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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

基本信息

批准号：
10679410
负责人：
Nicholas Andrew Geisse
金额：
$ 24.21万
依托单位：
CURI BIO 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：
2020-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10679410
关键词：
Acute Adverse reactions Animal Experimentation Animals Automobile Driving Benchmarking Biochemical Biological Assay Biological Markers Biological Models Biology Biomedical Engineering Biomimetics Cardiac Cardiotoxicity Cell Culture Techniques Cell Line Cell Maturation Cell Survival Cells Cellular Assay Chronic Clinical Clinical Trials Consensus Cues Data Detection Development Disease Dose Drug Costs Drug toxicity Early Diagnosis Electric Stimulation Electrophysiology (science)Engineering Environment Exhibits Exposure to Extracellular Matrix Failure Fetal Tissues Goals Heart Human Image In Vitro Industrialization Industry Industry Standard Laboratories Longitudinal Studies Measures Mechanics Metabolic Metabolism Methods Mission Modeling Molecular Outcome Patients Pharmaceutical Preparations Phase Phenotype Physiological Play Poison Predisposition Process Production Protein Isoforms Quality Control Risk Role Safety Scheme Source Specific qualifier value Standardization Statistical Data Interpretation Stimulus Structure Surface System Technology Testing Time Tissue Model Tissues Torsades de Pointes Toxic effect Toxicity Tests Up-Regulation Validation acute toxicity base clinical risk clinically relevant combinatorial cost design drug development drug discovery early onset extracellular falls functional genomics high throughput screening human tissue improved in vitro Model in vivo induced pluripotent stem cell induced pluripotent stem cell derived cardiomyocytes instrument next generation novel patient population pre-clinical preclinical toxicity predictive modeling response screening stem cells tool wasting

项目摘要

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.

项目总结