Off-target messenger RNA (Off-target mRNA)

Off-target messenger RNA refers to the broad set of mRNA transcripts that are unintentionally targeted by oligonucleotide-based therapeutics, such as small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs) (Jackson & Linsley, 2010). These interactions occur when a drug sequence possesses sufficient complementarity to a non-target mRNA, leading to its degradation or translational inhibition (Fedorov et al., 2006). In the case of siRNAs, this is frequently driven by the 'seed region' (nucleotides 2-8), which can bind to 3' untranslated regions (UTRs) of unintended genes in a manner similar to microRNAs (Birmingham et al., 2006). Such off-target activity is a significant concern in drug development as it can lead to cellular toxicity, altered metabolic pathways, and adverse clinical side effects (Janas et al., 2018). Strategies to mitigate these effects include chemical modifications of the ribose sugar and careful bioinformatic screening during lead optimization (Bramsen & Kjems, 2012).

Other names

Unintended mRNA targetsOff-target transcriptsNon-specific mRNA bindingSeed-sequence-mediated off-targets

Unintended hybridization and degradation of non-target mRNA transcripts through partial sequence complementarity, often mediated by the RISC complex in the case of siRNAs or RNase H for ASOs (Jackson & Linsley, 2010; Fedorov et al., 2006).