EPI-743 reverses the progression of the pediatric mitochondrial disease—Genetically defined Leigh Syndrome

Martinelli, Diego; Catteruccia, Michela; Piemonte, Fiorella; Pastore, Anna; Tozzi, Giulia; Dionisi‐Vici, Carlo; Pontrelli, Giuseppe; Corsetti, Tiziana; Livadiotti, Susanna; Kheifets, Viktoria; Hinman, A. Scott; Shrader, William D.; Thoolen, Martin; Klein, Matthew B.; Bertini, Enrico; Miller, Guy

doi:10.1016/j.ymgme.2012.09.007

Cited by 165 publications

(125 citation statements)

References 18 publications

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“…Comparison of these outcomes with a literature review of 180 children with Leigh syndrome associated with the similar mutations of this EPI-743-treated trial cohort showed a better outcome than frequent rapidly degenerative outcomes and early childhood death in the historical group, although these EPI-743 treated cases may have been more stable before treatment [44]. As a result of these 2 initial open trials of EPI-743, a randomized, placebo-controlled trial in genetically-proven Leigh syndrome is in progress [42,43].…”

Section: Epi-743mentioning

confidence: 84%

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Review of Clinical Trials for Mitochondrial Disorders: 1997–2012

Kerr

2013

Neurotherapeutics

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Over the last 15 years, some 16 open and controlled clinical trials for potential treatments of mitochondrial diseases have been reported or are in progress, and are summarized and reviewed herein. These include trials of administering dichloroacetate (an activator of pyruvate dehydrogenase complex), arginine or citrulline (precursors of nitric oxide), coenzyme Q 10 (CoQ 10 ; part of the electron transport chain and an antioxidant), idebenone (a synthetic analogue of CoQ 10 ), EPI-743 (a novel oral potent 2-electron redox cycling agent), creatine (a precursor of phosphocreatine), combined administration (of creatine, α-lipoate, and CoQ 10 ), and exercise training (to increase muscle mitochondria). These trials have included patients with various mitochondrial disorders, a selected subcategory of mitochondrial disorders, or specific mitochondrial disorders (Leber hereditary optic neuropathy or mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes). The trial designs have varied from open-label/uncontrolled, openlabel/controlled, or double-blind/placebo-controlled/crossover. Primary outcomes have ranged from single, clinicallyrelevant scores to multiple measures. Eight of these trials have been well-controlled, completed trials. Of these only 1 (treatment with creatine) showed a significant change in primary outcomes, but this was not reproduced in 2 subsequent trials with creatine with different patients. One trial (idebenone treatment of Leber hereditary optic neuropathy) did not show significant improvement in the primary outcome, but there was significant improvement in a subgroup of patients. Despite the paucity of benefits found so far, well-controlled clinical trials are essential building blocks in the continuing search for more effective treatment of mitochondrial disease, and current trials based on information gained from these prior experiences are in progress. Because of difficulties in recruiting sufficient mitochondrial disease patients and the relatively large expense of conducting such trials, advantageous strategies include crossover designs (where possible), multicenter collaboration, and the selection of very few, clinically relevant, primary outcomes.

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Section: Epi-743mentioning

confidence: 84%

“…Another clinical trial of EPI-743 for children with genetically-defined Leigh syndrome was conducted in Rome [43]. This also was an open-label trial.…”

Section: Epi-743mentioning

confidence: 99%

Review of Clinical Trials for Mitochondrial Disorders: 1997–2012

Kerr

2013

Neurotherapeutics

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“…The EPI-743 treatment was beneficial to patients with LS due to mutations in SURF1 and in LS with secondary COX deficiency due to mutated ETHE1. 17 In vitro studies in patient fibroblasts showed that copper 18 and copper with bezafibrate supplementation rescued cells harboring mutations in SCO2 encoding a COX copper-chaperone 19 while L-cystein supplementation improved mitochondrial function in cells with TRMU mutations. 20 However, as the COX6B1 defect does not cause LS and the protein is not a copper chaperone but an integral COX subunit, we evaluated a number of other potentially beneficial molecules for their ability to improve mitochondrial function in the patient's fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial complex IV deficiency, caused by mutated COX6B1, is associated with encephalomyopathy, hydrocephalus and cardiomyopathy

