Cystic fibrosis transmembrane conductance regulator (CFTR) exon 23 5' splice site (CFTR exon 23 5'ss)

The CFTR exon 23 5' splice site is a specific sequence in the pre-mRNA of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene that defines the boundary between exon 23 and the following intron (SpliSense, 2023). This site is a primary therapeutic target for antisense oligonucleotides (ASOs) aimed at treating Cystic Fibrosis patients with the W1282X nonsense mutation, which is located within exon 23 (Kim et al., 2022). By binding to this 5' splice site, ASOs can sterically block the splicing machinery, leading to the exclusion of exon 23 from the mature mRNA transcript (Michaels et al., 2022). Because exon 23 is 84 nucleotides long, its removal preserves the reading frame, allowing for the translation of a truncated but partially functional CFTR protein that lacks the mutation-bearing segment (Cystic Fibrosis Foundation, 2023). This "exon skipping" strategy is designed to restore chloride channel function in patients who do not benefit from existing CFTR modulators like ivacaftor or elexacaftor (SpliSense, 2023). Therapeutic development targeting this site, such as the candidate SPLS-1282, represents a precision medicine approach for rare or difficult-to-treat CF genotypes (SpliSense, 2023). The success of this approach depends on the efficient delivery of the ASO to the lung epithelium and the ability of the resulting Δ23-CFTR protein to traffic to the cell surface and facilitate ion transport (Kim et al., 2022).

Other names

CFTR exon 23 donor splice siteCFTR exon 26 5' splice siteCFTR pre-mRNA exon 23 5'ssCFTR c.3846G>A splice targetCFTR exon 23 5-prime splice site

Induction of exon skipping via steric hindrance of the splicing machinery to bypass nonsense mutations while maintaining the reading frame.