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

计算和心脏微生理学系统相结合的药物诱发心律失常筛查方法

基本信息

批准号：
10268209
负责人：
Samuel Wall
金额：
$ 53.71万
依托单位：
ORGANOS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-21 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10268209
关键词：
Address Adult Agreement Algorithms Behavior Belief Biological Biological Markers Biological Models Biology Cardiac Cardiac Myocytes Cardiotoxicity Cardiovascular Agents Cell Line Cells Clinic Computer Analysis Computer software Computing Methodologies Data Data Analyses Data Collection Development Devices Disease Pathway Drug Costs Drug Industry Drug Screening Engineering Goals Heart Heart Diseases Hour Human Hypertrophy In Vitro Individual Investments Laboratories Lead Letters Licensing Measurement Measures Medicine Metabolic Methodology Modality Modeling Organ Patients Pharmaceutical Preparations Phenotype Physiological Poison Population Pre-Clinical Model Process Risk Safety Speed Structure System Systems Analysis Techniques Technology Testing Time Tissue Model Tissues Torsades de Pointes Toxic effect Translations Triage Ventricular Tachycardia base clinical risk cohort cost drug candidate drug development drug discovery drug efficacy drug response prediction drug testing gene interaction improved in silico in vivo Model individual response induced pluripotent stem cell innovation lead optimization medication safety microphysiology system new therapeutic target novel patient population predictive tools professor research and development response screening software systems stem cells success tool

项目摘要

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.

项目摘要/摘要