Advances in antisense technology for cardiovascular drug discovery: from gene silencing to therapeutics.
TL;DR
The principles that shape cardiovascular ASO candidate development are discussed, with emphasis on mechanism selection, chemical design, and exposure feasibility, and sequence optimization with exposure-informed target qualification and therapeutic-index engineering throughout ASO candidate selection.
Abstract
INTRODUCTION Cardiovascular diseases remain a major cause of morbidity and mortality, and many disease-relevant RNA mechanisms remain difficult to address with conventional therapeutic modalities. Antisense oligonucleotides (ASOs) provide a sequence-defined RNA-targeting modality to modulate transcript abundance, splicing, and regulatory RNA function. In cardiovascular drug discovery, however, target complementarity is only the starting point. Translational success requires early alignment between target biology, tissue exposure, and therapeutic index. AREAS COVERED Based on PubMed and Web of Science searches through June 2026, this review discusses the principles that shape cardiovascular ASO candidate development, with emphasis on mechanism selection, chemical design, and exposure feasibility. Selected examples from lipoprotein-related targets and transthyretin amyloidosis are used to illustrate why target compartment and pharmacodynamic evidence are central to translational decision-making. EXPERT OPINION The near-term impact of cardiovascular ASO therapeutics is likely to be strongest for targets in accessible compartments, particularly liver-derived mediators with clear links to cardiovascular pathology. Applications requiring direct engagement of cardiovascular tissues, including vascular and myocardial targets, will require evidence that target engagement can be achieved in the relevant cell populations at tolerable exposure levels. Future development should therefore integrate sequence optimization with exposure-informed target qualification and therapeutic-index engineering throughout ASO candidate selection.