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The current drug discovery process is inefficient, with a significant number of drugs halting clinical trials, pending more investigational work to understand causality, or failing due to unforeseen toxicity. These unexpected outcomes stem from limitations in existing testing methods. Traditional in vitro assays lack physiological complexity, while animal models often fail to accurately reflect human responses, potentially misclassifying drugs due to their interspecies differences. Organ-on-a-chip (OOC) technology offers a complementary solution to plug the gaps by providing a more physiologically relevant platform for drug safety assessment.
Understanding Mechanistic Toxicity Is Key
High failure rates (30% due to toxicity) in clinical trials translate into wasted resources and missed opportunities for potentially life-saving drugs. OOC models are specifically designed to address the challenge of minimizing drug attrition due to toxicity. They more accurately mimic human organs, offering a more sensitive platform for the early identification of potential toxicity issues. Furthermore, some OOC technologies shed light on the underlying mechanisms of toxicity by delivering a plethora of endpoints, including clinically relevant biomarkers, to aid data translatability. This deeper understanding empowers scientists to address potential problems early, saving time, money, and resources while increasing the success rate of drug development.
OOC Technology Offers Advantages for Specific Challenges
OOC models excel at assessing drug-induced liver injury (DILI), which contributes to about 18% of drug failures due to safety concerns. There are three main types of DILI: intrinsic, indirect, and idiosyncratic. Generally, intrinsic DILI risk can be weeded out using the standard battery of in vitro tests. However, the latter two require advanced assays that are more human-relevant, long-lived, highly functional, and metabolically active.
The PhysioMimix® OOC range of microphysiological systems is well-equipped for the job. The platform utilizes PDMS-free multichip plates to minimize the nonspecific absorption of drugs, or secreted cellular biomarkers, from the cell culture media for accurate predictions and higher throughput studies. The Liver-on-a-chip model combines primary human hepatocytes (PHH) and Kupffer cells (KCs) to represent the organ’s innate immune system, and form microtissues within a perfused 3D collagen-coated scaffold. When used in the PhysioMimix DILI assay, hepatocytes express highly functional CYPs that facilitate the production of toxic phase I and II metabolites, human-specific transporters to identify transporter-mediated toxicity, and bile acid machinery to detect cholestatic injury. The assay provides large amounts of recoverable material (media and tissue) for in-depth analysis of biotransformation and mechanisms of toxicity. Glutathione (GSH) highlights reactive metabolite toxicity/mitochondrial perturbation, in addition to other clinically relevant endpoint measurements such as albumin, urea, ATP, ALT/AST, and miR122. The cell number and medium volume are optimized to allow RNAseq and -omics analysis from a single well to derive even more insight from each replicate. Scaffolds are recoverable and amenable to confocal imaging for visual confirmation of results using immunofluorescent labeling.
OOC models are also well suited for testing new drug modalities with human-specific mechanisms of action, a growing area of pharmaceutical research. Traditional testing methods are limited in their ability to predict human immune system activation. To capture a more complete picture of a drug’s safety profile, OOC models can be adapted to incorporate key immune system elements.
OOC as a Complementary Approach
OOC technology is not a replacement for existing methods but a complementary tool. Each preclinical test has limitations, and OOC models are most effective when used alongside other tests. OOC data informs animal studies, leading to a more refined and efficient testing process with reduced animal use. This complementary approach offers significant advantages for integrated toxicology workflows.
The Time to Act Is Now
The high cost and complexity of drug discovery are unsustainable. OOC technology presents a path forward for a more efficient and successful process. Early adoption of OOC models provides a competitive edge, and regulatory bodies are increasingly recognizing the value of OOC data. Embracing this technology signifies a commitment to a future of safer and more effective medications.
Read the full article for a more comprehensive overview at https://bit.ly/3JhIDXJ.
