Antisense oligonucleotides for inherited retinal diseases: a comprehensive review

Abstract

Inherited retinal diseases (IRDs) are a genetically and clinically heterogeneous group of disorders that cause progressive vision loss and often lead to blindness. The complexity of these conditions arises from pathogenic variants in over 330 different genes, making the development of effective treatments highly challenging. Antisense oligonucleotides (ASOs) have emerged as a promising therapeutic approach for IRDs, offering precise regulation of transcript expression and composition. Unlike traditional gene augmentation therapies, ASOs provide a flexible and sequence-specific strategy by modulating splicing patterns, blocking translation, or promoting RNA degradation. Advancements in ASO chemistry, including backbone and sugar modifications, have significantly improved their uptake, stability, specificity, and therapeutic efficacy, facilitating their application in a variety of diseases. This review provides a comprehensive analysis of ASO-based strategies for IRDs, touching upon their mechanisms of action, chemical modifications, delivery strategies, and current clinical advancements. Additionally, we discuss the challenges that remain, such as off-target effects, delivery barriers, and long-term safety concerns, while highlighting future innovations that may enhance the efficacy and safety of ASOs and broaden their clinical applicability. As ASO-based therapies continue to progress through preclinical and clinical development, they hold significant potential to reshape the therapeutic landscape for IRDs, offering personalized and targeted treatments for patients with these devastating conditions.