RNA editing of pathogenic variants causing inherited retinal diseases using endogenous ADAR-current and future...

Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous group of disorders affecting millions worldwide, with limited therapeutic options for the majority of patients. Recent advances in RNA editing-particularly adenosine-to-inosine (A-to-I) editing mediated by adenosine deaminases acting on RNA (ADAR)- offer a promising approach for correcting pathogenic variants at the RNA level without altering the genome. This review presents a comprehensive overview of the molecular basis of ADAR-mediated RNA editing, its natural occurrence in retinal tissues, and the growing array of strategies that harness endogenous ADAR enzymes for site-directed RNA editing (SDRE). We discuss design principles and optimization strategies for guide RNAs (gRNAs), including linear, circular, and chemically modified formats such as LEAPER, RESTORE, CLUSTER, CadRNAs, and AIMers. Additionally, we explore high-throughput screening systems for guide selection, cellular models for assessing RNA editing efficiency, and current in vitro and in vivo approaches targeting IRD pathogenic variants. Finally, we highlight the translational potential of endogenous and exogenous ADAR-based RNA editing, emphasizing its relevance as a precision medicine strategy for IRDs and beyond.