Golodirsen Leads to Sarcolemmal Dystrophin Expression in Patients With Genetic Mutations Amenable to Exon 53 Skipping

Purpose: Golodirsen (formerly SRP-4053) is a phosphorodiamidate morpholino oligomer (PMO) that binds to dystrophin messenger ribonucleic acid, and targets and excludes exon 53 during mRNA processing, facilitating the production of internally shortened dystrophin protein. A 2-part, first-in-human, multicenter trial (clinicaltrials.gov identifier: NCT02310906) is evaluating the safety, tolerability, and efficacy of golodirsen in patients with Duchenne muscular dystrophy (DMD) and genetic mutations amenable to exon 53 skipping. We report dystrophin production, exon 53 skipping, and dystrophin cellular localization at baseline and after 48 weeks of treatment with golodirsen. Methods: Part 1 of this trial, which has been completed, included a randomized, double-blind, placebo-controlled, 12-week dose escalation of golodirsen. Part 2, which is ongoing, is a 168-week open-label evaluation of once-weekly golodirsen 30 mg/kg. In preplanned interim analyses, eligible patients had paired muscle biopsies of the biceps brachii taken at baseline and at Week 48 of once-weekly treatment with golodirsen. Patients newly enrolled in part 2 had the same biopsies at baseline of part 2 and at Week 48. A validated western blot method quantified dystrophin production (primary biological end point). Exon 53 skipping was evaluated using reverse transcription polymerase chain reaction (RT-PCR). Immunohistochemistry assessed dystrophin localization and sarcolemmal fiber intensity Results: Biopsies were obtained and analyzed from 25 patients. Mean percent of normal dystrophin protein increased from 0.095% at baseline to 1.019% at Week 48, a significant mean change of +0.924% (P<0.001). Muscle biopsy samples from all patients displayed a significant increase from baseline in exon 53 skipping via RT-PCR at Week 48 (P<0.001), demonstrating the intended mechanism of action. A positive correlation between exon 53 skipping and de novo dystrophin production was observed (Spearman r=0.500; P=0.011). Mean fiber intensity analysis showed a significant increase from baseline in de novo dystrophin production (P<0.001) and confirmed correct dystrophin localization to the sarcolemma. Conclusion: Increased mean dystrophin protein production, exon 53 skipping, and correct sarcolemmal localization of dystrophin were observed in muscle biopsies from golodirsen-treated patients. Golodirsen is the second PMO shown to increase dystrophin protein expression and to demonstrate membrane localization following initiation of exon skipping. These findings add to the growing body of evidence of a role for the PMO technology platform in the treatment of DMD.