The administration of antisense oligonucleotide golodirsen reduces pathological regeneration in patients with Duchenne muscular dystrophy

Abstract

During the last decade, multiple clinical trials for Duchenne muscular dystrophy (DMD) have focused on the induction of dystrophin expression using different strategies. Many of these trials have reported a clear increase in dystrophin protein following treatment. However, the low levels of the induced dystrophin protein have raised questions on its functionality. In our present study, using an unbiased, high-throughput digital image analysis platform, we assessed markers of regeneration and levels of dystrophin associated protein via immunofluorescent analysis of whole muscle sections in 25 DMD boys who received 48-weeks treatment with exon 53 skipping morpholino antisense oligonucleotide (PMO) golodirsen. We demonstrate that the de novo dystrophin induced by exon skipping with PMO golodirsen is capable of conferring a histological benefit in treated patients with an increase in dystrophin associated proteins at the dystrophin positive regions of the sarcolemma in post-treatment biopsies. Although 48 weeks treatment with golodirsen did not result in a significant change in the levels of fetal/developmental myosins for the entire cohort, there was a significant negative correlation between the amount of dystrophin and levels of regeneration observed in different biopsy samples. Our results provide, for the first time, evidence of functionality of induced dystrophin following successful therapeutic intervention in the human.

Long-Term Safety and Efficacy Data of Golodirsen in Ambulatory Patients with Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping: A First-in-human, Multicenter, Two-Part, Open-Label, Phase 1/2 Trial

“…2C ) [ 22 ], and that myofiber regeneration decreased after golodirsen treatment, indicated by fewer fibers positive for fetal/developmental myosin at week 48 compared with baseline ( Fig. 2D ) [ 23 ].…”

“…In vitro studies have also demonstrated the molecular functionality of dystrophin protein produced by DMD myotubes after golodirsen treatment [ 24 ]. Consistently, we have previously demonstrated in post-treatment biopsy data from golodirsen-treated patients that increased dystrophin was associated with a 2.2% decrease in fibers positive for the regeneration marker fetal/developmental myosin [ 23 ].…”

Upper limb disease evolution in exon 53 skipping eligible patients with Duchenne muscular dystrophy

“… 23 This study was initially planned to pave the way for a clinical trial in this population. 24 Given the approval of golodirsen, an antisense oligonucleotide that induces skipping of exon 53, 25 , 26 and the development of other therapies with similar modes of action, the present set of data offers the opportunity to benchmark treated patients with natural history of patients with the same genotype.…”

Current Advances in RNA Therapeutics for Human Diseases

“…This drug behaves similarly to eteplirsen, in that it enables exon skipping; however, it leads to the exclusion of exon 53 instead of exon 51 [ 114 ]. This results in functional dystrophin and improves symptomology of patients with DMD caused by mutations that are acquiescent to exon 53 skipping [ 19 ].…”