In
Duchenne muscular dystrophy (DMD),
dystrophin deficiency leading to progressive muscular degeneration is caused by frame-shifting mutations in the DMD gene.
Antisense oligonucleotides (AONs) aim to restore the reading frame by skipping of a specific exon(s), thereby allowing the production of a shorter, but semifunctional
protein, as is found in the mostly more mildly affected patients with
Becker muscular dystrophy. AONs are currently being investigated in phase 3 placebo-controlled clinical trials. Most of the participating patients are treated symptomatically with
corticosteroids (mainly predniso[lo]ne) to stabilize the muscle fibers, which might affect the uptake and/or efficiency of AONs. Therefore the effect of
prednisolone on 2'-O-methyl phosphorothioate AON efficacy in patient-derived cultured muscle cells and the mdx mouse model (after local and systemic AON treatment) was assessed in this study. Both in vitro and in vivo skip efficiency and
biomarker expression were comparable between saline- and
prednisolone-cotreated cells and mice. After systemic exon 23-specific AON (23AON) treatment for 8 weeks,
dystrophin was detectable in all treated mice. Western blot analyses indicated slightly higher
dystrophin levels in
prednisolone-treated mice, which might be explained by better muscle condition and consequently more target
dystrophin pre-mRNA. In addition, fibrotic and regeneration
biomarkers were normalized to some extent in
prednisolone- and/or 23AON-treated mice. Overall these results show that the use of
prednisone forms no barrier to participation in clinical trials with AONs.