Prednisolone treatment does not interfere with 2'-O-methyl phosphorothioate antisense-mediated exon skipping in Duchenne muscular dystrophy.
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.
Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
Ingrid E C
IE
Verhaart
Hans
H
Heemskerk
Tatyana G
TG
Karnaoukh
Ingrid G M
IG
Kolfschoten
Anne
A
Vroon
Gert-Jan B
GJ
van Ommen
Judith C T
JC
van Deutekom
Annemieke
A
Aartsma-Rus
D000818:Animals; D002478:Cells, Cultured; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism; D005091:Exons; D015316:Genetic Therapy; D006801:Humans; D051379:Mice; D018101:Mice, Inbred mdx; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D011239:Prednisolone / Q000008:administration & dosage* / Q000627:therapeutic use
D016189:Dystrophin; D016376:Oligonucleotides, Antisense; D011239:Prednisolone