Journal http://jcn.sagepub.com/ of Child Neurology
Treatment of Mitochondrial Disorders: Antioxidants and Beyond Gregory M. Enns J Child Neurol 2014 29: 1235 originally published online 30 June 2014 DOI: 10.1177/0883073814538509 The online version of this article can be found at: http://jcn.sagepub.com/content/29/9/1235
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Original Article
Treatment of Mitochondrial Disorders: Antioxidants and Beyond
Journal of Child Neurology 2014, Vol. 29(9) 1235-1240 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814538509 jcn.sagepub.com
Gregory M. Enns, MB, ChB1
Abstract Although mitochondrial disorders are among the most common inherited conditions that cause neurologic impairment, there are currently no US Food and Drug Administration (FDA)-approved medications designed to treat primary mitochondrial disease. This is in part related to the lack of biomarkers to monitor disease status or response to treatment and the paucity of randomized, controlled clinical trials focused on mitochondrial disease therapies. Despite this discouraging historical precedent, a number of new approaches to mitochondrial disease therapy are on the horizon. By studying metabolites central to redox chemistry, investigators are gaining new insights into potential noninvasive biomarkers. Controlled clinical trials designed to study the effects of novel redox-modulating therapies, such as EPI-743, in patients with inherited mitochondrial disease are also underway. Furthermore, several new compounds with potential effects on inner mitochondrial membrane function and mitochondrial biogenesis are in development. Such advances are providing the foundation for a new era in mitochondrial disease therapeutics. Keywords Bendavia, coenzyme q10, epi-743, epicatechin, mitochondrial disease, therapies, vitamins Received May 05, 2014. Received revised May 05, 2014. Accepted for publication May 06, 2014.
Although mitochondrial disorders are among the most common inherited conditions that cause neurologic impairment, with a conservative estimated prevalence of 1 in 5000 in the general population,1 there are currently no US Food and Drug Administration (FDA)–approved medications designed to treat primary mitochondrial disease. This is in part related to the paucity of randomized, controlled clinical trials focused on mitochondrial disease therapies.2 Mitochondrial disorders are heterogeneous, both from a molecular and clinical standpoint, and there is also a lack of robust biomarkers and clinical outcome measures for mitochondrial disease.3 A review of PubMed citations related to mitochondrial disease showed more than 140 000 related to ‘‘mitochondria,’’ but only 10— representing 7 10–5%—concerned randomized, controlled trials in genetic mitochondrial disease.4 Despite the discouraging historical precedent, a number of new approaches to the treatment of mitochondrial disease are on the horizon, and controlled clinical trials are underway for several traditional and novel therapies designed to treat the oxidative stress associated with mitochondrial dysfunction. Most physicians caring for mitochondrial disease patients use pharmacologic doses of a variety of vitamins and cofactors as a mainstay of therapy, with L-arginine (for metabolic strokes), coenzyme Q10 (as ubiquinol or ubiquinone), 5 L-carnitine, and creatine being most commonly recommended. Many physicians use a combination of 3 to 6 compounds, a socalled ‘‘mitochondrial cocktail,’’ but the composition of such
‘‘cocktails’’ is not standardized.5-12 Although treatment with these compounds is based on current understanding of the pathophysiology of mitochondrial disease, there is a limited evidence base of clinical efficacy.2,5,13
Coenzyme Q10 Coenzyme Q10, an electron carrier of the mitochondrial electron transport chain with antioxidant properties, is the most commonly used compound for mitochondrial disease therapy.5 Primary disorders of coenzyme Q10 synthesis are rare causes of mitochondrial dysfunction, but are important to recognize because response to supplementation with coenzyme Q10 can be dramatic.14-17 There have been relatively few placebo-controlled studies of coenzyme Q10 in mitochondrial disorders as a whole.13,18 Sixteen mitochondrial disease patients participating in a randomized, placebo-controlled, crossover study of coenzyme Q10 in combination with other cofactors 1
Department of Pediatrics, Division of Medical Genetics, Stanford University and the Lucile Packard Children’s Hospital, Stanford, CA, USA
Corresponding Author: Gregory M. Enns, MB, ChB, Department of Pediatrics, Division of Medical Genetics, Lucile Packard Children’s Hospital, Stanford University, 300 Pasteur Drive, H-315, Stanford, CA 94305-5208, USA. Email: [email protected]
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showed lower resting plasma lactate levels and urinary 8isoprostanes (a measure of oxidative stress), as well as attenuation of the decline in peak ankle dorsiflexion strength.19 Other randomized, placebo-controlled trials using coenzyme Q10 alone have shown mild benefits in patients with supranuclear palsy20 or a variety of genetic mitochondrial cytopathies.21 Anecdotal, albeit modest, improvement following coenzyme Q10 supplementation has been reported in mitochondrial DNA depletion syndromes22 and Kearns-Sayre syndrome as well.23 Coenzyme Q10 has also been evaluated in randomized, controlled trials involving disorders associated with secondary mitochondrial dysfunction, such as Parkinson disease; treatment is well tolerated and safe, but no clear clinical benefit has been demonstrated.24,25 A phase 3, placebo-controlled, double-blind, randomized, multicenter trial of coenzyme Q10 in children and adolescents with mitochondrial disorders (Identifier: NCT00432744) was recently completed and results are pending.2
cases.34 A placebo-controlled, randomized trial in 60 Parkinson disease patients did not show any effect on overall Unified Parkinson’s Disease Rating Scale scores or dopamine transporter single-photon emission computed tomography (SPECT), although patients reported improved mood.35
B Vitamins
