Duchenne muscular dystrophy (DMD) is a genetic disorder characterized by loss of functional dystrophin. Phosphorodiamidate morpholino oligomer (PMO) therapy, an exon-skipping strategy, has been explored to compensate for dystrophin deficiency by inducing the production of truncated but functional dystrophin. However, poor target tissue delivery, low efficacy and high dose-induced off-target toxicity hinder the development of PMOs as an effective therapy. The transforming growth factor-β family members activin A, activin B, and myostatin are potent negative regulators of skeletal muscle and bone. Here, we tested whether combining PMO therapy with simultaneous inhibition of activins and myostatin using RKER-065, the research form of KER-065, an investigational, modified type II activin receptor ligand trap, can better remedy muscle weakness and comorbidities associated with DMD than PMO single therapy.
Nine-week-old male D2MDX mice underwent an 8-week treatment regimen with vehicle (Tris-buffered saline (TBS), IP, BIW), RKER-065 (10mg/kg, IP, BIW) or PMO (25mg/kg, IV, QW), either alone or in combination (RKER-065+PMO). DBA2J mice treated with TBS IP served as controls (WT). All animals were assessed for lean mass, grip strength, lumbar vertebral bone volume and structure, and muscle dystrophin expression.
Dystrophic mice (Vehicle) showed lower lean mass gain, grip strength, and bone volume compared to WT mice. PMO treatment alone did not yield improvements in these parameters. However, combined RKER-065+PMO treatment was comparable to WT in lean mass, grip strength, and bone volume, significantly outperforming vehicle and PMO groups. Notably, RKER-065+PMO treatment increased dystrophin mRNA levels 2.8-fold versus Vehicle, with a 1.8-fold increase over PMO only, suggesting RKER-065 enhanced exon skipping and dystrophin expression by PMOs.
Our study demonstrated RKER-065’s effect in ameliorating muscle and bone loss in a DMD mouse model. The observation that RKER-065 treatment augmented PMO-induced dystrophin expression highlighted the potential synergistic benefit of using KER-065 and PMO combination therapy for DMD.