Ultraminiaturized microfluidics-based drug toxicity screening platform using iPSC

使用 iPSC 的超小型基于微流体的药物毒性筛选平台

基本信息

批准号：
8619264
负责人：
Yoon Young Jang
金额：
$ 22.49万
依托单位：
EUVEDA BIOSCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-03 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8619264
关键词：
Address Adoption Adverse effects Adverse event Biological Biological Assay Cell Count Cell Culture Techniques Cell Line Cell model Cells Clinical Trials Complex Cytochrome P450 Detection Drug Industry Drug toxicity Ensure Enzymes Evaluation Failure Genetic Gold Government Hepatocyte Hepatotoxicity Human In Vitro Libraries Liquid substance Liver Measures Metabolic Methods Microfluidics Miniaturization Modeling Outcome Pathway interactions Patients Persons Pharmaceutical Preparations Pharmacologic Substance Phase Population Preclinical Drug Development Preclinical Drug Evaluation Price Primary carcinoma of the liver cells Process Protocols documentation Reagent Research Personnel Risk Assessment Safety Sampling Small Business Innovation Research Grant Solutions Source Stem cells System Technology Testing Time Validation Withdrawal Xenobiotic Metabolism base cell type compound 30 cost cost effectiveness design drug discovery enzyme activity high throughput screening improved in vivo induced pluripotent stem cell innovation miniaturize novel pre-clinical public health relevance response screening success

项目摘要

DESCRIPTION (provided by applicant): Hepatotoxicity is a leading cause of drug adverse events and clinical trial failure. The current gold standard for preclinical detection of hepatotoxicity involves assaying primary hepatocytes, but the inability to obtain large samples of such cells and resulting concerns about batch-to-batch variability limit their use in drug screening. In comparison, induced pluripotent stem cells (iPSCs) can in principle provide a replenish able supply of hepatocytes, which would enable extensive screening on a single stem cell line or across cell lines to evaluate patient-specific responses. However, it is expensive and time-consuming to grow stem cells or their progeny, thus as with cell-based assays in general, successful application of these cells for high-throughput drug screening requires miniaturization. Miniaturization reduces the number of cells required thereby increasing throughput per batch of differentiated hepatocytes, and it also decreases costs through reduced usage of expensive reagents. To address this issue, Euveda Biosciences has developed a novel cell-based assay platform based on microfluidic technology that reduces assay sample volumes by orders of magnitude compared to multiwell plates while improving fluid handling accuracy. In this Phase I project, we will combine the advantages of iPSC-derived cells and our miniaturized cell-based assay technology to create a more predictive, high-throughput hepatotoxicity screening platform. Successful completion of this project would demonstrate proof-of-principle that iPSC-derived hepatocytes maintain their viability and functionality in our microfluidic chip and display relevant drug responses. We envision a subsequent Phase II project primarily focused on validating a large set of iPSC-derived hepatocyte cell lines with representative genetic backgrounds for use in the platform, which would enable drug response variability in the human population to be modeled. Together, the chips and cells would be an attractive product to academic and industry pharmaceutical researchers that can dramatically improve the safety profile of compounds advanced to clinical trials.

描述（由申请人提供）：肝毒性是药物不良事件和临床试验失败的主要原因。当前用于肝毒性临床前检测的黄金标准涉及分析原发性肝细胞，但无法获得此类细胞的大样本，并引起人们对批处理变异性的担忧，限制了它们在药物筛查中的使用。相比之下，诱导的多能干细胞（IPSC）原则上可以提供能够补充的肝细胞供应，这将在单个干细胞系或跨细胞系上进行广泛的筛查以评估患者特异性反应。但是，它很昂贵，耗时的生长干细胞或其后代，因此与一般基于细胞的测定一样，这些细胞在高通量药物筛查中的成功应用需要微型化。小型化可以减少所需的细胞数量，从而增加每批分化的肝细胞的吞吐量，并且还通过减少昂贵试剂的使用来降低成本。为了解决这个问题，Euveda Biosciences开发了一种基于微流体技术的基于细胞的新型测定平台，该平台与多层板相比，通过数量级来减少测定样品量，同时提高流体处理精度。在此I阶段项目中，我们将结合IPSC衍生的细胞的优势和我们的小型细胞测定技术，以创建一个更具预测性，高通量的肝毒性筛选平台。该项目的成功完成将证明原理证明IPSC衍生的肝细胞保持其在微流体芯片中的生存能力和功能相关药物反应。我们设想了一个随后的II期项目，主要致力于验证一大批具有代表性遗传背景的IPSC衍生的肝细胞细胞系用于该平台，这将使人群的药物反应变异性能够建模。芯片和细胞一起将是学术和行业制药研究人员的有吸引力的产品，这些产品可以大大提高临床试验的化合物的安全性。