L-Carnitine supplementation is a common therapeutic modality for the treatment of a number of neurometabolic disorders, including fatty acid oxidation disorders and organic acidemias.26,27 There have been no clinical trials exploring the use of carnitine for the treatment of mitochondrial disease, although carnitine supplementation is also commonly used in this patient population.5 Case reports or small series describing therapy with L-carnitine, typically used in combination with other supplements, have shown possible benefit in some mitochondrial disease patients.28-30
B vitamins, in combination with coenzyme Q10 and L-carnitine, are also sometimes recommended for treatment of mitochondrial disease patients in clinical practice,5 but no randomized trials have explored the efficacy of this treatment. Riboflavin, thiamine, and nicotinamide supplementation alone or in combination with other cofactors have shown variable efficacy in ameliorating clinical and biochemical abnormalities in case reports or small, open-label studies.29,30,36-41 An open-label study in 16 mitochondrial disease patients evaluated the use of multiple vitamins and cofactors, including thiamine, niacin, riboflavin, vitamin C, vitamin K3, and coenzyme Q10, but no significant treatment effects were observed.42 On the other hand, multiple acyl-CoA dehydrogenase deficiency, acylCoA dehydrogenase 9 deficiency, haploinsufficiency of GPR172B, and Brown-Vialetto-Van Laere and Fazio-Londe syndromes may respond to riboflavin,43,44 although these conditions are not considered to be primary mitochondrial disorders. Central nervous system folate (vitamin B9) can be low in patients with mitochondrial disease, especially those with mitochondrial DNA deletion syndrome, and folinic acid supplementation is relatively common in clinical practice.45-48 Folinic acid, the reduced form of folate, is preferred because of its ability to cross the blood-brain barrier.48
Creatine
Alpha-Lipoic Acid, Vitamin C, and Vitamin E
Several controlled trials have studied the effects of creatine supplementation. Seven adults, 6 of whom had a diagnosis of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) and 1 with mitochondrial myopathy, showed a 19% increase in hand-grip strength after taking creatine, but when they were compared with controls, no differences were noted in a 2-minute walk test, cycle ergometry, body composition, or activities of daily living questionnaire.31 Other controlled trials have not detected significant differences between creatine supplementation and placebo in a variety of outcome measures, including muscle strength, postexercise blood lactate or phosphocreatine recovery, Activities of Daily Living Scale, motor abilities, neuromuscular symptoms, function time test, or ataxia score.32,33 A study described above evaluated creatine supplementation in conjunction with coenzyme Q10 and alpha-lipoic acid and noted statistically significant decreases in blood lactate and urine 8-isoprostanes after combined therapy, but no significant differences were seen in handgrip or ankle strength and pulmonary function tests.19 Creatine, in conjunction with other supplements, including coenzyme Q10, riboflavin, alpha-lipoic acid, and vitamin E, has shown anecdotal clinical benefit in some
Alpha-lipoic acid, vitamin C, and vitamin E are relatively commonly used in mitochondrial disease therapy as part of a ‘‘mitochondrial cocktail.’’ Like other compounds discussed above, there is a paucity of controlled clinical trials related to these supplements, although case reports and small studies have noted modest benefits in some mitochondrial disease patients.19,34,40,49 Combined use of vitamin C and vitamin K3 showed clinical benefit in single patients with isolated complex III deficiency.50,51
L-Carnitine
Idebenone Patients with Leber hereditary optic neuropathy, caused by mitochondrial DNA point mutations in complex I, have shown improved vision after taking idebenone, a short-chain synthetic benzoquinone.52-56 These findings led to the first randomized, controlled clinical trial in this disease.57 Eighty-five patients with Leber hereditary optic neuropathy who had pathogenic mitochondrial DNA mutations (m.3460G>A, m.11778G>A, m.14484T>C) were treated with idebenone over a period of 24 weeks. Although the primary end point (best recovery of visual acuity) was not met, all secondary end points—including
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change in the best visual acuity, changes in visual acuity in the best eye at baseline, and changes in visual acuity for both eyes—differed significantly between idebenone and placebo groups in patients with Leber hereditary optic neuropathy with discordant visual acuity at baseline.57 Idebenone was found to be safe and patients with Leber hereditary optic neuropathy with discordant visual acuities were considered most likely to benefit from supplementation.57 A follow-up study evaluated visual acuity data in 58 patients with Leber hereditary optic neuropathy who participated in the initial 24-week clinical trial to determine whether the observed treatment effects persisted after discontinuation of idebenone.58 The beneficial response to idebenone was found to persist despite discontinuation of treatment for a median time of 30 months.58 A large retrospective study evaluated 103 patients with Leber hereditary optic neuropathy, 44 of whom were treated with idebenone (59 were untreated).59 The proportion of patients who demonstrated recovery of vision was higher in the idebenone-treated subjects compared with the untreated group, suggesting that idebenone may improve the natural history of the disease.59 Idebenone was also evaluated as a therapy for Friedreich ataxia in 70 children who participated in a 6-month randomized, double-blind, placebo-controlled trial.60 Patients treated with idebenone improved by 2.5 points on the mean International Cooperative Ataxia Rating Scale, compared with a 1.3-point improvement in the placebo group. Idebenone-treated patients also improved on the Friedreich Ataxia Rating Scale by 1.6 points, while the placebo group improved by 0.6 points. Statistical significance was not reached for either end point, and the authors concluded that larger studies of longer duration may be needed to assess the potential of drugs to treat neurologic dysfunction in Friedreich ataxia.60 At this time, idebenone is not being evaluated further for the treatment of Friedreich ataxia.
