The development of antisense oligonucleotide therapies for Duchenne muscular dystrophy: Report on a TREAT-NMD workshop hosted by the European Medicines Agency (EMA), on September 25th 2009

Antisense-mediated exon skipping for DMD. In this example, the open reading frame is disrupted by a deletion of exons 48–50, resulting in a premature stop codon and a shortened dystrophin, which is unable to fulfil all its cellular functions. AOs can be employed to restore the open reading frame (lower panel). Specific AOs bind to exon 51 and hide this exon from the splicing machinery, resulting in the splicing out of exon 51 with its flanking intron. This restores the open reading frame, allowing the generation of an internally deleted dystrophin that is partially to largely functional, as it contains both domains for the linker function.

Structure of the modifications on the AOs referred to in this study. (A) Phosphorodiamidate morpholino oligonculeotide (PMO) e.g. AVI-4658 (B) 2′-O-methyl phosphorothioate (PS oligomer) e.g. PRO051.