Complementary disease-associated messenger RNA (mRNA)

Complementary disease-associated messenger RNA (mRNA) refers to the specific ribonucleic acid sequences targeted by antisense oligonucleotides (ASOs) and other RNA-based therapeutics to treat various pathological conditions (NCI Thesaurus, Code C459). These targets are identified based on their role in the synthesis of proteins that are either overexpressed, mutated, or improperly spliced in a disease state (Crooke et al., 2021). By utilizing Watson-Crick base pairing, therapeutic agents bind to the target mRNA with high specificity, leading to outcomes such as the degradation of the mRNA transcript by endogenous enzymes like RNase H1, the physical inhibition of the ribosomal translation machinery, or the alteration of pre-mRNA splicing patterns (Rinaldi & Wood, 2018). This therapeutic strategy allows for the modulation of gene expression at the post-transcriptional level, enabling the targeting of proteins that are difficult to reach with traditional small-molecule inhibitors. Clinical applications include the treatment of spinal muscular atrophy via SMN2 mRNA targeting (Nusinersen) and hereditary transthyretin-mediated amyloidosis via TTR mRNA targeting (Inotersen) (FDA, 2016; FDA, 2018). Despite its precision, the approach faces challenges such as ensuring efficient cellular uptake, avoiding off-target hybridization, and managing potential immune responses to synthetic nucleotides (Bennett, 2019).

Other names

Target mRNADisease-associated mRNASense strand mRNADisease-related mRNA

Antisense oligonucleotides and siRNAs bind to complementary mRNA sequences to induce degradation (via RNase H or RISC), block translation, or modulate splicing (Crooke et al., 2021; Setten et al., 2019).