Five Reasons to Implement In Vitro Phenotypic Screening in Preclinical Safety
Reason 1 – Animals Aren’t Predictive of Humans
Rodents, in particular, are small, do not live long, and are typically housed in clean facilities. Mechanisms regulating hemostasis, DNA repair, and the immune system are different in rodents than in humans.
More reading on why animals are not predictive of humans
- Of Mice and Not Men: Differences between Mouse and Human Immunology
- Genomic responses in mouse models poorly mimic human inflammatory diseases
- A Pragmatic Comparison of Human In Vitro with Animal In Vivo Approaches to Predicting Toxicity in Human Medicines
- Comparison of the transcriptional landscapes between human and mouse tissue
Reason 2 – Few Toxicity Targets Are Known
Despite the availability of large panels of safety pharmacology assays, 20-30% of drugs fail in clinical testing due to safety issues. In many cases, the toxicity mechanisms underlying these problems are never known. There is pressure within pharmaceutical organizations to move on from failed programs, redirect scarce resources to active projects, and forgo the potential learnings from these safety failures.
Reason 3 – In Vitro Culture Methods Have Advanced
Human cells are available and can be run reproducibly in miniaturized high throughput formats. Automated methods and technology developments (often showcased by SLAS and ELRIG), have been driving these advances over the past 10 years and are highlighted in the Journal of Biomolecular Screening and the Journal of Laboratory Automation special issues here, here, and here.
Reason 4 – Phenotypic Drug Discovery Has Evolved
Phenotypic assays are no longer the black boxes that they once were. Omics and other profiling technologies have been applied to create large datasets of genetic and/or chemical perturbations. Indeed, large chemical biology datasets, suitable for data mining, are becoming available from the NIH and the EPA. Using network biology tools, the analysis of these datasets is revealing the inner workings of cell signaling networks.
Reason 5 – Phenotypic Assays Uncover New Mechanisms of Toxicity
Phenotypic assays are target agnostic and can detect the activities of multiple targets along a pathway, as well as the activities of pathway networks. Connecting multiple targets to the same clinical outcome improves our understanding of complex disease biology (see here for example). This information also contributes to the construction of adverse outcome pathways. In toxicity testing, adverse outcome pathways (AOPs) help us organize our knowledge in a framework that can be applied for risk assessment.
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