Clinical trials of exon skipping in Duchenne muscular dystrophy

Introduction: DMD is most common form of severe childhood muscular dystrophy. The large size of the DMD gene challenges DNA repair or replacement. However, experimental in vitro and in vivo studies using antisense oligonucleotides (AONs) showed that exon skipping could result in production of a truncated dystrophin protein with potential to modify the dystrophic phenotype. This provided the impetus for clinical testing as discussed in this review. Area covered: Clinical trials were begun using alternative strategies employing antisense oligonucleotides to correct the reading frame of the mutant DMD gene. Exon 51 was target for skipping because it potentially captures the largest subgroup of DMD patients estimated to be 13% of the affected patients. One strategy used drisapersen, a 2'-O-methyl-phosphorothioate oligonucleotide (2OMePS) while the other employed a phosphorodiamidate morpholino oligomer (PMO) called eteplirsen. Expert opinion: Drisapersen initially introduced by intramuscular injection appeared to favorably skip exon 51 but follow up subcutaneous injections, attempting to produce more widespread skipping resulted in unexpected adverse events and failure to show clinical improvement. In contrast clinical experience using eteplirsen not only precisely skipped exon 51 but also resulted in clinical benefit showing a change in the rate of clinical decline and preservation of ambulation compared to natural history controls with minimal drug-related adverse events.