Mitochondrial dysfunction is a common cause of inherited multisystem disease that often involves the nervous system. Despite major advances in our understanding of the pathophysiology of mitochondrial diseases, clinical management of these conditions remains largely supportive. Using a systematic approach, we identified 1,039 publications on treatments for mitochondrial diseases, only 35 of which included observations on more than five patients. Reports of a positive outcome on the basis of a biomarker of unproven clinical significance were more common in nonrandomized and nonblinded studies, suggesting a publication bias toward positive but poorly executed studies. Although trial design is improving, there is a critical need to develop new biomarkers of mitochondrial disease. In this Perspectives article, we make recommendations for the design of future treatment trials in mitochondrial diseases. Patients and physicians should no longer rely on potentially biased data, with the associated costs and risks.
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G. Pfeffer is the recipient of a Bisby Fellowship from the Canadian Institutes of Health Research. A. Suomalainen is supported by the Sigrid Juselius Foundation and the Jane and Atos Erkko Foundation. R. McFarland is an honorary consultant paediatric neurologist at Newcastle upon Tyne Foundation Hospitals NHS Trust and a DoH/HEFCE-funded Clinical Senior Lecturer. J. Smeitink receives additional support from the Eurostars Programme (ESTAR 11205), ZonMW PM Rare and the Dutch Science Organisation (NWO) CSBR Program (853.00.130). P. F. Chinnery is an Honorary Consultant Neurologist at Newcastle upon Tyne Foundation Hospitals NHS Trust, is a Wellcome Trust Senior Fellow in Clinical Science (084980/Z/08/Z), and a UK National Institute for Health Research (NIHR) Senior Investigator. P. F. Chinnery receives additional support from the Wellcome Trust Centre for Mitochondrial Research (096919Z/11/Z), the Medical Research Council (UK) Centre for Translational Research in Neuromuscular Diseases, EU FP7 TIRCON, and the NIHR Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. The support of the Marriott Foundation is gratefully acknowledged. The views expressed are those of the authors and not necessarily those of the NHS, MF, ZonMW, NOW, the NIHR or the Department of Health. M. Zeviani (GPP10005) and V. Carelli are supported by Telethon Italy. For this study, T. Klopstock acknowledges funding from the German Federal Ministry of Education and Research (BMBF, grant number 01GM1113A) for the German Network for Mitochondrial Disorders (mitoNET). T. Klopstock receives additional support from the BMBF (German Centre for Vertigo and Balance Disorders, grant number 01EO0901) and from the European Commission Seventh Framework Programme (FP7/2007-2013, HEALTH-F2-2011, grant agreement No. 277984, TIRCON).
T. Klopstock has been a principal investigator or investigator on industry-sponsored trials funded by Santhera Pharmaceuticals (idebenone in LHON, idebenone in Friedreich ataxia) and by H. Lundbeck A/S (carbamylated erythropoietin in Friedreich ataxia); has received research support from Santhera Pharmaceuticals, Actelion Pharmaceuticals, and H. Lundbeck A/S; serves on scientific advisory boards for Santhera Pharmaceuticals and Actelion Pharmaceuticals; has received speaker honoraria and travel costs from, Eisai, Santhera Pharmaceuticals, Actelion Pharmaceuticals, Boehringer Ingelheim Pharma, and GlaxoSmithKline; and has consulted for Gerson Lehrman Group, USA, and FinTech Global Capital, Japan. V. K. Mootha is a paid consultant for Ember Therapeutics. V. Carelli is an investigator on two industry-sponsored trials: Edison Pharmaceuticals, USA for EPI-743 and Sigma-tau, Italy for L-acetyl carnitine. J. Smeitink is CEO of Khondrion (http://www.khondrion.com)—a spin-off company of the Radboud University Nijmegen Medical Centre, Netherlands. P. F. Chinnery was the academic independent Chief Investigator on the RHODOS trial, sponsored by Santhera Pharmaceuticals. The other authors declare no competing interests.
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Pfeffer, G., Horvath, R., Klopstock, T. et al. New treatments for mitochondrial disease—no time to drop our standards. Nat Rev Neurol 9, 474–481 (2013). https://doi.org/10.1038/nrneurol.2013.129
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