Non-canonical and off-target messenger RNAs

Non-canonical and off-target messenger RNAs (mRNAs) encompass a broad range of transcripts that either deviate from standard genomic annotations or are unintentionally affected by therapeutic agents. Non-canonical mRNAs include those arising from alternative splicing, circularization, or translation of non-coding regions, often contributing to proteomic diversity through the synthesis of micropeptides (Nature Reviews Molecular Cell Biology, 2020). These transcripts can play significant roles in cellular regulation and are frequently dysregulated in diseases such as cancer and neurodegeneration. Off-target mRNAs are transcripts that are inadvertently targeted by sequence-specific drugs, such as antisense oligonucleotides (ASOs) or siRNAs, due to partial sequence homology (Nucleic Acids Research, 2018). Such unintended interactions can lead to the degradation of essential transcripts, resulting in cellular toxicity or a reduced therapeutic index. In the context of precision medicine, identifying and quantifying these transcripts is vital for assessing drug safety and understanding the biological impact of cryptic translation (Science, 2014). Monitoring these species typically requires advanced sequencing techniques, such as Ribo-seq or high-depth RNA-seq, to ensure that therapeutic interventions remain highly specific. Overall, while not a single therapeutic target, this category of mRNAs represents a critical consideration for the development of RNA-based and splicing-modulating therapies.

Other names

Non-canonical transcriptsOff-target transcriptsCryptic mRNAsAlternative mRNA isoformsUnintended transcriptsAberrant transcripts

Therapeutic agents interact with these mRNAs primarily through Watson-Crick base pairing or by influencing the spliceosome, leading to unintended transcript degradation, translational inhibition, or the production of aberrant protein products.