Lipid nanoparticle screening in nonhuman primates with minimal loss of life

Abstract

Understanding how well delivery in mice predicts delivery in nonhuman primates (NHPs) could make lipid nanoparticle (LNP) discovery more efficient. Yet, few LNP-mRNA drug candidates are tested in NHPs, in part because the experiments require more animals than is considered ethical. Here, to minimize animal use, we create a pool of sterile barcoded LNPs that are frozen, aliquoted and administered when an end-of-life NHP—an animal that is independently scheduled for euthanasia due to spontaneous disease—becomes available. We then administer this pool of 45 LNP-aVHH mRNAs with different chemistries intravenously to mice and NHPs and observe a higher amount of aVHH expression in NHPs than in mice. We characterize systemic physiological responses to LNP treatment using 47 clinically relevant variables and analyze the transcriptomic response alongside delivery in single cells from three tissues in vivo. These data suggest that multiple lipoprotein receptors may be associated with delivery. Altogether, end-of-life NHPs reduce animal use and may be informative preclinical models.