The complexities of oligonucleotide therapeutics: analytical challenges and opportunities within early drug discovery

Oligonucleotide therapeutics, primarily represented by single-stranded antisense oligonucleotides (ASOs) and double-stranded small interfering RNAs (siRNAs), is an attractive modality in modern medicine. It expands the range of drug targets to include otherwise untargetable transcripts, enabling precise gene modulation [1] with minimized off-target effects [1,2]. In addition, its drug development process is more efficient compared to traditional small molecules and monoclonal antibody therapies [1,3]. Currently, the modality boasts 21 marketed therapies (including 11 ASOs, 8 siRNAs, and 2 aptamers) [4,5], with expectations for substantial growth in the near future. There are now over a thousand oligonucleotide programs in development, including more than 200 drug candidates advancing through phases I to III of clinical trials [6,7].