Other partially complementary cellular mRNAs

Other partially complementary cellular mRNAs refers to the broad set of endogenous messenger RNA transcripts that share partial sequence homology with a therapeutic oligonucleotide (Jackson & Linsley, 2010, Nature Reviews Drug Discovery). These molecules are not the intended targets of therapy but can be inadvertently bound by drugs such as small interfering RNAs (siRNAs) or antisense oligonucleotides (ASOs) (Corey, 2007, Chemical Biology & Drug Design). Such interactions typically occur through seed region complementarity or partial hybridization, leading to unintended gene silencing via the RNA-induced silencing complex (RISC) or RNase H-mediated degradation (Birmingham et al., 2006, Nature Methods). This process is the primary mechanism behind sequence-dependent off-target effects, which can result in cellular toxicity or the disruption of non-target biological pathways (FDA, 2018, Onpattro Prescribing Information). In the context of drug development, these mRNAs represent a significant safety challenge that must be addressed through rigorous bioinformatic screening and chemical modification of the drug candidate. Therefore, they are considered off-target liabilities rather than therapeutic receptors or enzymes. Understanding the landscape of these partially complementary transcripts is essential for predicting the safety profile and therapeutic index of RNA-based medicines.

Other names

Off-target transcriptsNon-target mRNAsPartially matched cellular RNAsOff-target cellular mRNAs

Unintended sequence-specific hybridization leading to RNA-induced silencing complex (RISC) mediated cleavage or RNase H1-mediated degradation of non-target transcripts.