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New treatments for mitochondrial disease—no time to drop our standards


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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Figure 1: Trials of treatments for mitochondrial disease.
Figure 2: Adverse outcome reporting improves with study quality.


  1. 1

    Murphy, S. M., Puwanant, A. & Griggs, R. C. Unintended effects of orphan product designation for rare neurological diseases. Ann. Neurol. 72, 481–490 (2012).

    Article  Google Scholar 

  2. 2

    Kesselheim, A. S. Ethical considerations in orphan drug approval and use. Clin. Pharmacol. Ther. 92, 153–155 (2012).

    CAS  Article  Google Scholar 

  3. 3

    Pfeffer, G., Majamaa, K., Turnbull, D. M., Thorburn, D. & Chinnery, P. F. Treatment for mitochondrial disorders. Cochrane Database of Systematic Reviews, Issue 4. Art. No.: CD004426.

  4. 4

    Pons, R. & De Vivo, D. C. Primary and secondary carnitine deficiency syndromes. J. Child. Neurol. 10 (Suppl. 2), S8–S24 (1995).

    PubMed  Google Scholar 

  5. 5

    Majamaa, K., Rusanen, H., Remes, A. M., Pyhtinen, J. & Hassinen, I. E. Increase of blood NAD+ and attenuation of lactacidemia during nicotinamide treatment of a patient with the MELAS syndrome. Life Sci. 58, 691–699 (1996).

    CAS  Article  Google Scholar 

  6. 6

    Lou, H. C. Correction of increased plasma pyruvate and plasma lactate levels using large doses of thiamine in patients with Kearns–Sayre syndrome. Arch. Neurol. 38, 469 (1981).

    CAS  Article  Google Scholar 

  7. 7

    Stacpoole, P. W. The pharmacology of dichloroacetate. Metabolism 38, 1124–1144 (1989).

    CAS  Article  Google Scholar 

  8. 8

    Bernsen, P. L., Gabreëls, F. J., Ruitenbeek, W. & Hamburger, H. L. Treatment of complex I deficiency with riboflavin. J. Neurol. Sci. 118, 181–187 (1993).

    CAS  Article  Google Scholar 

  9. 9

    Rauchová, H., Drahota, Z. & Lenaz, G. Function of coenzyme Q in the cell: some biochemical and physiological properties. Physiol. Res. 44, 209–216 (1995).

    PubMed  Google Scholar 

  10. 10

    Orsucci, D., Mancuso, M., Lenco, E. C., LoGerfo, A. & Siciliano, G. Targeting mitochondrial dysfunction and neurodegeneration by means of coenzyme Q10 and its analogues. Curr. Med. Chem. 18, 4053–4064 (2011).

    CAS  Article  Google Scholar 

  11. 11

    Shrader, W. D. et al. α-Tocotrienol quinone modulates oxidative stress response and the biochemistry of aging. Bioorg. Med. Chem. Lett. 21, 3693–3698 (2011).

    CAS  Article  Google Scholar 

  12. 12

    Shoffner, J. M. et al. Spontaneous Kearns–Sayre/chronic external ophthalmoplegia plus syndromes associated with a mitochondrial DNA deletion: a slip-replication model and metabolic therapy. Proc. Natl Acad. Sci. USA 86, 7952–7956 (1989).

    CAS  Article  Google Scholar 

  13. 13

    Eleff, S. et al. 31P NMR study of improvement in oxidative phosphorylation by vitamins K3 and C in a patient with a defect in electron transport at complex III in skeletal muscle. Proc. Natl Acad. Sci. USA 81, 3529–3533 (1984).

    CAS  Article  Google Scholar 

  14. 14

    Mancuso, M. et al. Oxidative stress biomarkers in mitochondrial myopathies, basally and after cysteine donor supplementation. J. Neurol. 257, 774–781 (2010).

    CAS  Article  Google Scholar 

  15. 15

    Liet, J. M. et al. The effect of short-term dimethylglycine treatment on oxygen consumption in cytochrome oxidase deficiency: a double-blind randomized crossover clinical trial. J. Pediatr. 142, 62–66 (2003).

    CAS  Article  Google Scholar 

  16. 16

    Wallimann, T., Tokarska-Schlattner, M. & Schlattner, U. The creatine kinase system and pleiotropic effects of creatine. Amino Acids 40, 1271–1296 (2011).

    CAS  Article  Google Scholar 

  17. 17

    Cejudo, P. et al. Exercise training in mitochondrial myopathy: a randomized controlled trial. Muscle Nerve 32, 342–350 (2005).

