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

项目总结 近90%正在研发的药物未能上市。这些故障中的许多都是由于 心脏毒性。在少数值得注意的案例中，一些药物通过了临床前筛选和临床试验，但最终被取消 一旦在大量患者中发现有毒影响，就会从市场上撤出。这些失败代表着 巨大的废物来源，并构成了将一种药物带到 市场。因此，FDA现在规定，所有药物在使用前都必须经过体外心脏毒性测试。 在人体上进行了测试。这导致了对工具和技术的巨大且不断增长的市场，这些工具和技术支持更早 在接触患者之前检测毒性效应。然而，目前的筛查方法并不能预测 药物在体内的表现；事实上，迫切需要更具预测性的模型系统。此外， 大多数筛查集中在急性毒性上，而不测试较长期的结构性毒性，后者通常只是 患者在长期治疗过程中接触到这种药物后被发现。人诱导多能干细胞来源 心肌细胞(hPSC-CMS)是一种有吸引力的体外临床前毒性筛选模型； 易于维护，从人类组织中提取，并有可能减少对动物的需求 实验。然而，目前，基于hPSC-CM的检测不能正确复制 人类的心脏。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 已知效果的药物；在某些情况下，已知的不良反应药物未能在hPSC-CMS中诱导毒性，而另一些情况下 只有当接触到超生理剂量的相关药物时才会显示出效果。药物的发现 工业及其监管机构认识到hPSC-CMS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有很大限制。因此， 显然，能够准确概括体内药物反应的成熟心脏组织的产生 这是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.的目标是应用生物工程方法来增强hPSC-CM细胞的成熟度和预测能力 用于高预测性药物诱导的心脏毒性筛查。我们假设这些细胞会提供更多 急性和慢性毒性机制的体外心脏毒性检测的预测结果。我们将首先 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)。在此验证之后，我们 将表征这些细胞的表型，并将它们用于各种旨在了解 多种特定的毒性机制，在实验室中很难筛选(第二阶段)。我们会 使用这些数据来了解细胞成熟度在毒性检测中所起的作用，并为 全面的心脏毒性筛查框架。

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.