Webinar Abstract
Featured session at Boston MPS Day, which took place on 11/1/2023.
In this presentation, Dr. Samantha Atkins from Moderna discusses the use of the Emulate human Liver-Chip to predict and understand toxicity mechanisms associated with lipid nanoparticle (LNP) and mRNA therapeutics. Traditional animal models, such as rodent studies, sometimes fail to predict adverse outcomes seen later in non-human primate (NHP) studies or clinical settings, particularly when novel LNP chemistries are involved. By leveraging the Emulate human Liver-Chip, Dr. Atkins aims to identify early signatures of fibrosis and other forms of liver damage, thereby guiding safer and more effective therapeutic design before proceeding to NHP studies.
Using the Liver-Chips, Dr. Atkins’ team demonstrated the ability to pinpoint gene signatures and collagen remodeling patterns corresponding to pro-fibrotic LNPs. This helps flag problematic compounds early, reducing reliance on costly and time-consuming animal studies. Moreover, the chips provided mechanistic insights into both LNP-driven and mRNA-mediated toxicity, revealing pathways such as necroptosis in certain constructs. Such mechanistic understanding helps tailor safer LNP formulations and mRNA constructs.
Key learnings from this presentation include:
- Human liver-on-a-chip systems can successfully model liver fibrosis and flag toxicity that might be missed by animal models.
- Early gene signatures identified on the chip correlate with adverse outcomes in NHP models, enabling preclinical down-selection of safer LNP candidates.
- The platform aids in distinguishing between LNP-induced versus mRNA-mediated toxicity, offering valuable mechanistic insights.
- Leveraging these in vitro models can save time and reduce costs associated with late-stage animal testing.
- Mechanistic understanding of cell death pathways (e.g., necroptosis) informs rational modifications to improve therapeutic safety profiles.