    Article  Google Scholar 

  18. 18

    Koga, Y. et al. L-Arginine improves the symptoms of strokelike episodes in MELAS. Neurology 64, 710–712 (2005).

    CAS  Article  Google Scholar 

  19. 19

    Walcott, B. P. et al. Steroid responsive A3243G mutation MELAS: clinical and radiographic evidence for regional hyperperfusion leading to neuronal loss. Neurologist 18, 159–170 (2012).

    Article  Google Scholar 

  20. 20

    Hassani, A., Horvath, R. & Chinnery, P. F. Mitochondrial myopathies: developments in treatment. Curr. Opin. Neurol. 23, 459–465 (2010).

    CAS  Article  Google Scholar 

  21. 21

    Bresolin, N. et al. Ubidecarenone in the treatment of mitochondrial myopathies: a multi-center double-blind trial. J. Neurol. Sci. 100, 70–78 (1990).

    CAS  Article  Google Scholar 

  22. 22

    Kerr, D. S. Treatment of mitochondrial electron transport chain disorders: a review of clinical trials over the past decade. Mol. Genet. Metab. 99, 246–255 (2010).

    CAS  Article  Google Scholar 

  23. 23

    CureMito [online], (2012).

  24. 24

    United Mitochondrial Disease Foundation [online], (2013).

  25. 25

    Barshop, B. A. et al. Chronic treatment of mitochondrial disease patients with dichloroacetate. Mol. Genet. Metab. 83, 138–149 (2004).

    CAS  Article  Google Scholar 

  26. 26

    Blankenberg, F. G. et al. Brain uptake of Tc99m-HMPAO correlates with clinical response to the novel redox modulating agent EPI-743 in patients with mitochondrial disease. Mol. Genet. Metab. 107, 690–699 (2012).

    CAS  Article  Google Scholar 

  27. 27

    Campos, Y. et al. Plasma carnitine insufficiency and effectiveness of L-carnitine therapy in patients with mitochondrial myopathy. Muscle Nerve 16, 150–153 (1993).

    CAS  Article  Google Scholar 

  28. 28

    Chen, R. S., Huang, C. C. & Chu, N. S. Coenzyme Q10 treatment in mitochondrial encephalomyopathies. Short-term double-blind, crossover study. Eur. Neurol. 37, 212–218 (1997).

    CAS  Article  Google Scholar 

  29. 29

    De Stefano, N. et al. Short-term dichloracetate treatment improves indices of cerebral metabolism in patients with mitochondrial disorders. Neurology 45, 1193–1198 (1995).

    CAS  Article  Google Scholar 

  30. 30

    Duncan, G. E., Perkins, L. A., Theriaque, D. W., Neiberger, R. E. & Stacpoole, P. W. Dichloroacetate therapy attenuates the blood lactate response to submaximal exercise in patients with defects in mitochondrial energy metabolism. J. Clin. Endocrinol. Metab. 89, 1733–1738 (2004).

    CAS  Article  Google Scholar 

  31. 31

    Enns, G. M. et al. Initial experience in the treatment of inherited mitochondrial disease with EPI-743. Mol. Genet. Metab. 105, 91–102 (2012).

    CAS  Article  Google Scholar 

  32. 32

    Glover, E. I. et al. A randomized trial of coenzyme Q10 in mitochondrial disorders. Muscle Nerve 42, 739–748 (2010).

    CAS  Article  Google Scholar 

  33. 33

    Gold, R. et al. Phosphorus magnetic resonance spectroscopy in the evaluation of mitochondrial myopathies: results of a 6-month therapy study with coenzyme Q. Eur. Neurol. 36, 191–196 (1996).

    CAS  Article  Google Scholar 

  34. 34

    Kaufmann, P. et al. Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology 66, 324–330 (2006).

    CAS  Article  Google Scholar 

  35. 35

    Klopstock, T. et al. A placebo-controlled crossover trial of creatine in mitochondrial diseases. Neurology 55, 1748–1751 (2000).

    CAS  Article  Google Scholar 

  36. 36

    Klopstock, T. et al. A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy. Brain 134, 2677–2686 (2011).

    Article  Google Scholar 

  37. 37

    Koga, Y. et al. Effects of L-arginine on the acute phase of strokes in three patients with MELAS. Neurology 58, 827–828 (2002).

    CAS  Article  Google Scholar 

  38. 38

    Komura, K., Hobbiebrunken, E., Wilichowski, E. K. & Hanefeld, F. A. Effectiveness of creatine monohydrate in mitochondrial encephalomyopathies. Pediatr. Neurol. 28, 53–58 (2003).

