Restoration of full-length dystrophin expression through exon skipping in Duchenne muscular dystrophy patients with single exon duplications


Clinical Trials

Poster Number: 102


Stefan Nicolau, MD, Nationwide Children's Hospital, Jyoti Malhotra, Sarepta Therapeutics, Megan Iammarino, DPT, Nationwide Children's Hospital, Natalie Reash, DPT, Nationwide Children's Hospital, Linda Lowes, PT, PhD, Nationwide Children's Hospital, Kevin Flanigan, MD, Nationwide Children's Hospital

Background: Duchenne muscular dystrophy is an X-linked myopathy most frequently caused by out-of-frame deletions in the DMD gene. Four antisense oligonucleotides have been approved to correct the reading frame in a subset of these patients through skipping of exons 45, 51, or 53. Duplications of these exons are comparatively much rarer, but skipping of a duplicated exon has the potential to be highly therapeutic, as it aims to restore full-length dystrophin expression.

Objectives: We conducted a 48-week open label study of approved exon skipping drugs in 3 subjects with single exon duplications.

Results: Two subjects had exon 45 duplication and were treated with casimersen, while one had exon 53 duplication and was treated with golodirsen. No serious adverse events were recorded. In two subjects who were non-ambulatory at baseline, upper limb and pulmonary function remained stable over the duration of the study. Autism spectrum disorder precluded meaningful functional assessment in one ambulatory subject. Cardiac function remained stable in all subjects. In all subjects dystrophin expression measured by western blot was increased, from a mean of 0.94% of normal at baseline to 5.1% at 48 weeks post treatment. Percent dystrophin positive fibers also increased from a mean of 14% at baseline to 50% at 48 weeks.

Conclusions: Although limited in size, this study provides evidence of a substantial increase of dystrophin production and therefore supports the use of exon skipping drugs in patients with amenable single exon duplications.