Off-target messenger RNAs with partial complementarity

Off-target messenger RNAs (mRNAs) with partial complementarity are unintended transcripts that are silenced or regulated by oligonucleotide-based drugs, such as small interfering RNAs (siRNAs) or antisense oligonucleotides (ASOs) (Setten et al., 2019, Nature Reviews Drug Discovery). This phenomenon occurs when the drug sequence binds to an mRNA that shares partial sequence homology, particularly within the 5' seed region (nucleotides 2-8) of an siRNA, mimicking the natural mechanism of microRNAs (miRNAs) (Birmingham et al., 2006, Nature Methods). Such interactions can lead to the degradation of the off-target mRNA or the inhibition of its translation, potentially resulting in cellular toxicity or clinical adverse effects (Jackson et al., 2003, Nature Biotechnology). In the context of drug development, these off-targets are considered a major safety hurdle rather than a therapeutic goal. Minimizing these effects is a primary focus of medicinal chemistry, often involving chemical modifications like 2'-O-methyl or locked nucleic acids to increase specificity (Khvorova & Watts, 2017, Nature Biotechnology). Rigorous bioinformatic screening and in vitro transcriptomic assays are standard practices used to identify and eliminate sequences with high off-target potential.

Other names

Seed-mediated off-targetsUnintended mRNA targetsmiRNA-like off-target effectsNon-specific mRNA hybridizationRNAi off-targets

Unintended hybridization of oligonucleotide drugs to non-target transcripts, primarily mediated by seed-region complementarity, leading to RISC-mediated cleavage or translational repression (Jackson et al., 2003, Nature Biotechnology).