    Article  Google Scholar 

  39. 39

    Martinelli, D. et al. EPI-743 reverses the progression of the pediatric mitochondrial disease--genetically defined Leigh Syndrome. Mol. Genet. Metab. 107, 383–388 (2012).

    CAS  Article  Google Scholar 

  40. 40

    Mashima, Y., Kigasawa, K., Wakakura, M. & Oguchi, Y. Do idebenone and vitamin therapy shorten the time to achieve visual recovery in Leber hereditary optic neuropathy? J. Neuroophthalmol. 20, 166–170 (2000).

    CAS  Article  Google Scholar 

  41. 41

    Mathews, P. M., Andermann, F., Silver, K., Karpati, G. & Arnold, D. L. Proton MR spectroscopic characterization of differences in regional brain metabolic abnormalities in mitochondrial encephalomyopathies. Neurology 43, 2484–2490 (1993).

    CAS  Article  Google Scholar 

  42. 42

    Mori, M., Yamagata, T., Goto, T., Saito, S. & Momoi, M. Y. Dichloroacetate treatment for mitochondrial cytopathy: long-term effects in MELAS. Brain Dev. 26, 453–458 (2004).

    Article  Google Scholar 

  43. 43

    Ogawa, T. et al. Multi-center trial on the early effects of silodosin on lower urinary tract symptoms associated with benign prostatic hyperplasia [Japanese]. Hinyokika Kiyo 54, 757–764 (2008).

    PubMed  Google Scholar 

  44. 44

    Panetta, J., Smith, L. J. & Boneh, A. Effect of high-dose vitamins, coenzyme Q and high-fat diet in paediatric patients with mitochondrial diseases. J. Inherit. Metab. Dis. 27, 487–498 (2004).

    CAS  Article  Google Scholar 

  45. 45

    Remes, A. M. et al. Ubiquinone and nicotinamide treatment of patients with the 3243A-->G mtDNA mutation. Neurology 59, 1275–1277 (2002).

    CAS  Article  Google Scholar 

  46. 46

    Rodriguez, M. C. et al. Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders. Muscle Nerve 35, 235–242 (2007).

    CAS  Article  Google Scholar 

  47. 47

    Sadun, A. A. et al. Effect of EPI-743 on the clinical course of the mitochondrial disease Leber hereditary optic neuropathy. Arch. Neurol. 69, 331–338 (2012).

    Article  Google Scholar 

  48. 48

    Stacpoole, P. W. et al. Evaluation of long-term treatment of children with congenital lactic acidosis with dichloroacetate. Pediatrics 121, e1223–e1228 (2008).

    Article  Google Scholar 

  49. 49

    Stacpoole, P. W. et al. Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children. Pediatrics 117, 1519–1531 (2006).

    Article  Google Scholar 

  50. 50

    Suzuki, S. et al. The effects of coenzyme Q10 treatment on maternally inherited diabetes mellitus and deafness, and mitochondrial DNA 3243 (A to G) mutation. Diabetologia 41, 584–588 (1998).

    CAS  Article  Google Scholar 

  51. 51

    Taivassalo, T. et al. Endurance training and detraining in mitochondrial myopathies due to single large-scale mtDNA deletions. Brain 129, 3391–3401 (2006).

    Article  Google Scholar 

  52. 52

    Tarnopolsky, M. A., Roy, B. D. & MacDonald, J. R. Randomised control trial of creatine monohydrate in patients with mitochondrial cytopathies. Muscle Nerve 20, 1502–1509 (1997).

    CAS  Article  Google Scholar 

  53. 53

    Jadad, A. R. et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control. Clin. Trials 17, 1–12 (1996).

    CAS  Article  Google Scholar 

  54. 54

    Mazzone, E. et al. Functional changes in Duchenne muscular dystrophy: a 12-month longitudinal cohort study. Neurology 77, 250–256 (2011).

    CAS  Article  Google Scholar 

  55. 55

    US National Library of Medicine. [online], (2013).

  56. 56

    Notice of compliance with conditions—NOC/c (therapeutic products). Health Canada [online], (2013).

  57. 57

    Di Prospero, N. A., Baker, A., Jeffries, N. & Fischbeck, K. H. Neurological effects of high-dose idebenone in patients with Friedreich's ataxia: a randomised, placebo-controlled trial. Lancet Neurol. 6, 878–886 (2007).

    CAS  Article  Google Scholar 

  58. 58

    Lynch, D. R., Perlman, S. L. & Meier, T. A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia. Arch. Neurol. 67, 941–947 (2010).

