Expanding the toolbox: Emerging antisense oligonucleotide mechanisms for modulating gene expression

Decades of research have cemented antisense oligonucleotides (ASOs) as a cornerstone of molecular medicine. Advancements in synthesis and chemical modification, together with an improved understanding of the human genome and transcriptome, have enabled their emergence as highly specific and tailorable therapeutics across a wide variety of conditions. Although the greatest strength of ASOs lies in their nucleic acid composition that confers the theoretical ability to target any known genetic sequence, effective ASO design requires a holistic approach considering the molecular mechanism underlying the desired therapeutic outcome. Initially considered straightforward inhibitors of gene expression, ASOs have now evolved into versatile modulators capable of exploiting an increasingly diverse array of molecular processes. Despite this progress, their full therapeutic potential remains far from realized. Emerging research, driven by a deepening understanding of RNA biology, continues to expand the repertoire of mechanisms through which ASOs can modulate gene expression. Collectively, these studies demonstrate that ASOs can be designed to modulate numerous pre-mRNA processing events, including splicing, polyadenylation, microRNA activity, and translation initiation and termination, thereby broadening the range of conditions and patients that may benefit from ASO-based therapeutics.