Iterative Engineering And Optimization Strategies For Maximizing LNP-Mediated Gene Editing In The Liver

Achieving high editing efficiency in the liver requires coordinating optimization across multiple variables simultaneously: mRNA modification chemistry, guide RNA design, LNP formulation, and editor selection. In this ASGCT 2026 presentation, K. Tyler McCullough, Associate Director of Translational Biology, details how iterative murine studies using HAO1 and PCSK9 as model targets generated a compounding series of potency gains, with specific mRNA and guide RNA modifications producing two- to three-fold improvements.

Crucially, optimizations identified in nuclease experiments translated directly across editing modalities, including RT editing and adenine base editing, shortening the path to NHP-ready formulations. In NHP, LNP1-delivered A-base editing achieved greater than 50% target protein reduction with a favorable liver enzyme profile compared to an industry peer at the same dose. Platform-level feedforward, connecting protein engineering, RNA chemistry, and in vivo results, then accelerated selection of next-generation editor variants with demonstrated 2-fold in vitro potency improvements.

Explore the full presentation to learn more.