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Going predictive with in-vitro assays
RESEARCH TRIANGLE PARK, N.C.—In a collaboration that is expected by its partners to “accelerate innovative toxicity testing research,” The Hamner Institutes for Health Sciences and Madison, Wis.-based Cellular Dynamics International (CDI) recently announced an agreement under which they will develop predictive in-vitro screening assays for pharmaceutical toxicology, chemical and environmental assessments that utilize CDI’s human induced pluripotent stem (iPS) cell-derived hepatocytes.
As the two organizations note, in-vitro models of liver function traditionally have employed immortalized cell lines, animal models and primary tissue isolates extracted from human cadavers—model systems that each present limitations in functionality, reproducibility, translatability and availability.
Human iPS cell-derived hepatocytes reportedly hold the promise of providing a consistent, reproducible and limitless source of liver tissue that better reflects native liver function and therefore may be a significant improvement over existing in-vitro models. Moreover, it is expected that conducting toxicity testing schemes in vitro using human iPS cell-derived hepatocytes will speed testing of important compounds already on the market in addition to compounds being developed or just coming into use.
“More rapid testing will also help assess the backlog of thousands of chemicals for which there is very limited toxicity test data,” the partners note. “As these test technologies mature, they could also provide a means to speed drug discovery by providing assessments of safety far earlier in the drug development process.”
Focusing in on these points about reproducibility, availability and acceleration of testing, Scimitar Equity’s Regenerative Medicine Investors made a “hold” recommendation in December regarding CDI stock, noting that this “is a long-term project—so don’t expect any short- or near-term milestones.”
As part of the collaboration, CDI will provide iCell Hepatocytes to The Hamner for use in an ongoing program of research called “Toxicity Testing in the 21st Century: Toxicity Pathways and Network Biology.” This program employs several prototypical toxicity pathway case studies to develop human cell-based assays that map and model key cell signaling pathways in order to evaluate dose response. These assays, once validated with prototype chemicals, would theoretically enable toxicity testing and risk assessments based solely on in-vitro test results, without progressing to toxicity studies in intact animals.
The Hamner toxicity pathway research program is a precompetitive, multiorganization partnership designed to advance an integrated systems biology approach to toxicity testing research. Partners sponsoring the research include a number of large companies, among them Agilent Technologies Inc. and Illumina. The Long-Range Research Initiative of the American Chemistry Council supported earlier stages of this research. CDI will join this consortium and will collaborate with Hamner scientists on technical aspects of assay development.
According to Dr. Melvin Andersen, project director at The Hamner, “The Hamner’s multi-stakeholder toxicity testing program needs a variety of normal cell types for studying chemical toxicity in human cells. New iPS-cell technologies, spearheaded by CDI, promise to make many stem cell-derived products available to transform in-vitro testing. We are particularly enthusiastic about the use of iCell Hepatocytes to create models of liver toxicity and for evaluating pathways of metabolism. More broadly, stem cell products enhance work on the whole suite of pathways of interest to our diverse partners. As other stem cell platforms develop, we can connect them sequentially and examine multiday treatment for many tissues with realistic exposures. These iCell Hepatocytes and other emerging stem cell-based products provide great value for safety assessments for all our partners.”
Expressing his pleasure over working with The Hamner and its consortium, Chris Parker, chief commercial officer of CDI, looks forward to working “toward better predictivity of human response to chemical compounds,” saying that current models can miss toxicities that sometimes only manifest themselves in a human cell model as well as falsely misidentify toxicities in compounds that are actually safe. “Published studies have shown numerous examples of our human iPS cell-derived iCell products to be more predictive than comparison current cell models. Through this collaboration we hope to further improve the safety of chemical compounds as well as the efficiency of research studies.”
The Hamner Institutes for Health Sciences is a nonprofit translational biomedical research institute that works on drug and chemical safety in collaboration with academic, corporate and government partners. Novel technologies used at The Hamner include genomic and bioinformatic approaches for improving toxicity testing, in-silico models for predictive toxicology, in-vitro models that utilize human cells or cell lines to evaluate perturbations of cellular responses and in-vivo models to elucidate genes that play a role in susceptibility to drug-induced toxicities.
CDI is a leading developer of induced pluripotent stem cell technologies for in-vitro drug development, stem cell banking and in-vivo cellular therapeutic research. CDI harnesses its unique manufacturing technology to produce differentiated tissue cells in industrial quality, quantity and purity from any individual’s induced pluripotent stem cell line created from a standard blood draw.