Adenine base editing with engineered virus-like particles rescues the CFTR mutation G542X in patient-derived intestinal organoids

• DOI: 10.1016/j.isci.2025.111979
• Publication Date: 2025-02-21T08:30:27Z
• Authors: Lucia Nicosia; Iwona Pranke; Roberta V. Latorre; Joss B. Murray; Lisa Lonetti; Kader Cavusoglu-D...; Elise Dreano; James P. Costello; Michael Carroll; Paola Melotti; Claudio Sorio; Isabelle Sermet-G...; Martina F. Scallan; Patrick T. Harrison
• Keywords: Science; Cellular therapy; Genetic engineering; Q; cystic fibrosis, base editing, gene therapy, nasal cells, intestinal organoids, CFTR; Health sciences; Clinical genetics

Summary: Cystic fibrosis (CF) is a life-shortening autosomal recessive disease, caused by loss-of-function mutations that affect the CF transmembrane conductance regulator (CFTR) anion channel. G542X is the second-most common CF-causing variant, and it does not respond to current CFTR modulator drugs. Our study explores the use of adenine base editing to edit G542X to a non-CF-causing variant, G542R, and recover CFTR function. Using base editor engineered virus-like particles (BE-eVLPs) in patient-derived intestinal organoids, we achieved ∼2% G542X-to-G542R editing efficiency and restored CFTR-mediated chloride transport to ∼6.4% of wild-type levels, independent of modulator treatment, and with no bystander edits. This proof-of-principle study demonstrates the potential of base editing to rescue G542X and provides a foundation for future in-vivo applications.