Ultraminiaturized microfluidics-based drug toxicity screening platform using iPSC

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。目前临床前检测肝毒性的金标准涉及测定原代肝细胞，但无法获得此类细胞的大样本以及由此产生的对批次间变异性的担忧限制了其在药物筛选中的应用。相比之下，诱导多能干细胞（iPSC）原则上可以提供可补充的肝细胞供应，这将使得能够对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。然而，它是昂贵的， 培养干细胞或它们的后代是耗时的，因此，与通常的基于细胞的测定一样，将这些细胞成功应用于高通量药物筛选需要小型化。小型化减少了所需的细胞数量，从而增加了每批分化肝细胞的通量，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新型细胞检测平台，与多孔板相比，该平台将检测样品体积减少了几个数量级，同时提高了流体处理的准确性。在这个I期项目中，我们将联合收割机结合iPSC衍生细胞的优势和我们基于微型化细胞的检测技术，打造一个更具预测性、高通量的肝毒性筛查平台。该项目的成功完成将证明iPSC衍生的肝细胞在我们的微流控芯片和显示器中保持其活力和功能性的原理证明 相关的药物反应。我们设想随后的II期项目主要集中在验证大量iPSC衍生的肝细胞系，这些细胞系具有代表性的遗传背景，可用于该平台，这将使人类群体中的药物反应变异性得以建模。总之，芯片和细胞将成为学术和工业制药研究人员的一个有吸引力的产品，可以显着提高进入临床试验的化合物的安全性。

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.