Submitted and edited by Leigh Maria K. Ramos-Platt, MD
Charleston, JS, et. al. Eteplirsen treatment for Duchenne muscular dystrophy: Exon skipping and dystrophin production
. 2018 Jun 12;90(24):e2146-e2154.
Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder that affects 1:3500-1:5000 boys stemming from a pathogenic mutation in the dystrophin gene. Most cases are associated with exon deletions that interrupt the reading frame.
Eteplirsen is an intervention which was designed to restore the reading frame in mature mRNA for certain exon deletion mutations. These mutations are those who are amenable to exon 51 skipping.
Charleston et al report on the results of Sarepta’s study 202, an observational, open-label extension of study 201. Study 201 was the randomized controlled study looking at the efficacy and safety of Eteplirsen in DMD boys with exon 51 skip amenable mutations.
The question raised by the authors was whether 4 different assays on muscle biopsies taken from Study 202 subjects could support the effects of Eteplirsen’s ability to skip exon 51 and thus result in increased dystrophin production after 180 days of therapy. 12 patients were included in the study. The assays used were RT-PCR, Western Blot, percent dystrophin positive fibers (immunohistochemical staining for dystrophin, PDPF), and immunoflourescence intensity (Bioquant).
11/12 patients consented to a biopsy on study week 180. On RT-PCR, all 12 patients confirmed positive exon skipping and 9/11 available biopsies demonstrated an increase of dystrophin. In Western blot (measured as % normal), Bioquant, and PDPF means were 0.93 vs 0.37, 22.61 vs 9.41, and 37.33 vs 5.04 respectively.
In September 2016, Eteplirsen received accelerated FDA approval for the treatment of DMD patients with exon 51 skip amenable mutations. While questions remain regarding whether increased dystrophin expression results in increased strength, this study does demonstrate that Eteplirsen increases dystrophin production. There is a subset of Duchenne patients who spontaneously skip exons resulting in small amounts of dystrophin. These patients (exon 44 skip amenable patients) tend to have a milder disorder. It would be important to follow the boys in Study 202 over time to assess if they follow the same trajectory as the subpopulation of Duchenne patients who spontaneously skip.