et al. 2014

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Isolated cytochrome c oxidase (COX) deficiency is a prevalent cause of mitochondrial disease and is mostly caused by nuclear-encoded mutations in assembly factors while rarely by mutations in structural subunits. We hereby report a case of isolated COX deficiency manifesting with encephalomyopathy, hydrocephalus and hypertropic cardiomyopathy due to a missense p.R20C mutation in the COX6B1 gene, which encodes an integral, nuclear-encoded COX subunit. This novel mutation was predicted to be severe in silico. In accord, enzymatic activity was undetectable in muscle and fibroblasts, was severely decreased in lymphocytes and the COX6B1 protein was barely detectable in patient's muscle mitochondria. Complementation with the wild-type cDNA by a lentiviral construct restored COX activity, and mitochondrial function was improved by 5-aminoimidazole-4-carboxamide ribonucleotide, resveratrol and ascorbate in the patient's fibroblasts. We suggest that genetic analysis of COX6B1should be included in the investigation of isolated COX deficiency, including patients with cardiac defects. Initial measurement of COX activity in lymphocytes may be useful as it might circumvent the need for invasive muscle biopsy. The evaluation of ascorbate supplementation to patients with mutated COX6B1 is warranted.

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“…63 Although its precise mechanism of cellular action has yet to be fully elucidated, EPI-743 treatment has been shown to replenish the level of the antioxidant, reduced glutathione (GSH), possibly resulting from its ability to facilitate the transfer of electrons between NOQ1 and GSH reductase. 64 In addition to its ability to restore cellular GSH status, the beneficial effects of EPI-743 in the treatment of mitochondrial disease may result from its possible interaction with the transcription factor, nuclear factor E2-related factor 2 (Nrf2), which regulates both the expression of antioxidant proteins and cellular energy metabolism. 63,65 Although a number of small studies and case reports have illustrated the potential benefits of CoQ 10 in the treatment of patients with MRC disorder, 25 few controlled clinical trials have been conducted to evaluate its effectiveness.…”

Section: Treatment Of Mrc Disordersmentioning

confidence: 99%

Coenzyme Q₁₀ in the Treatment of Mitochondrial Disease

Neergheen

Chalasani

Wainwright

et al. 2017

Journal of Inborn Errors of Metabolism and Screening

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Currently, there is a paucity of available treatment strategies for oxidative phosphorylation disorders. Coenzyme Q 10 (CoQ 10 ) and related synthetic quinones are the only agents to date that have proven to be beneficial in the treatment of these heterogeneous disorders. The therapeutic efficacy of CoQ 10 is not restricted to patients with an underlying CoQ 10 deficiency and is thought to result from its ability to restore electron flow in the mitochondrial respiratory chain (MRC) as well as to increase the cellular antioxidant capacity. At present, however, there is no consensus on the appropriate dosage or therapeutic plasma level of CoQ 10 , and this information will be required before CoQ 10 can be utilized effectively in the treatment of mitochondrial disease. The following review will outline our current knowledge on the use of CoQ 10 in the treatment of MRC disorders and primary CoQ 10 deficiencies.

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EPI-743 reverses the progression of the pediatric mitochondrial disease—Genetically defined Leigh Syndrome

Cited by 165 publications

References 18 publications

Review of Clinical Trials for Mitochondrial Disorders: 1997–2012

Review of Clinical Trials for Mitochondrial Disorders: 1997–2012

Mitochondrial complex IV deficiency, caused by mutated COX6B1, is associated with encephalomyopathy, hydrocephalus and cardiomyopathy

Coenzyme Q₁₀ in the Treatment of Mitochondrial Disease

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EPI-743 reverses the progression of the pediatric mitochondrial disease—Genetically defined Leigh Syndrome

Cited by 165 publications

References 18 publications

Review of Clinical Trials for Mitochondrial Disorders: 1997–2012

Review of Clinical Trials for Mitochondrial Disorders: 1997–2012

Mitochondrial complex IV deficiency, caused by mutated COX6B1, is associated with encephalomyopathy, hydrocephalus and cardiomyopathy

Coenzyme Q10 in the Treatment of Mitochondrial Disease

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Product

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Coenzyme Q₁₀ in the Treatment of Mitochondrial Disease