Bridging the translational gap: humanized liver models as predictive tools for RNA therapeutic success

RNA therapeutics, particularly siRNAs, are advancing drug development, but traditional animal models often fail to predict human responses, leading to clinical trial failures. This article explores humanized liver chimeric mouse models, such as the PXB-mouse, as a solution to improve preclinical predictions of siRNA efficacy and safety. It highlights the limitations of conventional models and demonstrates, through case studies in viral hepatitis, metabolic disorders, and lipid regulation, how PXB-mice address challenges like off-target effects and therapeutic efficacy. These models offer a more human-relevant platform, potentially reducing late-stage failures and accelerating RNA therapeutic development. The PXB-mouse model features a liver that is highly engrafted with human hepatocytes, while other cell types remain of mouse origin—a factor to consider when assessing RNA therapeutics. Despite this limitation, humanized liver mice can provide greater confidence in the translational potential of investigational therapeutics than conventional animal models alone.