Off-target complementary RNA

Off-target complementary RNAs are unintended messenger RNA (mRNA) transcripts that possess sequence complementarity to therapeutic nucleic acids, such as small interfering RNAs (siRNAs), antisense oligonucleotides (ASOs), or CRISPR guide RNAs [1]. These interactions typically occur when a therapeutic agent binds to a non-target transcript due to partial sequence homology, most notably within the 2-8 nucleotide seed region of an siRNA [1][2]. Such binding can trigger the RNA-induced silencing complex (RISC) to degrade the off-target mRNA or inhibit its translation, potentially leading to the suppression of proteins vital for normal cellular function [2]. This phenomenon is a major source of toxicity and side effects in the development of RNA-based therapeutics, necessitating rigorous bioinformatic screening and chemical modifications to enhance specificity [2][3]. Understanding and predicting these off-target interactions is essential for the safety profile of modern genomic medicines [1][2]. [1] Jackson AL, Linsley PS. Recognizing and understanding siRNA off-target effects. Nat Rev Drug Discov. 2010;9(1):57-67. [2] Setten RL, Rossi JJ, Han SP. The current state and future directions of RNAi therapeutics. Nat Rev Drug Discov. 2019;18(6):421-446. [3] Smith CH, et al. Delivery of antisense oligonucleotides to the central nervous system. Nat Rev Neurol. 2021;17(3):129-145.

Other names

Off-target transcriptsUnintended RNA targetsSeed-match off-targetsOff-target mRNANon-target RNA

Unintended hybridization of therapeutic oligonucleotides to non-target mRNA sequences, leading to RISC-mediated cleavage or steric hindrance of translation [1][2].