EPI-743 EPI-743 is a para-benzoquinone analog with potent cellular protective activity against oxidative stress.61 EPI-743 has shown initial promise as a therapy for mitochondrial disease in 3 open-label studies. Thirteen children and one adult (Leigh syndrome, n ¼ 4; polymerase g deficiency, n ¼ 4; MELAS, n ¼ 3; mitochondrial DNA deletion syndrome, n ¼ 2; Friedreich ataxia, n ¼ 1) were enrolled in an emergency treatment protocol in which patients were considered to be within 90 days of end-of-life care by physicians experienced in caring for mitochondrial disease patients.62 Twelve of the patients survived and 11 of the survivors showed clinical improvement, with 3 showing partial relapse. No significant drug-related adverse events were noted. The Newcastle Paediatric Mitochondrial Disease Scale63 was used as a measure of clinical response, and 10 of the survivors had improvements in quality of life (section IV). In addition, 12 participants underwent serial brain imaging using technetium-99m-hexamethylpropyleneamine oxime (HMPAO) SPECT. All subjects had decreased HMPAO uptake
at baseline, with most patients showing decreased uptake in multiple brain anatomic sites. Following 3 months of treatment with EPI-743, whole-brain uptake of HMPAO increased significantly (P ¼ .0186).62 HMPAO is a lipophilic radionuclide tracer that is retained in cells based on intracellular redox status.64 A follow-up study of 22 mitochondrial disease patients enrolled in the EPI-743 emergency treatment protocol further evaluated the use of HMPAO SPECT imaging for monitoring the oxidative state of the brain and response to redox-modulating therapy.65 Although additional studies in a more homogeneous group of patients were recommended, a significant linear correlation between the increase in cerebellar uptake of HMPAO and improvement in Newcastle score (r ¼ 0.623; P ¼ .00161) was identified. Furthermore, the MELAS subgroup (n ¼ 5) also showed a significant relationship between whole-brain uptake of HMPAO and Newcastle score (r ¼ 0.917; P ¼ .028).65 The authors postulated that HMPAO SPECT imaging may be a useful method for quantifying in vivo redox imbalance and response to redox-modulating medications.62,65 Another open-label study evaluated the use of EPI-743 in 10 children with genetically confirmed Leigh syndrome.66 In remarkable contrast to the natural history of this condition, all children showed stabilization and reversal of disease progression that was independent of underlying genotype or clinical severity at the time of treatment. A variety of functional outcome measures were used, including the Newcastle Paediatric Mitochondrial Disease Scale, Gross Motor Function Measure, and PedsQL Neuromuscular Module, and a statistically significant improvement was noted for each of these primary end points (P < .05). Each participating child also demonstrated an improvement in one class of the Movement Disorder-Childhood Rating Scale, which is indicative of improvement in symptoms related to dystonia and spasticity.66 No drug-related adverse events were noted.66 Low leukocyte glutathione has been described in mitochondrial disease patients.67 As part of the open-label study, the Leigh syndrome patients also had their in vivo redox status monitored before and after treatment with EPI-743.68 At baseline, Leigh syndrome patients had a profound decrease in total and reduced glutathione in peripheral blood lymphocytes, and associated high levels of oxidized forms of glutathione. A marked increase in reduced glutathione (P < .001) and a 96% decrease in the oxidized/reduced glutathione ratio (P < .001) was observed following EPI-743 therapy.68 These results support the role of thiol redox balance in mitochondrial disease, and glutathione status may represent an important biomarker for monitoring disease status and response to therapy.68 EPI-743 is currently being evaluated in several ongoing randomized, double-blind, placebo-controlled clinical trials, including studies focusing on Leigh syndrome (identifier: NCT01721733) and Friedreich ataxia (identifier: NCT01728064).
BendaviaÔ Bendavia, a peptide named after the physician Dr. Carl Benda who in 1898 was the first to use the term ‘‘mitochondria,’’ is
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another therapy that shows promise for the treatment of mitochondrial disease. This compound targets the inner mitochondrial membrane and binds selectively to cardiolipin, and by doing so exerts a protective effect on mitochondrial cristae, promotes adenosine triphosphate synthesis, and inhibits mitochondrial permeability transition.69,70 Cardiolipin is an attractive target for mitochondrial therapeutics because of its central role in maintaining the fluidity and folding of the inner mitochondrial membrane, which has direct effects on the organization of electron transport chain subunits and cristae formation.69,70 Although Bendavia has not been studied in clinical trials involving primary mitochondrial disorders, beneficial effects have been reported in experimental models of conditions associated with hypoxemia and mitochondrial damage, including ischemia/reperfusion cardiac injury and renovascular hypertension.70-74
with specific therapeutic effects may ultimately prove to be the most effective approach to treating mitochondrial disease. In addition, the development of redox biomarkers, such as glutathione and HMPAO, has the potential to assist in the design of further clinical trials dedicated to the treatment of redox imbalance caused by mitochondrial dysfunction. Such advances are providing the foundation for a new era in mitochondrial disease therapeutics. Author’s Note This work is based on a paper delivered at the 2013 Neurobiology of Disease in Children Symposium: Mitochondrial Disease, held in conjunction with the 42nd Annual Meeting of the Child Neurology Society, Austin, Texas, October 30, 2013.
