Complementary target RNA sequence recognized by antisense oligonucleotide (RNA)

The complementary target RNA sequence recognized by an antisense oligonucleotide (ASO) refers to the specific nucleotide segment within a ribonucleic acid molecule—such as mRNA, pre-mRNA, or non-coding RNA—that serves as the binding site for a therapeutic ASO. ASOs are synthetic, single-stranded nucleic acid analogs designed to bind to these sequences through highly specific Watson-Crick base pairing (Bennett, 2019, Annual Review of Medicine). This binding event can trigger the degradation of the target RNA by endogenous enzymes like RNase H1, or it can physically block cellular machinery to alter splicing patterns or inhibit protein translation (Rinaldi & Wood, 2018, Nature Reviews Neurology). By targeting the RNA directly, this approach allows for the modulation of genes that may be 'undruggable' at the protein level. This mechanism is currently utilized in the treatment of various conditions, including spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD), where ASOs either reduce the levels of toxic proteins or restore the production of functional ones. However, therapeutic success depends on the precise selection of the target sequence to minimize off-target effects and ensure efficient delivery to the relevant tissues (Chi et al., 2017, Nucleic Acid Therapeutics).

Other names

Target RNAASO target sequenceSense RNA sequenceTarget mRNATarget pre-mRNAAntisense target

Antisense oligonucleotides (ASOs) bind to the complementary target RNA sequence via Watson-Crick base pairing. This binding triggers several potential mechanisms: 1) recruitment of RNase H1 to cleave the RNA strand in an RNA-DNA heteroduplex, leading to degradation of the target; 2) steric hindrance of the translation machinery to prevent protein synthesis; 3) modulation of pre-mRNA splicing by blocking splice sites or regulatory elements (e.g., exon skipping or inclusion); and 4) disruption of RNA-protein or RNA-RNA interactions (Crooke et al., 2021, Nature Reviews Drug Discovery; Rinaldi & Wood, 2018, Nature Reviews Neurology).