分析中 很难在实验室中筛选的各种特定毒性机制（第 2 阶段）。 使用这些数据来了解细胞成熟度在毒性检测中的作用，并为细胞成熟度制定路线图 全面的心脏毒性筛查框架。