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


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.


CONCLUSIONS
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.
Buyse
Gunnar M
GM
Department of Pediatric Neurology, University Hospitals Leuven, Herestraat, Leuven, Belgium.
Van der Mieren
Gerry
G
Erb
Michael
M
D'hooge
Jan
J
Herijgers
Paul
P
Verbeken
Erik
E
Jara
Alejandro
A
Van Den Bergh
An
A
Mertens
Luc
L
Courdier-Fruh
Isabelle
I
Barzaghi
Patrizia
P
Meier
Thomas
T
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D002316:Cardiotonic Agents; D003971:Diastole; D004280:Dobutamine; D004452:Echocardiography; D005355:Fibrosis; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D028361:Mitochondrial Diseases / Q000188:drug therapy / Q000378:metabolism; D018482:Muscle, Skeletal / Q000503:physiopathology; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology; D018384:Oxidative Stress; D010805:Physical Conditioning, Animal; D010919:Placebos; D016037:Single-Blind Method; D013997:Time Factors; D019210:Troponin I / Q000097:blood; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000627:therapeutic use
D000975:Antioxidants; D015415:Biomarkers; D002316:Cardiotonic Agents; D010919:Placebos; D019210:Troponin I; D014451:Ubiquinone; D004280:Dobutamine; C036619:idebenone
Acta Myol. 2004 Sep;23(2):V-IX
15605947
Eur J Heart Fail. 2006 Dec;8(8):777-83
16716661
Cardiovasc Res. 2008 Mar 1;77(4):766-73
18056762
J Mol Histol. 2004 Jun;35(5):489-99
15571326
Curr Opin Neurol. 2003 Oct;16(5):577-83
14501841
Cardiology. 2003;99(1):1-19
12589117
Drugs Aging. 1994 Aug;5(2):133-52
7981485
J Child Neurol. 2005 Mar;20(3):246-8
15832620
Am J Physiol. 1998 Apr;274(4):H1416-22
9575947
Nature. 2005 Aug 18;436(7053):1025-9
16025101
Pflugers Arch. 1998 Dec;437(1):168-71
9817804
Free Radic Biol Med. 2003 May 1;34(9):1217-20
12706502
Proc Natl Acad Sci U S A. 1984 Feb;81(4):1189-92
6583703
Am J Physiol Heart Circ Physiol. 2007 Sep;293(3):H1969-77
17573457
Neuromuscul Disord. 2004 Oct;14(10):675-82
15351425
Am J Cardiol. 2004 Mar 15;93(6):724-7
15019877
J Appl Physiol (1985). 2007 Apr;102(4):1677-86
17095633
FEBS Lett. 1985 May 6;184(1):48-51
3987906
Arch Gerontol Geriatr. 1990 Nov-Dec;11(3):177-86
15374467
Muscle Nerve. 2002 Feb;25(2):207-11
11870688
Mol Cell Biochem. 1998 Jun;183(1-2):87-96
9655182
Hum Mol Genet. 2004 May 15;13(10):1017-24
15028670
Biochem Biophys Res Commun. 1984 Dec 28;125(3):1046-52
6517932