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European Heart Journal Advance Access originally published online on September 10, 2008
European Heart Journal 2009 30(1):116-124; doi:10.1093/eurheartj/ehn406
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org.

Long-term blinded placebo-controlled study of SNT-MC17/idebenone in the dystrophin deficient mdx mouse: cardiac protection and improved exercise performance

Gunnar M. Buyse1,*, Gerry Van der Mieren2, Michael Erb3, Jan D'hooge4, Paul Herijgers2, Erik Verbeken5, Alejandro Jara6, An Van Den Bergh2, Luc Mertens7, Isabelle Courdier-Fruh3, Patrizia Barzaghi3 and Thomas Meier3

1 Department of Pediatric Neurology, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium
2 Department of Experimental Cardiac Surgery, University Hospitals Leuven, Leuven, Belgium
3 Santhera Pharmaceuticals, Liestal, Switzerland
4 Department of Cardiovascular Imaging and Dynamics, University Hospitals Leuven, Leuven, Belgium
5 Department of Morphology and Molecular Pathology, University Hospitals Leuven, Leuven, Belgium
6 Biostatistical Center KU Leuven, Leuven, Belgium
7 Department of Pediatric Cardiology, University Hospitals Leuven, Leuven, Belgium

Received 1 February 2008; revised 8 August 2008; accepted 21 August 2008; online publish-ahead-of-print 10 September 2008.

* Corresponding author. Tel: +32 16 34 38 45, Fax: +32 16 34 38 42, Email: gunnar.buyse{at}uzleuven.be

Aims: Duchenne muscular dystrophy (DMD) is a severe and still incurable disease, with heart failure as a leading cause of death. The identification of a disease-modifying therapy may require early-initiated and long-term administration, but such type of therapeutic trial is not evident in humans. We have performed such a trial of SNT-MC17/idebenone in the mdx mouse model of DMD, based on the drug’s potential to improve mitochondrial respiratory chain function and reduce oxidative stress.

Methods and results: In this study, 200 mg/kg bodyweight of either SNT-MC17/idebenone or placebo was given from age 4 weeks until 10 months in mdx and wild-type mice. All evaluators were blinded to mouse type and treatment groups. Idebenone treatment significantly corrected cardiac diastolic dysfunction and prevented mortality from cardiac pump failure induced by dobutamine stress testing in vivo, significantly reduced cardiac inflammation and fibrosis, and significantly improved voluntary running performance in mdx mice.

Conclusion: We have identified a novel potential therapeutic strategy for human DMD, as SNT-MC17/idebenone was cardioprotective and improved exercise performance in the dystrophin-deficient mdx mouse. Our data also illustrate that the mdx mouse provides unique opportunities for long-term controlled prehuman therapeutic studies.

Key Words: Muscular dystrophy • Therapy • Cardiomyopathy • Hemodynamics • Heart failure • Animal model

This paper was guest edited by Dr Philipp Bonhoeffer, Great Ormond Street Hospital for Children, London, UK


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