Overview

• A genome-wide CRISPR/Cas9 screen identified AP1M1 and other trafficking genes that regulate endosome-to-lysosome transport of antisense oligonucleotides (ASOs).
• Knockout of AP1M1 in cell cultures and mouse models prolonged ASO residence in endosomes and significantly boosted target RNA suppression without increasing dosage.
• This strategy addresses a key delivery barrier that limits the efficacy of ASO treatments for disorders such as ALS and Duchenne muscular dystrophy.
• Following in vitro and in vivo validation, researchers are extending the approach to optimize delivery for a wider array of RNA-based therapeutics.
• Investigators are evaluating whether modulating endosomal transport can also hinder bacterial and viral escape, pointing to potential anti-pathogen applications.