ePrints

Prednisolone treatment does not interfere with 2'-O-methyl phosphorothioate antisense-mediated exon skipping in Duchenne muscular dystrophy

Lookup NU author(s): Dr Ingrid Verhaart, Professor Annemieke Aartsma-Rus

Downloads

Full text for this publication is not currently held within this repository. Alternative links are provided below where available.

Abstract

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.

Publication metadata

Author(s): Verhaart IE, Heemskerk H, Karnaoukh TG, Kolfschoten IG, Vroon A, van Ommen GJ, van Deutekom JC, Aartsma-Rus A

Publication type: Article

Publication status: Published

Journal: Human Gene Therapy

Year: 2012

Volume: 23

Issue: 3

Pages: 262-273

Print publication date: 09/03/2012

Online publication date: 21/10/2011

ISSN (print): 1043-0342

ISSN (electronic): 1557-7422

Publisher: Mary Ann Liebert, Inc.

URL: http://dx.doi.org/10.1089/hum.2011.127

DOI: 10.1089/hum.2011.127

PubMed id: 2017442

Altmetrics

Share