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Cryopreserving Stem Cell-Derived Cardiomyocytes in Ready-to-use Assay Plates for Improved Reproducibility of Drug Toxicity Testing

在即用型检测板中冷冻保存干细胞衍生的心肌细胞，以提高药物毒性测试的重现性

基本信息

批准号：
10082253
负责人：
Eli Fine
金额：
$ 25.21万
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：
2020-09-11 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10082253
关键词：
Address Adoption Affect Animal Experimentation Behavior Biological Assay Biological Models Biomimetics Carbon Dioxide Cardiac Cardiac Myocytes Cardiotoxicity Cell Survival Cells Cellular Morphology Chronic Clinical Clinical Trials Cryopreservation Cryopreserved Tissue Data Detection Development Devices Disease Drug Costs Drug toxicity Early Diagnosis Economics Electronics Electrophysiology (science)Elements Exposure to Extravasation Failure Fluorescence Freezing Frequencies Funding Generations Giant Cells Heart Human In Vitro Industry Industry Standard Isoproterenol Letters Liquid substance Logistics Manufacturer Name Methods Microelectrodes Modification Optics Outcome Pain Patients Pattern Pharmaceutical Preparations Phase Phenotype Physiological Preparation Price Procedures Process Production Protocols documentation Publications Quality Control Reader Reproducibility Research Personnel Robotics Safety Screening procedure Shipping Ships Site Source Stress Structure System Technology Temperature Testing Time Tissues Toxic effect Toxicity Tests Translating Work atmospheric carbon dioxide axion base cell motility cell type commercialization cost cryogenics design dofetilide drug candidate drug development drug discovery experience experimental study falls health care delivery human subject human tissue improved in vitro Model induced pluripotent stem cell luminescence microscopic imaging monolayer multi-electrode arrays nanopattern next generation novel strategies novel therapeutics patient population pre-clinical preclinical toxicity predictive modeling prevent process optimization response screening stem cells tool validation studies wasting

项目摘要

PROJECT SUMMARY / ABSTRACT 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 preclinical 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. Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) are an attractive model for in vitro preclinical toxicity screening; they are derived from human tissue and have the potential to reduce the need for animal experimentation. However, at present, preparation of iPSC-CM assay plates (particularly the highly popular multi- electrode array plate) is technically challenging, which leads to higher operator-induced experimental variability and low site-to-site reproducibility. The drug discovery industry and its regulators realize the potential of iPSC-CMs for early cardiotoxicity screening, but also understand that there are currently signiﬁcant limitations to their use in the drug development process caused by experimental variability. To address this, some companies currently provide “assay-ready” plates with cells already inside, which are then shipped to customers at ambient conditions. However, cells are not normally exposed to ambient conditions for such long periods of time—calling into question the scientiﬁc validity of that approach—and the inability to store the perishable product causes pain points in manufacturing and customer use. Nevertheless, the high demand for the current generation of ambient assay- ready plates (see Letters of Support) makes it clear that they represent a signiﬁcant opportunity for reducing cost and waste in drug development. NanoSurface Biomedical, Inc. aims to develop the next generation of “assay- ready” technology by shipping customers cryogenically frozen assay plates containing iPSC-CM monolayers. We hypothesize that recent advances in cryopreserving monolayers of other cell types can be successfully translated and optimized for iPSC-CMs. We will ﬁrst focus on demonstrating that iPSC-CMs and assay plates maintain viability and integrity after cryogenic storage as a monolayer (Aim 1), then conduct proof-of-concept studies showing that the iPSC-CM function is not adversely affected by the freeze/thaw process (Aim 2). Subsequent Phase 2 commercialization efforts will focus on optimizing the freezing and thawing process for scaling and commercial production, fully characterizing structural and functional phenotypes of the iPSC-CM plates after thaw, identifying a set of key physiological metrics that will be used for quality control, and designing and building ancillary hardware devices that will allow optimal reproducibility at the customer site during the thawing process.

项目摘要/摘要