Applications

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High-throughput Screening

Drug failure in the clinic is most often attributed to either unforeseen toxicity or a lack of demonstrated efficacy.

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High-throughput Screening

Discovery

Drug failure in the clinic is most often attributed to either unforeseen toxicity or a lack of demonstrated efficacy. Thus, predictive in vitro models that more accurately reflect in vivo disease states can inform the preclinical processes of drug discovery and development ensuring higher success rate in the eventual clinical setting. CDI’s iCell and MyCell products offer a wide range of innate, engineered, and induced disease models for screening, hit-to-lead, and lead optimization efforts. The cells are amenable to gene modulation and culture in high-density multiwell plates. iCell and MyCell products have been used in high-throughput screens across various disease areas including infectious disease, neurological disorders, diabetes, and cardiomyopathies.

Modeling Hepatitis Infection

Hepatitis infection mediated by HCV and HBV is a common cause of liver disease and failure.

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Modeling Hepatitis Infection

Discovery, Disease Modeling

Hepatitis infection mediated by HCV and HBV is a common cause of liver disease and failure. Developing effective therapies for hepatitis has been limited due to the lack of physiologically relevant human disease models. CDI’s hepatocytes express hepatitis receptors (SR-B1, CD91, occludin, claudin-1), which support uptake and replication of clinically relevant hepatitis virus genotypes. These hepatocytes are being used in large-scale screens for novel therapeutic candidates. CDI offers hepatocytes from multiple donors including one with an IFNL4 function that does not readily clear HCV infection.

Measuring Drug Metabolism

Drug metabolism is a key function of the human liver and is largely accomplished via the activity of P450 cytochromes and other enzymes within hepatocytes.

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Measuring Drug Metabolism

Toxicity

Drug metabolism is a key function of the human liver and is largely accomplished via the activity of P450 cytochromes and other enzymes within hepatocytes. Understanding drug metabolism pathways is critical to defining the availability of therapeutic agents and identifying toxic metabolites. CDI’s hepatocytes exhibit P450 activity that is sustained for over 7 days in culture. In addition, functional P450 induction in response to known inducers has been demonstrated.

  1. P450-Glo Assays. Promega Technical Bulletin.

Monitoring Hepatotoxicity

Unforeseen liver toxicity is a primary mode of clinical failure for drugs in development.

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Monitoring Hepatotoxicity

Toxicity

Unforeseen liver toxicity is a primary mode of clinical failure for drugs in development. The long-term stability of CDI’s hepatocytes in culture affords the opportunity to perform repeat dosing at physiologically relevant concentrations to aid in the identification of drug toxicity. Specific mechanisms of hepatotoxicity, such as cell viability, mitochondrial toxicity, and phospholipidosis, can be measured using platforms including:

  1. Sirenko O, Hesley J, et al. (2014) High-content Assays for Hepatotoxicity Using Induced Pluripotent Stem Cell-derived Cells. Assay Drug Dev Technol 12(1):43-54.
  2. Berger DR, Ware BR, et al. (2014) Enhancing the Functional Maturity of iPSC-derived Human Hepatocytes via Controlled Presentation of Cell-Cell Interactions In Vitro. Hepatology 61(4):1370-81.
  3. Einhorn S, Lu J, et al. (2013) Detection of Xenobiotic-induced Hepatotoxicity in Human iPSC-derived Hepatocytes. Poster Presentation, ISSX.
  4. Lu J, Metushi I, et al. (2013) Investigation of Isoniazid DILI Mechanisms in Human Induced Pluripotent Stem Cell Derived Hepatocytes. Poster Presentation, ISSX.
  5. Einhorn S, Salvagiotto G, et al. (2013) Characterization and Function of iPSC derived Hepatocytes for Use in Toxicity. Poster Presentation, SOT.
  6. Mann DA. (2014) Human Induced Pluripotent Stem Cell-derived Hepatocytes for Toxicology Testing. Exp Opin Drug Metab & Toxicol 11(1):1-5.

Genetic Manipulation of Hepatocytes

The ability to interrogate and monitor gene expression is critical to understanding biological pathways that underlie normal and pathogenic cellular function.

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Genetic Manipulation of Hepatocytes

Discovery, Regenerative Medicine, Toxicity

The ability to interrogate and monitor gene expression is critical to understanding biological pathways that underlie normal and pathogenic cellular function. CDI has evaluated various genetic manipulation tools to enable the development of assays using its hepatocytes.

Advanced Hepatocyte Cell Culture

Advanced cell culture techniques including 3D spheroids, micropatterned co-culture, bioengineered and flow-based systems, and bioprinting offer the potential to better mimic in vivo tissue structure and function.

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Advanced Hepatocyte Cell Culture

Discovery, Regenerative Medicine, Toxicity

Advanced cell culture techniques including 3D spheroids, micropatterned co-culture, bioengineered and flow-based systems, and bioprinting offer the potential to better mimic in vivo tissue structure and function. CDI’s hepatocytes are amenable to these culture techniques as pure cell populations or in co-culture with other CDI cell types.

3D Spheroid Cell Culture

3D spheroid culture of iCell Hepatocytes 2.0 for enhanced functional maturity and prolonged culturability.

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3D Spheroid Cell Culture

Discovery, Regenerative Medicine, Toxicity

Moving beyond traditional static-plated culture yields a more liver-like environment for hepatocyte assays and generates more predictive biology in vitro. The combination of iPSC technology with advanced culture techniques offers advantages over existing models.  Conditions developed allow for a tunable spheroid size with maintenance of viability and put the control over engineered tissue in the hands of the user. This novel workflow allows for the generation of iCell® Hepatocytes 2.0 microtissues in low-attachment plates.