Acknowledgment The author thanks Melanie Fridl Ross, MSJ, ELS, for editing this paper.
(–)-Epicatechin Agents that cause mitochondrial biogenesis are another active area of research related to mitochondrial therapeutics. Bezafibrate and resveratrol are thought to act by stimulating the peroxisome proliferator–activated receptor g (PPARg) coactivator 1a (PGC1a) pathway, which leads to transcription of genes involved in energy metabolism.75 Although its mechanism of action is uncertain, (–)-epicatechin, a flavonoid found in high concentration in dark chocolate, is another compound that has mitochondrial biogenesis properties. Health effects attributed to cocoa consumption include neuroprotection and decreased risk of diabetes, hypertension, or myocardial infarction.76 Mice fed with (–)-epicatechin demonstrated improved exercise performance and evidence for mitochondrial biogenesis, such as a significant increase in levels of electron transport chain proteins, mitofilin, porin, the neuronal isoform of nitric oxide synthase, and mitochondrial transcription factor A (Tfam). In addition, increased mitochondrial volume and cristae abundance were present following (–)-epicatechin supplementation.77 (–)-Epicatechin is currently being evaluated in a pilot study focusing on Becker muscular dystrophy (identifier: NCT01856868) but has not been used to date in patients with primary mitochondrial disorders.
Conclusion In conclusion, despite the current lack of therapies for inherited mitochondrial disorders, ongoing basic and translational research is robust. EPI-743 has shown promise in openlabel studies, and this agent is currently being evaluated in randomized, controlled clinical trials. Other compounds with different mechanisms of action, including Bendavia and (–)epicatechin, are in development and show promise for improving mitochondrial function. Because these therapeutics have different methods of action (ie, redox modulation, inner mitochondrial membrane stabilization, and stimulation of mitochondrial biogenesis) the potential benefits of combination therapy are worth considering; the use of multiple agents
Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: GME has received unrestricted gift research funds from Edison Pharmaceuticals, Inc. This presentation is due to the participation in the 2013 Neurobiology of Disease in Children Symposium funded by the National Institute of Neurological Disorders & Stroke (R13 NS040925).
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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47. Garcia-Cazorla A, Serrano M, Perez-Duenas B, et al. Secondary abnormalities of neurotransmitters in infants with neurological disorders. Dev Med Child Neurol. 2007;49:740-744. 48. Parikh S, Saneto R, Falk MJ, et al. A modern approach to the treatment of mitochondrial disease. Curr Treat Options Neurol. 2009;11:414-430. 49. Peterson PL. The treatment of mitochondrial myopathies and encephalomyopathies. Biochim Biophys Acta. 1995;1271: 275-280. 50. Eleff S, Kennaway NG, Buist NR, 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 U S A. 1984;81:3529-3533. 51. Mowat D, Kirby DM, Kamath KR, et al. Respiratory chain complex III [correction of complex] in deficiency with pruritus: a novel vitamin responsive clinical feature. J Pediatr. 1999;134: 352-354. 52. Mashima Y, Hiida Y, Oguchi Y. Remission of Leber’s hereditary optic neuropathy with idebenone. Lancet. 1992;340:368-369. 53. Cortelli P, Montagna P, Pierangeli G, et al. Clinical and brain bioenergetics improvement with idebenone in a patient with Leber’s hereditary optic neuropathy: a clinical and 31P-MRS study. J Neurol Sci. 1997;148:25-31. 54. Carelli V, Barboni P, Zacchini A, et al. Leber’s Hereditary Optic Neuropathy (LHON) with 14484/ND6 mutation in a North African patient. J Neurol Sci. 1998;160:183-188. 55. 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. 2000;20: 166-170. 56. Barnils N, Mesa E, Munoz S, et al. Response to idebenone and multivitamin therapy in Leber’s hereditary optic neuropathy [in Spanish]. Arch Soc Esp Oftalmol. 2007;82:377-380. 57. Klopstock T, Yu-Wai-Man P, Dimitriadis K, et al. A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy. Brain. 2011;134(pt 9):2677-2686. 58. Klopstock T, Metz G, Yu-Wai-Man P, et al. Persistence of the treatment effect of idebenone in Leber’s hereditary optic neuropathy. Brain. 2013;136(pt 2): e230. 59. Carelli V, La Morgia C, Valentino ML, et al. Idebenone treatment in Leber’s hereditary optic neuropathy. Brain. 2011;134(pt 9): e188. 60. Lynch DR, Perlman SL, Meier T. A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia. Arch Neurol. 2010;67:941-947. 61. Shrader WD, Amagata A, Barnes A, et al. Alpha-Tocotrienol quinone modulates oxidative stress response and the biochemistry of aging. Bioorg Med Chem Lett. 2011;21:3693-3698. 62. Enns GM, Kinsman SL, Perlman SL, et al. Initial experience in the treatment of inherited mitochondrial disease with EPI-743. Mol Genet Metab. 2012;105:91-102.
