Wingless-related integration site pathway component messenger RNAs (Wnt pathway mRNAs)

Wingless-related integration site (Wnt) pathway component messenger RNAs (mRNAs) encompass the transcript sequences of various proteins involved in the Wnt signaling cascade, such as Wnt ligands, Frizzled receptors, and intracellular mediators like Beta-catenin (CTNNB1). These mRNAs serve as therapeutic targets for RNA-based medicines, including small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs), designed to downregulate the expression of proteins that are overexpressed or mutated in diseases like cancer and fibrosis (Nusse & Clevers, 2017). In many malignancies, particularly colorectal carcinoma, the pathway is constitutively active due to mutations that prevent the degradation of Beta-catenin, making its mRNA a primary target for silencing (Kahn, 2014). Targeting the mRNA level allows for the inhibition of components that lack traditional small-molecule binding pockets, effectively expanding the druggable proteome. However, because Wnt signaling is vital for the maintenance of stem cell populations and tissue regeneration in the gut, skin, and bone, therapeutic strategies must balance efficacy with the risk of systemic toxicity (Zhan et al., 2017). Clinical development has explored candidates like DCR-BCAT, an siRNA targeting Beta-catenin mRNA, though challenges in delivery and tissue specificity remain (ClinicalTrials.gov NCT02110563).

Other names

Wnt signaling pathway transcriptsWnt pathway mRNA targetsWingless-type MMTV integration site pathway mRNAsWnt pathway component transcripts

The primary mechanism of action involves the sequence-specific binding of therapeutic nucleic acids, such as small interfering RNAs (siRNAs) or antisense oligonucleotides (ASOs), to the target Wnt component mRNA. siRNAs utilize the RNA-induced silencing complex (RISC) to catalyze the cleavage of the target mRNA, while ASOs can induce RNase H-mediated degradation or sterically block translation, both resulting in the potent reduction of protein synthesis for the targeted Wnt pathway member (Setten et al., 2019; Nusse & Clevers, 2017).