Off-target RNAs with partial sequence complementarity

Off-target RNAs with partial sequence complementarity refers to a collective group of unintended RNA transcripts that interact with oligonucleotide-based therapeutics, such as small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs). These interactions occur when a drug's sequence matches a non-target mRNA, often through a short seed region of 6-8 nucleotides, typically located in the 3' untranslated region (UTR) (Jackson et al., 2003, Nature Biotechnology; Lewis et al., 2005, Cell). While these are not therapeutic targets, they represent a significant challenge in drug development because their unintended silencing can lead to off-target effects, resulting in cellular toxicity or altered physiological pathways (Setten et al., 2019, Nature Reviews Drug Discovery). Modern drug design utilizes chemical modifications, such as 2'-O-methyl or 2'-fluoro substitutions, and advanced bioinformatic algorithms to minimize these interactions and enhance the specificity of the therapeutic lead (Janas et al., 2018, Nature Communications; Khvorova & Watts, 2017, Nature Biotechnology). Understanding the landscape of these off-target RNAs is crucial for assessing the safety profile and therapeutic index of any RNA-targeting drug candidate (Setten et al., 2019, Nature Reviews Drug Discovery).

Other names

Off-target transcriptsSeed-matched off-targetsCross-hybridizing RNAsUnintended RNA targetsNon-target messenger RNAs

Unintended sequence-specific binding to non-target RNA transcripts via partial Watson-Crick base pairing, leading to RNA-induced silencing complex (RISC)-mediated cleavage or translational repression (for siRNAs) or RNase H-mediated degradation or steric blocking (for ASOs).