RNA off-target substrates

RNA off-target substrates refer to the collective group of unintended RNA transcripts that are bound or modified by RNA-targeting therapeutics, such as antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), and CRISPR-based systems (Smith et al., 2020, Nature Reviews Drug Discovery). These interactions typically arise from partial sequence complementarity between the therapeutic agent and non-target RNA molecules, which can trigger unintended biological processes like RNase H-mediated cleavage or RISC-mediated silencing (Jackson & Linsley, 2010, Nature Reviews Drug Discovery). While the primary goal of these therapies is to modulate a specific disease-linked transcript, off-target binding can lead to significant cellular toxicity and adverse clinical outcomes, including hepatotoxicity and nephrotoxicity (Crooke et al., 2021, Nucleic Acids Research). Identifying and mitigating these interactions through chemical modifications and rigorous sequence screening is a critical challenge in the development of safe and effective oligonucleotide drugs (Khvorova & Watts, 2017, Nature Biotechnology). Consequently, RNA off-target substrates are not therapeutic targets but are instead a major safety consideration and a hurdle to achieving high drug specificity.

Other names

Off-target RNA transcriptsUnintended RNA targetsNon-specific RNA binding sitesOff-target effects

Unintended sequence-specific or non-specific binding to non-target RNA transcripts, leading to degradation, translational repression, or altered splicing.