Off-target messenger RNA (mRNA) (siRNA off-target)

Off-target mRNAs with partial complementarity to the siRNA guide strand represent a significant class of unintended molecular interactions in RNA interference (RNAi) therapy. These interactions occur when the siRNA guide strand binds to transcripts other than the intended therapeutic target, often driven by complementarity in the 'seed region' (nucleotides 2-8) of the siRNA (Birmingham et al., 2006, Nature Methods). This binding typically takes place in the 3' untranslated region (UTR) of the mRNA, mimicking the natural regulatory pathway of endogenous microRNAs (Jackson et al., 2003, Nature Biotechnology). Consequently, these off-target mRNAs may undergo degradation or translational repression, leading to the unintended downregulation of various proteins. In clinical drug development, such effects are a primary concern as they can lead to sequence-specific toxicity or unpredictable biological outcomes (Janas et al., 2018, Nature Communications). siRNA drugs like Patisiran and Inclisiran are carefully screened and chemically modified to minimize these interactions and ensure high specificity. Understanding and predicting these off-target profiles is essential for the safety assessment of all oligonucleotide-based therapeutics.

Other names

siRNA off-targetsSeed-mediated off-targetsmiRNA-like off-target effectsUnintended mRNA transcriptsOff-target mRNAs with partial complementarity to the siRNA guide strand

Unintended gene silencing via the RNA-induced silencing complex (RISC), where the siRNA guide strand binds to partially complementary sequences (primarily in the 3' UTR) of non-target mRNAs, leading to their degradation or translational inhibition (Jackson et al., 2003, Nature Biotechnology).