Figure 3. The general strategy for oligonucleotide-mediated exon skipping.

(a) A hypothetical stop codon mutation in exon 4 is translated into a nonfunctional truncated protein. (b) Normal splicing results in translation of full-length protein. (c) The antisense oligonucleotide (AON) blocks the splicing site for exon 4, resulting in its removal during the processing of the pre-mRNA into a mature mRNA transcript. In the case of the mdx mouse model of Duchenne muscular dystrophy, AONs have been used to target the stop codon mutation in exon 23, leading to removal of exon 23 from the pre-mRNA and joining of exons 22 and 24 (Ref. ¹³¹). Similarly, in Duchenne and Becker muscular dystrophies, targeting of dystrophin in this manner could lead to removal of exons containing stop codon or frameshift mutations. The translated protein, although internally deleted, will ideally retain critical functional domains. In myotonic dystrophy type 1 (DM1), chloride channels have been targeted to remove an exon normally expressed only in the neonatal isoform, but which is retained in DM1 muscles, to prevent generation of a dysfunctional protein in adult muscle (Ref. ³). Recent studies have demonstrated that the specific sequence targeted within a pre-mRNA is critical to the success of an AON (Ref. ¹⁴³).