The next DMD exon skipping trial: Selection of AO target

Duchenne muscular dystrophy (DMD) is caused by the lack of dystrophin protein, most commonly as a result of frame-shifting mutations, both deletions and duplications, in the dystrophin gene. Selective removal of exons flanking an out-of-frame DMD mutation can result in an in-frame mRNA transcript that may be translated into an internally-deleted, Becker muscular dystrophy (BMD)-like but functionally active dystrophin protein with therapeutic activity. Antisense oligonucleotides (AOs) have been designed to bind to complementary sequences in the targeted mRNA and modify premRNA splicing to correct the reading frame of a mutated transcript so that gene expression is restored. The rapid steady advances made in this field suggest that it is likely that AO-induced exon skipping will be the first gene therapy for DMD to reach the clinic. Indeed two different chemistries of AO continue to show encouraging results in clinical trials targeted at skipping exon 51 of the DMD gene, skipping of which would have the potential to treat 13% of DMD patients. However, the different deletions that cause DMD would require skipping of different exons, and the clinical workup of other AOs. A major UK consortium is currently developing a peptide-conjugated AO for the targeted skipping of exon 53 for use in the next clinical trial. This AO would have the potential to treat 8% of DMD patients. Detailed comparative analysis of an array of overlapping conjugated and naked AOs has been performed in DMD patient cells and the choice of AO for the next clinical trial will be presented.