63. Phoenix C, Schaefer AM, Elson JL, et al. A scale to monitor progression and treatment of mitochondrial disease in children. Neuromuscul Disord. 2006;16:814-820. 64. Jacquier-Sarlin MR, Polla BS, Slosman DO. Oxido-reductive state: the major determinant for cellular retention of technetium-99m-HMPAO. J Nucl Med. 1996;37:1413-1416. 65. Blankenberg FG, Kinsman SL, Cohen BH, 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. 2012;107:690-699. 66. Martinelli D, Catteruccia M, Piemonte F, et al. EPI-743 reverses the progression of the pediatric mitochondrial disease—genetically defined Leigh syndrome. Mol Genet Metab. 2012;107: 383-388. 67. Atkuri KR, Cowan TM, Kwan T, et al. Inherited disorders affecting mitochondrial function are associated with glutathione deficiency and hypocitrullinemia. Proc Natl Acad Sci U S A. 2009; 106:3941-3945. 68. Pastore A, Petrillo S, Tozzi G, et al. Glutathione: a redox signature in monitoring EPI-743 therapy in children with mitochondrial encephalomyopathies. Mol Genet Metab. 2013;109: 208-214. 69. Szeto HH. First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics. Br J Pharmacol. 2014;171:2029-2050. 70. Birk AV, Chao WM, Bracken C, et al. Targeting mitochondrial cardiolipin and the cytochrome c/cardiolipin complex to promote electron transport and optimize mitochondrial ATP synthesis. Br J Pharmacol. 2014;171:2017-2028. 71. Dai DF, Chen T, Wanagat J, et al. Age-dependent cardiomyopathy in mitochondrial mutator mice is attenuated by overexpression of catalase targeted to mitochondria. Aging Cell. 2010;9: 536-544. 72. Kloner RA, Hale SL, Dai W, et al. Reduction of ischemia/reperfusion injury with bendavia, a mitochondria-targeting cytoprotective Peptide. J Am Heart Assoc. 2012;1:e001644. 73. Brown DA, Hale SL, Baines CP, et al. Reduction of early reperfusion injury with the mitochondria-targeting Peptide bendavia. J Cardiovasc Pharmacol Ther. 2014;19:121-132. 74. Eirin A, Williams BJ, Ebrahimi B, et al. Mitochondrial targeted peptides attenuate residual myocardial damage after reversal of experimental renovascular hypertension. J Hypertens. 2014;32: 154-165. 75. Koene S, Smeitink J. Metabolic manipulators: a well founded strategy to combat mitochondrial dysfunction. J Inherit Metab Dis. 2011;34:315-325. 76. Katz DL, Doughty K, Ali A. Cocoa and chocolate in human health and disease. Antioxid Redox Signal. 2011;15:2779-2811. 77. Nogueira L, Ramirez-Sanchez I, Perkins GA, et al. (–)-Epicatechin enhances fatigue resistance and oxidative capacity in mouse muscle. J Physiol. 2011;589(pt 18):4615-4631.
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Treatment of Mitochondrial Disorders: Antioxidants and Beyond Gregory M. Enns J Child Neurol 2014 29: 1235 originally published online 30 June 2014 DOI: 10.1177/0883073814538509 The online version of this article can be found at: http://jcn.sagepub.com/content/29/9/1235
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Original Article
Treatment of Mitochondrial Disorders: Antioxidants and Beyond
Journal of Child Neurology 2014, Vol. 29(9) 1235-1240 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814538509 jcn.sagepub.com
Gregory M. Enns, MB, ChB1
Abstract Although mitochondrial disorders are among the most common inherited conditions that cause neurologic impairment, there are currently no US Food and Drug Administration (FDA)-approved medications designed to treat primary mitochondrial disease. This is in part related to the lack of biomarkers to monitor disease status or response to treatment and the paucity of randomized, controlled clinical trials focused on mitochondrial disease therapies. Despite this discouraging historical precedent, a number of new approaches to mitochondrial disease therapy are on the horizon. By studying metabolites central to redox chemistry, investigators are gaining new insights into potential noninvasive biomarkers. Controlled clinical trials designed to study the effects of novel redox-modulating therapies, such as EPI-743, in patients with inherited mitochondrial disease are also underway. Furthermore, several new compounds with potential effects on inner mitochondrial membrane function and mitochondrial biogenesis are in development. Such advances are providing the foundation for a new era in mitochondrial disease therapeutics. Keywords Bendavia, coenzyme q10, epi-743, epicatechin, mitochondrial disease, therapies, vitamins Received May 05, 2014. Received revised May 05, 2014. Accepted for publication May 06, 2014.
