Mouse dystrophin (Dmd) pre-mRNA exon 23 splice region (Dmd exon 23)

The mouse Dmd pre-mRNA exon 23 splice region is a critical therapeutic target in the mdx mouse model, which is the standard animal model for Duchenne Muscular Dystrophy (DMD) (Sicinski et al., 1989). This region contains a nonsense mutation (C-to-T transition) that results in a premature stop codon, leading to the absence of functional dystrophin protein and subsequent muscle fiber necrosis (Bulfield et al., 1984). Therapeutic strategies targeting this region utilize antisense oligonucleotides (ASOs) to bind to the splice donor or acceptor sites, or exonic splicing enhancers, to induce exon skipping (Mann et al., 2001). By masking these signals, the splicing machinery bypasses exon 23, restoring the reading frame and allowing for the production of a truncated but functional dystrophin protein (Lu et al., 2003). This approach has served as the foundational proof-of-concept for several FDA-approved exon-skipping drugs used in humans, such as eteplirsen and golodirsen (Heemskerk et al., 2009). Monitoring the efficacy of targeting this region involves measuring dystrophin restoration in muscle biopsies and assessing improvements in muscle function and serum biomarkers like creatine kinase. Challenges include achieving efficient systemic delivery to all muscle groups, particularly the heart, and managing potential immune responses to the newly expressed dystrophin protein.

Other names

mdx mutation siteDmd exon 23 splice siteDystrophin exon 23Dmd exon 23 splice donor/acceptor

Antisense-mediated steric hindrance of the spliceosome to induce exon skipping and restore the mRNA reading frame.