A Long-term Blinded Controlled Efficacy Study of SNT-MC17/Idebenone in the Dystrophin-Deficient MDX Mouse

Gunnar M. Buyse, Leuven, Belgium, Gerry Van der Mieren, Michael Erb, Jan D'Hooge, Paul Herijgers, Eric Verbeken, Alejandro Jara, Luc Mertens, Leuven, Belgium, Isabelle Courdier-Fruh, Patrizia Barzaghi, Thomas Meier, Liestal, Switzerland

 
BACKGROUND: The identification of a disease-modifying or protective compound for a certain disease may require early-started and long-term administration, but such type of therapeutic trial is not evident in human patients. We have performed such a trial of SNT-MC17/idebenone in the mdx mouse model of Duchenne muscular dystrophy (DMD), based on the drugs potential to improve mitochondrial respiratory chain function and reduce oxidative stress.

DESIGN/METHODS: 200 mg/kg bodyweight of either SNT-MC17/idebenone (ide) or vehicle/placebo (veh) was given from the age of 4 weeks until the age of 10 months in mdx mice (mdx-ide, n=18; mdx-veh, n=13) and wild-type mice (WT-veh, n=9). In vivo cardiac assessments at the age of 10 months included transthoracic echocardiography and strain rate imaging, and haemodynamic pressure-volume loop measurements for determination of intrinsic contractile properties in basal state and during dobutamine stress. Cardiac morphology was evaluated for degree of inflammation and fibrosis. Voluntary wheel running performance was recorded from week 5 to week 12. All evaluators were blinded to mouse type and treatment groups.

RESULTS: 10 month old mdx mice showed cardiac hypertrophy and diastolic dysfunction, the latter significantly improving with SNT-MC17/idebenone treatment. During physiological low dose dobutamine stress, placebo-treated mdx mice showed a 58% mortality due to systolic contractile failure, which was significantly reduced to 19% in the SNT-MC17/idebenone treated mdx group. SNT-MC17/idebenone treatment significantly improved long-term voluntary wheel running performance in the mdx mouse.

CONCLUSIONS/RELEVANCE: We show that the mdx animal model provides opportunities for long-term controlled preclinical therapeutic studies. We have identified a novel potential therapeutic strategy for DMD, as early-started and long-term treatment with SNT-MC17/idebenone was cardioprotective and improved exercise performance in the dystrophin-deficient mdx mouse. Encouraged by these animal data, SNT-MC17/idebenone is currently under investigation in a randomised controlled trial in DMD patients.