Other off-target messenger RNAs

Other off-target messenger RNAs (mRNAs) represent a collective category of unintended genetic transcripts that are inadvertently affected by RNA-based therapeutics, such as small interfering RNAs (siRNAs), antisense oligonucleotides (ASOs), or CRISPR-based tools [Jackson, A. L., & Linsley, P. S. (2010). Nature Reviews Drug Discovery]. These interactions typically occur due to partial sequence complementarity between the therapeutic agent and non-target mRNA sequences, leading to unintended gene silencing or degradation [Wittrup, A., & Lieberman, J. (2015). Nature Reviews Genetics]. In the context of drug development, minimizing effects on these off-target mRNAs is a critical safety objective to prevent cellular toxicity and adverse phenotypic changes [Kurreck, J. (2003). European Journal of Biochemistry]. While not a therapeutic target itself, the monitoring of off-target mRNA profiles is essential for assessing the specificity and safety of oligonucleotide drugs [Setten, R. L., et al. (2019). Nature Reviews Drug Discovery]. Advanced computational modeling and high-throughput transcriptomic sequencing, such as RNA-seq, are frequently employed to identify and mitigate these risks during the lead optimization phase of drug discovery [Smith, C. I., et al. (2020). Molecular Therapy].

Other names

Off-target transcriptsUnintended mRNA targetsNon-specific mRNA interactionsOff-target effects

Unintended hybridization of therapeutic oligonucleotides to non-target mRNA sequences, resulting in unintended gene silencing or degradation [Jackson, A. L., et al. (2010). Nature Reviews Drug Discovery].