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Dec 1, 2011 (Vol. 31, No. 21)

Emerging Trends for Predictive Toxicology

Novel Models Help Illuminate Safety Issues with Preclinical Drug Candidates

  • Stem Cells

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    A specialized “hanging droplet” culture plate developed by Roche allows for the generation of stem cell-derived 3-D spheroids compatible with standard laboratory robotics.

    “Chimeric mice and in vitro models complement each other in ADME/tox studies,” commented Claudia McGinnis, Ph.D., group head, NCS early and investigative toxicology at Roche. “In vitro models are essential for screening and valuable for early toxicity predictions. The key, however, is to reproduce the properties of human tissue in a complete environment to get meaningful results.”

    Roche collaborates with a number of academic research centers and start-up companies to develop models closely resembling hepatic tissues and maintain the classical hepatocyte characteristics enabling in-depth mechanistic studies.

    One such model Roche is using is from RegeneMed and contains three-dimensional interweaving nanofiber scaffolds for co-culturing liver-derived stromal cells and hepatocytes. Other 3-D systems developed by MIT and CellASIC add flow-through capabilities that may further aid hepatocyte functionality.

    “Primary hepatic cells have limited survival, reduced functionality, and high donor-to-donor variability,” continued Dr. McGinnis. “Sometimes the donors of these cells had significant health issues. The assays with primary cells are hard to standardize. Therefore, many scientists believe that deriving hepatocytes and other tissues from embryonic or adult stem cells is the way of the future. In addition to being a more available, standardized resource, SC-derived hepatocytes can also be genetically customized or be patient-specific.”

    Roche scientists have been successful in applying stem-cell based assays in the area of toxicology and developing customized strategies to aid this field. Roche has developed a stem-cell derived human cardiomyocyte assay that is highly predictive of arrhythmia.

    In addition, Roche scientists have developed a specialized “hanging droplet” culture plate that allows for the generation of stem cell-derived 3-D spheroids compatible with standard laboratory robotics, which allows full automation of a previously labor intensive manual process. Roche plans to utilize the plate in high-throughput miniaturized assays to predict for teratogenicity liabilities and other endpoints.

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