Although mitochondrial disorders are among the most common inherited conditions that cause neurologic impairment, with a conservative estimated prevalence of 1 in 5000 in the general population,1 there are currently no US Food and Drug Administration (FDA)–approved medications designed to treat primary mitochondrial disease. This is in part related to the paucity of randomized, controlled clinical trials focused on mitochondrial disease therapies.2 Mitochondrial disorders are heterogeneous, both from a molecular and clinical standpoint, and there is also a lack of robust biomarkers and clinical outcome measures for mitochondrial disease.3 A review of PubMed citations related to mitochondrial disease showed more than 140 000 related to ‘‘mitochondria,’’ but only 10— representing 7 10–5%—concerned randomized, controlled trials in genetic mitochondrial disease.4 Despite the discouraging historical precedent, a number of new approaches to the treatment of mitochondrial disease are on the horizon, and controlled clinical trials are underway for several traditional and novel therapies designed to treat the oxidative stress associated with mitochondrial dysfunction. Most physicians caring for mitochondrial disease patients use pharmacologic doses of a variety of vitamins and cofactors as a mainstay of therapy, with L-arginine (for metabolic strokes), coenzyme Q10 (as ubiquinol or ubiquinone), 5 L-carnitine, and creatine being most commonly recommended. Many physicians use a combination of 3 to 6 compounds, a socalled ‘‘mitochondrial cocktail,’’ but the composition of such
‘‘cocktails’’ is not standardized.5-12 Although treatment with these compounds is based on current understanding of the pathophysiology of mitochondrial disease, there is a limited evidence base of clinical efficacy.2,5,13
Coenzyme Q10 Coenzyme Q10, an electron carrier of the mitochondrial electron transport chain with antioxidant properties, is the most commonly used compound for mitochondrial disease therapy.5 Primary disorders of coenzyme Q10 synthesis are rare causes of mitochondrial dysfunction, but are important to recognize because response to supplementation with coenzyme Q10 can be dramatic.14-17 There have been relatively few placebo-controlled studies of coenzyme Q10 in mitochondrial disorders as a whole.13,18 Sixteen mitochondrial disease patients participating in a randomized, placebo-controlled, crossover study of coenzyme Q10 in combination with other cofactors 1
Department of Pediatrics, Division of Medical Genetics, Stanford University and the Lucile Packard Children’s Hospital, Stanford, CA, USA
Corresponding Author: Gregory M. Enns, MB, ChB, Department of Pediatrics, Division of Medical Genetics, Lucile Packard Children’s Hospital, Stanford University, 300 Pasteur Drive, H-315, Stanford, CA 94305-5208, USA. Email: [email protected]
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showed lower resting plasma lactate levels and urinary 8isoprostanes (a measure of oxidative stress), as well as attenuation of the decline in peak ankle dorsiflexion strength.19 Other randomized, placebo-controlled trials using coenzyme Q10 alone have shown mild benefits in patients with supranuclear palsy20 or a variety of genetic mitochondrial cytopathies.21 Anecdotal, albeit modest, improvement following coenzyme Q10 supplementation has been reported in mitochondrial DNA depletion syndromes22 and Kearns-Sayre syndrome as well.23 Coenzyme Q10 has also been evaluated in randomized, controlled trials involving disorders associated with secondary mitochondrial dysfunction, such as Parkinson disease; treatment is well tolerated and safe, but no clear clinical benefit has been demonstrated.24,25 A phase 3, placebo-controlled, double-blind, randomized, multicenter trial of coenzyme Q10 in children and adolescents with mitochondrial disorders (Identifier: NCT00432744) was recently completed and results are pending.2
cases.34 A placebo-controlled, randomized trial in 60 Parkinson disease patients did not show any effect on overall Unified Parkinson’s Disease Rating Scale scores or dopamine transporter single-photon emission computed tomography (SPECT), although patients reported improved mood.35
B Vitamins
L-Carnitine supplementation is a common therapeutic modality for the treatment of a number of neurometabolic disorders, including fatty acid oxidation disorders and organic acidemias.26,27 There have been no clinical trials exploring the use of carnitine for the treatment of mitochondrial disease, although carnitine supplementation is also commonly used in this patient population.5 Case reports or small series describing therapy with L-carnitine, typically used in combination with other supplements, have shown possible benefit in some mitochondrial disease patients.28-30
B vitamins, in combination with coenzyme Q10 and L-carnitine, are also sometimes recommended for treatment of mitochondrial disease patients in clinical practice,5 but no randomized trials have explored the efficacy of this treatment. Riboflavin, thiamine, and nicotinamide supplementation alone or in combination with other cofactors have shown variable efficacy in ameliorating clinical and biochemical abnormalities in case reports or small, open-label studies.29,30,36-41 An open-label study in 16 mitochondrial disease patients evaluated the use of multiple vitamins and cofactors, including thiamine, niacin, riboflavin, vitamin C, vitamin K3, and coenzyme Q10, but no significant treatment effects were observed.42 On the other hand, multiple acyl-CoA dehydrogenase deficiency, acylCoA dehydrogenase 9 deficiency, haploinsufficiency of GPR172B, and Brown-Vialetto-Van Laere and Fazio-Londe syndromes may respond to riboflavin,43,44 although these conditions are not considered to be primary mitochondrial disorders. Central nervous system folate (vitamin B9) can be low in patients with mitochondrial disease, especially those with mitochondrial DNA deletion syndrome, and folinic acid supplementation is relatively common in clinical practice.45-48 Folinic acid, the reduced form of folate, is preferred because of its ability to cross the blood-brain barrier.48
Creatine
Alpha-Lipoic Acid, Vitamin C, and Vitamin E
