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.

Public Health Relevance

Induced pluripotent stem cells (iPSCs) can in principle provide a fair amount of liver cells that can be used to determine whether a drug is harmful to the liver. Although these stem cells are very attractive to researchers evaluating potential new drugs, their adoption is hindered by the costly culture process. It thus requires miniaturized and reliable assays that can increase the throughput and decrease the cost of drug screening campaigns. We have developed an innovative and general platform for assaying cells that is significantly smaller and more reliable than the current alternatives. As part of this SBIR Phase I project, we propose to apply this platform to enable drug toxicity screening on liver cells derived from these stem cells, which will help improve drug safety.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
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Special Emphasis Panel (ZES1-SET-J (SB))
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Shaughnessy, Daniel
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Euveda Biosciences, Inc.
Ellicott City
United States
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Chaudhari, Pooja; Prasad, Neha; Tian, Lipeng et al. (2016) Determination of Functional Activity of Human iPSC-Derived Hepatocytes by Measurement of CYP Metabolism. Methods Mol Biol 1357:383-94
Tian, Lipeng; Prasad, Neha; Jang, Yoon-Young (2016) In Vitro Modeling of Alcohol-Induced Liver Injury Using Human-Induced Pluripotent Stem Cells. Methods Mol Biol 1353:271-83
Chaudhari, Pooja; Tian, Lipeng; Deshmukh, Abhijeet et al. (2016) Expression kinetics of hepatic progenitor markers in cellular models of human liver development recapitulating hepatocyte and biliary cell fate commitment. Exp Biol Med (Maywood) 241:1653-62
Tian, Lipeng; Deshmukh, Abhijeet; Ye, Zhaohui et al. (2016) Efficient and Controlled Generation of 2D and 3D Bile Duct Tissue from Human Pluripotent Stem Cell-Derived Spheroids. Stem Cell Rev 12:500-8