Other messenger RNAs (mRNAs) with partial or near-perfect complementarity

The term "Other messenger RNAs (mRNAs) with partial or near-perfect complementarity" refers to the collective group of non-target transcripts that may be inadvertently silenced by sequence-specific RNA therapeutics, such as small interfering RNAs (siRNAs) or antisense oligonucleotides (ASOs). While these drugs are engineered for high specificity toward a primary disease-associated transcript, sequence homology in other genes can lead to unintended binding and subsequent gene silencing. Near-perfect complementarity typically triggers endonucleolytic cleavage of the mRNA via the RNA-induced silencing complex (RISC) or RNase H, whereas partial complementarity—often involving the "seed region" of the oligonucleotide—can result in translational repression or mRNA destabilization (Jackson et al., 2003, Nature Biotechnology). This phenomenon is a significant hurdle in drug development, as off-target effects can lead to cellular toxicity, altered metabolic pathways, or other adverse clinical outcomes (Setten et al., 2019, Nature Reviews Drug Discovery). Consequently, rigorous bioinformatic screening and chemical modifications, such as 2-O-methyl or 2-fluoro substitutions, are employed during lead optimization to minimize these interactions and enhance the safety profile of RNA-based medicines (Birmingham et al., 2006, Nature Methods). Understanding these interactions is crucial for interpreting the safety data of approved RNAi drugs like Patisiran and Givosiran, which list this mechanism as a potential source of off-target effects in their prescribing information (FDA, 2018).

Other names

Off-target mRNAsUnintended mRNA targetsCross-reactive transcriptsPartial complementarity transcripts

RNA interference (RNAi) mediated by the RNA-induced silencing complex (RISC), leading to mRNA cleavage or translational repression (Jackson et al., 2003; Setten et al., 2019).