Miscellaneous RNA off-targets

Miscellaneous RNA off-targets represent a collective group of unintended RNA molecules that interact with therapeutic agents, particularly oligonucleotide-based drugs like antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs). These interactions typically arise from partial sequence complementarity between the drug and non-target mRNAs, leading to unintended gene silencing or degradation via RNase H or the RNA-induced silencing complex (RISC) (Jackson et al., 2003). Beyond sequence-specific effects, drugs may also bind non-specifically to RNA secondary structures or compete for limited cellular resources, such as RNA-binding proteins, which can disrupt normal cellular homeostasis (Frazier, 2015). In clinical development, these off-target interactions are a primary source of toxicity, often manifesting as liver or kidney damage and immune system activation (Roberts et al., 2020). Consequently, minimizing miscellaneous RNA off-target binding through chemical modifications, such as 2'-O-methyl or phosphorothioate linkages, and advanced bioinformatic design is a cornerstone of modern RNA-targeted drug discovery. These off-targets are not therapeutic goals but rather liabilities that must be characterized during the safety assessment of RNA-based therapeutics (Crooke et al., 2021).

Other names

RNA off-target effectsNon-specific RNA bindingUnintended RNA hybridizationOff-target gene silencingOligonucleotide off-targetsNon-specific RNA interactions

Drugs interact with these off-targets through partial sequence complementarity (hybridization), non-specific electrostatic interactions with the RNA backbone, or by saturating endogenous RNA processing pathways like the RISC complex (Jackson et al., 2003; Roberts et al., 2020).