Off-target human messenger RNAs (Off-target mRNAs)

Off-target human messenger RNAs (mRNAs) represent a broad category of unintended genetic transcripts that are inadvertently targeted by nucleic acid-based therapeutics, such as small interfering RNAs (siRNAs), antisense oligonucleotides (ASOs), and CRISPR-based systems (Jackson et al., 2003, Nature Biotechnology). These interactions occur when a therapeutic agent binds to an mRNA sequence with partial complementarity, leading to unintended gene silencing, degradation, or translational inhibition (Birmingham et al., 2006, Nature Methods). In drug discovery, these off-target effects are considered a significant liability rather than a therapeutic goal, as they can disrupt essential cellular processes and lead to toxicity (Fedisti et al., 2012, Drug Discovery Today). For instance, unintended knockdown of vital genes in the liver or central nervous system can result in severe adverse effects during clinical trials. Consequently, extensive bioinformatic screening and transcriptomic profiling are required to minimize these risks during the lead optimization phase of RNA-targeted drug development (Kulkarni et al., 2019, Nature Reviews Drug Discovery). Understanding and predicting these interactions is crucial for ensuring the safety and specificity of modern genomic medicines.

Other names

Off-target transcriptsUnintended mRNA targetsNon-specific mRNA bindingOff-target gene regulation

Unintended sequence-specific hybridization leading to mRNA degradation via RNase H or the RNA-induced silencing complex (RISC), or steric hindrance of translation (Jackson et al., 2003, Nature Biotechnology).