PPMO-based exon skipping therapy improves respiratory function in the mdx mouse model of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a severe X-linked recessive disorder caused by a deficiency of dystrophin, leading to progressive muscle degeneration and eventually cardiorespiratory failure. Exon-skipping therapies using cell-penetrating peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) restore production of a shortened but functional dystrophin protein. Since respiratory insufficiency is the leading cause of morbidity and mortality in DMD, we sought to examine the impact of PPMO on respiratory pathology. We evaluated the effects of RC-1001, a PPMO targeting a dystrophin mutation, in mdx mice, a preclinical model of DMD. These mice received monthly intravenous doses of RC-1001 (30, 50, or 100 mg/kg), starting at 2 months of age, and were monitored until the study endpoint at 12 months of age. Respiratory function was evaluated using whole-body plethysmography and the forced oscillometry technique, followed by histological and molecular analysis of respiratory muscles. PPMO-treated mice showed dose-independent improvements in respiratory function, with postmortem studies revealing significant dystrophin restoration, reduced inflammation, and decreased fibrosis in respiratory muscles. Additionally, dystrophin restoration and strength improvements were observed in limb muscles. Overall, PPMO-mediated exon skipping effectively targets respiratory pathology and is a promising therapy for respiratory insufficiency in patients with DMD.