Off-target cellular RNAs

Off-target cellular RNAs refer to unintended transcriptomic sequences that are bound or regulated by oligonucleotide-based therapeutics, such as antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), or CRISPR-based guide RNAs [1][2]. These interactions typically occur due to partial sequence complementarity, particularly within the 'seed region' of siRNAs or through short homologous sequences in ASOs, leading to the unintended degradation or translational inhibition of non-target messenger RNAs [3]. Beyond sequence-based effects, the chemical modifications used to stabilize these drugs, such as phosphorothioate backbones, can lead to non-specific binding with various cellular RNAs and proteins, potentially disrupting normal cellular homeostasis [4]. In the context of drug development, off-target RNA interactions are a major safety concern as they can result in unpredictable toxicities, including hepatotoxicity and immunogenicity, and may confound the interpretation of therapeutic efficacy [5]. Consequently, minimizing these interactions through advanced bioinformatic screening and chemical optimization is a critical requirement for the clinical success of transcriptomic medicines [6]. Therefore, off-target cellular RNAs are not therapeutic targets themselves but are rather a significant technical and safety hurdle to be avoided in precision medicine.

Other names

Off-target transcriptsUnintended RNA targetsNon-specific RNA binding sitesOff-target effects (OTE)Off-target gene silencing

Unintended sequence-specific hybridization leading to degradation via RNase H or the RNA-induced silencing complex (RISC), or non-specific protein-RNA binding induced by chemical modifications.