    Article  Google Scholar 

  59. 59

    Lagedrost, S. J. et al. Idebenone in Friedreich ataxia cardiomyopathy-results from a 6-month phase III study (IONIA). Am. Heart J. 161, 639.e1–645.e1 (2011).

    Article  Google Scholar 

  60. 60

    Kearney, M., Orrell, R. W., Fahey, M. & Pandolfo, M. Antioxidants and other pharmacological treatments for Friedreich ataxia. Cochrane Database of Systematic Reviews, Issue 4. Art. No.: CD007791.

  61. 61

    CATENA® (idebenone)—voluntary withdrawal of CATENA® from the Canadian market. Health Canada [online],. (2013).

  62. 62

    Woodcock, J. & Woosley, R. The FDA critical path initiative and its influence on new drug development. Annu. Rev. Med. 59, 1–12 (2008).

    CAS  Article  Google Scholar 

  63. 63

    Koene, S. et al. Towards the harmonization of outcome measures in children with mitochondrial disorders. Dev. Med. Child. Neurol.

  64. 64

    Koene, S. et al. Developing outcome measures for pediatric mitochondrial disorders: which complaints and limitations are most burdensome to patients and their parents? Mitochondrion 13, 15–24 (2013).

    CAS  Article  Google Scholar 

  65. 65

    Jeppesen, T. D. et al. Aerobic training is safe and improves exercise capacity in patients with mitochondrial myopathy. Brain 129, 3402–3412 (2006).

    Article  Google Scholar 

  66. 66

    Joppi, R., Bertele, V. & Garattini, S. Orphan drug development is not taking off. Br. J. Clin. Pharmacol. 67, 494–502 (2009).

    CAS  Article  Google Scholar 

  67. 67

    North American Mitochondrial Disease Consortium [online], (2013).

  68. 68

    The Children's Mitochondrial Disease Network [online], (2013).

  69. 69

    mitoNET—German Network for Mitochondrial Disorders [online], (2013).

  70. 70

    Heemstra, H. E., van Weely, S., Büller, H. A., Leufkens, H. G. & de Vrueh, R. L. Translation of rare disease research into orphan drug development: disease matters. Drug Discov. Today 14, 1166–1173 (2009).

    Article  Google Scholar 

  71. 71

    Hsu, C. C. et al. CPEO and carnitine deficiency overlapping in MELAS syndrome. Acta Neurol. Scand. 92, 252–255 (1995).

    CAS  Article  Google Scholar 

  72. 72

    Majamaa, K., Rusanen, H., Remes, A. & Hassinen, I. E. Metabolic interventions against complex I deficiency in MELAS syndrome. Mol. Cell Biochem. 174, 291–296 (1997).

    CAS  Article  Google Scholar 

  73. 73

    Kornblum, C. et al. Creatine has no beneficial effect on skeletal muscle energy metabolism in patients with single mitochondrial DNA deletions: a placebo-controlled, double-blind 31P-MRS crossover study. Eur. J. Neurol. 12, 300–309 (2005).

    CAS  Article  Google Scholar 

  74. 74

    Barbiroli, B. et al. Lipoic (thioctic) acid increases brain energy availability and skeletal muscle performance as shown by in vivo31P-MRS in a patient with mitochondrial cytopathy. J. Neurol. 242, 472–477 (1995).

    CAS  Article  Google Scholar 

  75. 75

    Taivassalo, T. et al. Aerobic training benefits patients with mitochondrial myopathies more than other chronic myopathies. Neurology 48, A214 (1997).

    Article  Google Scholar 

  76. 76

    Fu, K. et al. A novel heteroplasmic tRNAleu(UUR) mtDNA point mutation in a sporadic patient with mitochondrial encephalomyopathy segregates rapidly in muscle and suggests an approach to therapy. Hum. Mol. Genet. 5, 1835–1840 (1996).

    CAS  Article  Google Scholar 

  77. 77

    Clark, K. et al. Correction of a mitochondrial DNA defect in human skeletal muscle. Nat. Genet. 16, 222–224 (1997).

    CAS  Article  Google Scholar 

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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).

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G. Pfeffer, R. Horvath, and P. F. Chinnery performed data analysis. G. Pfeffer and P. F. Chinnery wrote the article. All authors provided substantial contribution to discussion of content, and to the review and/or editing of the manuscript before submission.

Corresponding author

Correspondence to Patrick F. Chinnery.

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Competing interests

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 (—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.

Supplementary information

Supplementary Table 1

Jadad score for included studies (DOC 36 kb)

Supplementary Table 2

Summary of P values for clinically relevant endpoints (DOC 35 kb)

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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).

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