Several controlled trials have studied the effects of creatine supplementation. Seven adults, 6 of whom had a diagnosis of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) and 1 with mitochondrial myopathy, showed a 19% increase in hand-grip strength after taking creatine, but when they were compared with controls, no differences were noted in a 2-minute walk test, cycle ergometry, body composition, or activities of daily living questionnaire.31 Other controlled trials have not detected significant differences between creatine supplementation and placebo in a variety of outcome measures, including muscle strength, postexercise blood lactate or phosphocreatine recovery, Activities of Daily Living Scale, motor abilities, neuromuscular symptoms, function time test, or ataxia score.32,33 A study described above evaluated creatine supplementation in conjunction with coenzyme Q10 and alpha-lipoic acid and noted statistically significant decreases in blood lactate and urine 8-isoprostanes after combined therapy, but no significant differences were seen in handgrip or ankle strength and pulmonary function tests.19 Creatine, in conjunction with other supplements, including coenzyme Q10, riboflavin, alpha-lipoic acid, and vitamin E, has shown anecdotal clinical benefit in some
Alpha-lipoic acid, vitamin C, and vitamin E are relatively commonly used in mitochondrial disease therapy as part of a ‘‘mitochondrial cocktail.’’ Like other compounds discussed above, there is a paucity of controlled clinical trials related to these supplements, although case reports and small studies have noted modest benefits in some mitochondrial disease patients.19,34,40,49 Combined use of vitamin C and vitamin K3 showed clinical benefit in single patients with isolated complex III deficiency.50,51
L-Carnitine
Idebenone Patients with Leber hereditary optic neuropathy, caused by mitochondrial DNA point mutations in complex I, have shown improved vision after taking idebenone, a short-chain synthetic benzoquinone.52-56 These findings led to the first randomized, controlled clinical trial in this disease.57 Eighty-five patients with Leber hereditary optic neuropathy who had pathogenic mitochondrial DNA mutations (m.3460G>A, m.11778G>A, m.14484T>C) were treated with idebenone over a period of 24 weeks. Although the primary end point (best recovery of visual acuity) was not met, all secondary end points—including
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change in the best visual acuity, changes in visual acuity in the best eye at baseline, and changes in visual acuity for both eyes—differed significantly between idebenone and placebo groups in patients with Leber hereditary optic neuropathy with discordant visual acuity at baseline.57 Idebenone was found to be safe and patients with Leber hereditary optic neuropathy with discordant visual acuities were considered most likely to benefit from supplementation.57 A follow-up study evaluated visual acuity data in 58 patients with Leber hereditary optic neuropathy who participated in the initial 24-week clinical trial to determine whether the observed treatment effects persisted after discontinuation of idebenone.58 The beneficial response to idebenone was found to persist despite discontinuation of treatment for a median time of 30 months.58 A large retrospective study evaluated 103 patients with Leber hereditary optic neuropathy, 44 of whom were treated with idebenone (59 were untreated).59 The proportion of patients who demonstrated recovery of vision was higher in the idebenone-treated subjects compared with the untreated group, suggesting that idebenone may improve the natural history of the disease.59 Idebenone was also evaluated as a therapy for Friedreich ataxia in 70 children who participated in a 6-month randomized, double-blind, placebo-controlled trial.60 Patients treated with idebenone improved by 2.5 points on the mean International Cooperative Ataxia Rating Scale, compared with a 1.3-point improvement in the placebo group. Idebenone-treated patients also improved on the Friedreich Ataxia Rating Scale by 1.6 points, while the placebo group improved by 0.6 points. Statistical significance was not reached for either end point, and the authors concluded that larger studies of longer duration may be needed to assess the potential of drugs to treat neurologic dysfunction in Friedreich ataxia.60 At this time, idebenone is not being evaluated further for the treatment of Friedreich ataxia.
EPI-743 EPI-743 is a para-benzoquinone analog with potent cellular protective activity against oxidative stress.61 EPI-743 has shown initial promise as a therapy for mitochondrial disease in 3 open-label studies. Thirteen children and one adult (Leigh syndrome, n ¼ 4; polymerase g deficiency, n ¼ 4; MELAS, n ¼ 3; mitochondrial DNA deletion syndrome, n ¼ 2; Friedreich ataxia, n ¼ 1) were enrolled in an emergency treatment protocol in which patients were considered to be within 90 days of end-of-life care by physicians experienced in caring for mitochondrial disease patients.62 Twelve of the patients survived and 11 of the survivors showed clinical improvement, with 3 showing partial relapse. No significant drug-related adverse events were noted. The Newcastle Paediatric Mitochondrial Disease Scale63 was used as a measure of clinical response, and 10 of the survivors had improvements in quality of life (section IV). In addition, 12 participants underwent serial brain imaging using technetium-99m-hexamethylpropyleneamine oxime (HMPAO) SPECT. All subjects had decreased HMPAO uptake
at baseline, with most patients showing decreased uptake in multiple brain anatomic sites. Following 3 months of treatment with EPI-743, whole-brain uptake of HMPAO increased significantly (P ¼ .0186).62 HMPAO is a lipophilic radionuclide tracer that is retained in cells based on intracellular redox status.64 A follow-up study of 22 mitochondrial disease patients enrolled in the EPI-743 emergency treatment protocol further evaluated the use of HMPAO SPECT imaging for monitoring the oxidative state of the brain and response to redox-modulating therapy.65 Although additional studies in a more homogeneous group of patients were recommended, a significant linear correlation between the increase in cerebellar uptake of HMPAO and improvement in Newcastle score (r ¼ 0.623; P ¼ .00161) was identified. Furthermore, the MELAS subgroup (n ¼ 5) also showed a significant relationship between whole-brain uptake of HMPAO and Newcastle score (r ¼ 0.917; P ¼ .028).65 The authors postulated that HMPAO