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

• 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
• 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

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.

说明(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。目前临床前肝毒性检测的金标准包括检测原代肝细胞，但无法获得大量此类细胞样本，以及由此产生的对批次之间变异性的担忧，限制了它们在药物筛选中的使用。相比之下，诱导多能干细胞(IPSCs)原则上可以提供可补充的肝细胞供应，这将使在单个干细胞系或跨细胞系进行广泛筛选以评估患者特异性反应成为可能。然而，它是昂贵的，而且 干细胞或其后代的培养非常耗时，因此，与一般的基于细胞的分析一样，成功地将这些细胞应用于高通量药物筛选需要微型化。小型化减少了所需的细胞数量，从而增加了每批分化的肝细胞的产量，并通过减少昂贵试剂的使用来降低成本。为了解决这一问题，欧维达生物科学公司开发了一种基于微流控技术的新型细胞化验平台，与多孔板相比，该平台将化验样本量减少了数量级，同时提高了流体处理精度。在这个第一阶段的项目中，我们将结合IPSC来源细胞的优势和我们基于细胞的微型化检测技术，创建一个更具预测性的、高通量的肝毒性筛查平台。该项目的成功完成将证明IPSC来源的肝细胞在我们的微流控芯片和显示器中保持其活性和功能 相关药物反应。我们设想随后的第二阶段项目主要专注于验证一大组具有代表性遗传背景的IPSC来源的肝细胞系用于该平台，这将使人类群体中的药物反应可变性得以建模。这些芯片和细胞加在一起，对学术和行业制药研究人员来说将是一个有吸引力的产品，可以显著改善进入临床试验的化合物的安全性。