Combined Computational and Cardiac Microphysiological System Approach for Drug-Induced Proarrhythmia Screening

项目概要/摘要 尽管有记录，但几乎没有一天不强调对新药的迫切需要。 R & D的投资水平。但毒品消耗的毒酒杯仍然存在， 新药流向需要的人。虽然这不是一个新问题，但 强烈认为最佳缓解有效候选药物安全性风险的能力将 来自于更精确的安全裕度估计， 理解从计算机模拟、体外和体内模型到人类的翻译。内 在过去的十年里，我们已经看到了诱导多能干细胞衍生的 心肌细胞（hiPSC-CMs）作为翻译理解心脏的重要工具 疾病生物学和心脏毒性预测。尽管它们具有相当大的优势， hiPSC-CM通常在结构和功能上不成熟，降低了其预测性。 潜力因此，更好地了解促进可持续发展的基本机制和进程， 成熟，如生理肥大，代谢和结构变化将改善 这种情况，因为它们被纳入体外组织模型。在这里，Organos Inc.提出 解决心血管药物责任领域的这些挑战， 体外心脏微生理系统（MPS）的商业开发，微组织 基于hiPSC-CM构建，结合新的计算机计算方法， 提供药物致心律失常责任的早期准确信息。在这个系统的核心 是成熟的框架，初步数据表明hiPSC-CM成熟是 在MPS模型中生物学上得到了改善，但我们也有可能在计算上 成熟的细胞，通过我们的新算法，提供了相当大的时间和成本降低 同时保持生理相关性。在本提案中，我们将验证我们的 集成心脏MPS测试和计算机模拟计算分析系统， 已知对心脏有影响的药物这两个具体目标将首先完善硬件外形 和计算方法，以提高预测，速度和系统的可扩展性， 并且第二验证组合的计算/MPS系统以将化合物与已知化合物进行排序。 根据尖端扭转型室性心动过速的临床风险，药物诱导的致心律失常风险（即， 室性心动过速）。

Project Summary / Abstract Barely a day goes by when the urgent need for new medicines is not highlighted despite record levels of investments into R&D. But the poison chalice of drug attrition remains, stagnating the flow of new medicines to those that need them. Whilst this is not a new problem, there is a strong belief that the ability to optimally mitigate safety risk in efficacious drug candidates will come from a greater refinement of safety margin estimates together with a greater understanding of translation from in silico, in vitro and in vivo models to humans. Within the last decade we have seen the emergence of induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as important tools for translational understanding of cardiac disease biology and prediction of cardiotoxicity. Despite their considerable advantages, hiPSC-CMs are typically structurally and functionally immature, reducing their predictive potential. Accordingly, greater understanding of the underlying mechanisms and processes for maturation such as physiological hypertrophy, metabolic and structural changes will improve this situation as they are incorporated into in vitro tissue models. Here, Organos Inc. proposes a solution to these challenges in the realm of cardiovascular drug liability through the commercial development of an in vitro cardiac microphysiological system (MPS), a microtissue construct based on hiPSC-CMs, combined with novel in silico computational methods to provide early, accurate information on drug proarrhythmia liabilities. At the heart of this system are frameworks for maturation, preliminary data indicates that hiPSC-CM maturation is improved biologically in the MPS model, but we also have the potential to computationally mature cells through our novel algorithms, offering considerable time and cost reduction opportunities whilst maintaining physiological relevance. In this proposal, we will validate our integrated cardiac MPS testing and in silico computational analysis system across a range of drugs with known cardiac effects. The two specific aims will first refine the hardware form factor and computational methodology to improve prediction, speed and scalability of the system, and second validate the combined computational/MPS system to rank compounds with known drug-induced proarrhythmia risk according to their clinical risk of Torsade de Pointes (i.e., ventricular tachycardia) for a patient population of cardiac MPS devices.