Rethinking nonsense suppression therapies in inherited retinal diseases

Nonsense mutations account for approximately 20% of pathogenic variants in inherited retinal diseases (IRDs). With advances in gene therapy, nucleic acid-based nonsense suppression strategies, including suppressor tRNAs, RNA pseudouridylation, and adenosine-to-inosine RNA editing, have demonstrated therapeutic potential in preclinical studies. These next-generation approaches offer substantial opportunities for engineering and optimization, with the potential to enable precise and efficient restoration of full-length functional proteins. In this review, we propose that IRDs represent an attractive group of diseases for the clinical translation of these next-generation therapies owing to their high burden of nonsense mutations and the unique advantages of ocular gene therapy. We further outline key strategies to accelerate clinical translation, spanning therapeutic engineering, preclinical validation, and mutation-guided clinical trial design.