Transcriptome-wide RNA off-target sites

Transcriptome-wide RNA off-target sites refer to the unintended RNA transcripts that are bound or modified by RNA-targeting therapeutics, such as antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), or RNA-editing tools (Jackson et al., 2003, Nature Biotechnology). These sites typically possess partial sequence complementarity to the therapeutic agent, leading to unintended gene silencing, RNA degradation via RNase H or RISC, or off-target base editing (Lindow & Kauppinen, 2012, Genes). Although not a therapeutic target, these sites are a primary focus of safety assessments because their modulation can lead to cellular toxicity, such as hepatotoxicity or neurotoxicity, and disrupt normal physiological processes (Frazer et al., 2018, Methods in Molecular Biology). Characterizing the off-target landscape is critical for the development of highly specific RNA-based drugs like Patisiran or Inotersen (FDA, 2018). Advanced computational algorithms and experimental methods like RNA-seq and degradome sequencing are employed to identify these sites during the lead optimization phase to ensure clinical safety (Cox et al., 2017, Science). Consequently, minimizing transcriptome-wide off-target activity is a central challenge in the field of precision medicine and nucleic acid therapeutics.

Other names

RNA off-targetsUnintended RNA binding sitesOff-target transcriptsTranscriptome-wide off-target effectsNon-specific RNA binding

Unintended hybridization-dependent cleavage, translational repression, or chemical modification of non-target RNA transcripts (Jackson et al., 2003; Lindow & Kauppinen, 2012).