SPECT imaging may be a useful method for quantifying in vivo redox imbalance and response to redox-modulating medications.62,65 Another open-label study evaluated the use of EPI-743 in 10 children with genetically confirmed Leigh syndrome.66 In remarkable contrast to the natural history of this condition, all children showed stabilization and reversal of disease progression that was independent of underlying genotype or clinical severity at the time of treatment. A variety of functional outcome measures were used, including the Newcastle Paediatric Mitochondrial Disease Scale, Gross Motor Function Measure, and PedsQL Neuromuscular Module, and a statistically significant improvement was noted for each of these primary end points (P < .05). Each participating child also demonstrated an improvement in one class of the Movement Disorder-Childhood Rating Scale, which is indicative of improvement in symptoms related to dystonia and spasticity.66 No drug-related adverse events were noted.66 Low leukocyte glutathione has been described in mitochondrial disease patients.67 As part of the open-label study, the Leigh syndrome patients also had their in vivo redox status monitored before and after treatment with EPI-743.68 At baseline, Leigh syndrome patients had a profound decrease in total and reduced glutathione in peripheral blood lymphocytes, and associated high levels of oxidized forms of glutathione. A marked increase in reduced glutathione (P < .001) and a 96% decrease in the oxidized/reduced glutathione ratio (P < .001) was observed following EPI-743 therapy.68 These results support the role of thiol redox balance in mitochondrial disease, and glutathione status may represent an important biomarker for monitoring disease status and response to therapy.68 EPI-743 is currently being evaluated in several ongoing randomized, double-blind, placebo-controlled clinical trials, including studies focusing on Leigh syndrome (identifier: NCT01721733) and Friedreich ataxia (identifier: NCT01728064).
BendaviaÔ Bendavia, a peptide named after the physician Dr. Carl Benda who in 1898 was the first to use the term ‘‘mitochondria,’’ is
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another therapy that shows promise for the treatment of mitochondrial disease. This compound targets the inner mitochondrial membrane and binds selectively to cardiolipin, and by doing so exerts a protective effect on mitochondrial cristae, promotes adenosine triphosphate synthesis, and inhibits mitochondrial permeability transition.69,70 Cardiolipin is an attractive target for mitochondrial therapeutics because of its central role in maintaining the fluidity and folding of the inner mitochondrial membrane, which has direct effects on the organization of electron transport chain subunits and cristae formation.69,70 Although Bendavia has not been studied in clinical trials involving primary mitochondrial disorders, beneficial effects have been reported in experimental models of conditions associated with hypoxemia and mitochondrial damage, including ischemia/reperfusion cardiac injury and renovascular hypertension.70-74
with specific therapeutic effects may ultimately prove to be the most effective approach to treating mitochondrial disease. In addition, the development of redox biomarkers, such as glutathione and HMPAO, has the potential to assist in the design of further clinical trials dedicated to the treatment of redox imbalance caused by mitochondrial dysfunction. Such advances are providing the foundation for a new era in mitochondrial disease therapeutics. Author’s Note This work is based on a paper delivered at the 2013 Neurobiology of Disease in Children Symposium: Mitochondrial Disease, held in conjunction with the 42nd Annual Meeting of the Child Neurology Society, Austin, Texas, October 30, 2013.
Acknowledgment The author thanks Melanie Fridl Ross, MSJ, ELS, for editing this paper.
(–)-Epicatechin Agents that cause mitochondrial biogenesis are another active area of research related to mitochondrial therapeutics. Bezafibrate and resveratrol are thought to act by stimulating the peroxisome proliferator–activated receptor g (PPARg) coactivator 1a (PGC1a) pathway, which leads to transcription of genes involved in energy metabolism.75 Although its mechanism of action is uncertain, (–)-epicatechin, a flavonoid found in high concentration in dark chocolate, is another compound that has mitochondrial biogenesis properties. Health effects attributed to cocoa consumption include neuroprotection and decreased risk of diabetes, hypertension, or myocardial infarction.76 Mice fed with (–)-epicatechin demonstrated improved exercise performance and evidence for mitochondrial biogenesis, such as a significant increase in levels of electron transport chain proteins, mitofilin, porin, the neuronal isoform of nitric oxide synthase, and mitochondrial transcription factor A (Tfam). In addition, increased mitochondrial volume and cristae abundance were present following (–)-epicatechin supplementation.77 (–)-Epicatechin is currently being evaluated in a pilot study focusing on Becker muscular dystrophy (identifier: NCT01856868) but has not been used to date in patients with primary mitochondrial disorders.
Conclusion In conclusion, despite the current lack of therapies for inherited mitochondrial disorders, ongoing basic and translational research is robust. EPI-743 has shown promise in openlabel studies, and this agent is currently being evaluated in randomized, controlled clinical trials. Other compounds with different mechanisms of action, including Bendavia and (–)epicatechin, are in development and show promise for improving mitochondrial function. Because these therapeutics have different methods of action (ie, redox modulation, inner mitochondrial membrane stabilization, and stimulation of mitochondrial biogenesis) the potential benefits of combination therapy are worth considering; the use of multiple agents
Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: GME has received unrestricted gift research funds from Edison Pharmaceuticals, Inc. This presentation is due to the participation in the 2013 Neurobiology of Disease in Children Symposium funded by the National Institute of Neurological Disorders & Stroke (R13 NS040925).
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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