Other mRNAs with partial sequence complementarity

Other mRNAs with partial sequence complementarity refers to a broad class of messenger RNA (mRNA) molecules that are unintentionally targeted by sequence-based therapeutics, such as small interfering RNAs (siRNAs) or antisense oligonucleotides (ASOs). This phenomenon, known as off-target activity, occurs when a therapeutic oligonucleotide binds to a transcript other than its intended target due to sufficient, though imperfect, base-pairing (Jackson et al., 2003, Nature Biotechnology). Such interactions typically involve the seed region of the oligonucleotide and can trigger the RNA-induced silencing complex (RISC) or RNase H-mediated cleavage, leading to the degradation or translational inhibition of these non-target mRNAs (Birmingham et al., 2006, Nature Methods). In the context of drug development, these interactions are a significant safety concern because silencing essential genes can result in cellular toxicity, organ damage, or other adverse clinical outcomes (Kamola et al., 2015, Nucleic Acids Research). Consequently, extensive bioinformatic screening and experimental validation, such as RNA-seq, are required to minimize the risk of these interactions during the design of RNA-targeted therapies (FDA, 2022, Guidance for Industry). Minimizing off-target effects is critical for ensuring the specificity and therapeutic index of modern oligonucleotide drugs (Khvorova & Watts, 2017, Nature Biotechnology).

Other names

Off-target transcriptsNon-target mRNAsPartial match transcriptsOff-target RNA sequences

Unintended sequence-specific hybridization leading to mRNA degradation or translational repression.