Figure 4.

Mechanism of multiexon skipping of exons 45 through 55 to rescue 60% of patients with Duchenne muscular dystrophy with dystrophin deletions A, More than 60% of deletion mutations of the dystrophin gene occur within the hot-spot range of exons 45 through 55 (exon 45 is deleted in this schematic [del]) in Duchenne muscular dystrophy muscles. The messenger RNA (mRNA) of remaining exons is spliced together but the reading frame is disrupted, resulting in failure of the production of functional dystrophin protein. CK indicates creatine kinase; Ca²⁺, calcium ions. B, An antisense oligonucleotide (AO) cocktail targeting exons 45 through 55 likely enters the Duchenne muscular dystrophy muscle through its leaky membranes, then binds to the dystrophin mRNA in a sequence-specific manner. The AOs block the splicing machinery and prevent inclusion of all exons between exons 45 and 55. Skipping these exons restores the reading frame of mRNA, allowing production of quasi-dystrophin containing exons 1 through 44 and exons 56 through 79, which is not normal but likely retains considerable function as evidenced by patients with clinically milder Becker muscular dystrophy with identical partial dystrophin.