key: cord-1015054-ij2dprj3
authors: Almannai, Mohammed; El-Hattab, Ayman W.; Ali, May; Soler-Alfonso, Claudia; Scaglia, Fernando
title: Clinical trials in mitochondrial disorders, an update
date: 2020-10-06
journal: Mol Genet Metab
DOI: 10.1016/j.ymgme.2020.10.002
sha: c5fe26e74133992ed2cb3f3f8c9046f3d5707235
doc_id: 1015054
cord_uid: ij2dprj3

Mitochondrial disorders comprise a molecular and clinically diverse group of diseases that are associated with mitochondrial dysfunction leading to multi-organ disease. With recent advances in molecular technologies, the understanding of the pathomechanisms of a growing list of mitochondrial disorders has been greatly expanded. However, the therapeutic approaches for mitochondrial disorders have lagged behind with treatment options limited mainly to symptom specific therapies and supportive measures. There is an increasing number of clinical trials in mitochondrial disorders aiming for more specific and effective therapies. This review will cover different treatment modalities currently used in mitochondrial disorders, focusing on recent and ongoing clinical trials.

supplementation with CoQ 10 leads to a favorable outcome in primary CoQ 10 deficiency 13 . The use of CoQ 10 in a randomized clinical trial in 30 patients with mitochondrial disorders (15 patients with Mitochondrial Lactic Acidosis and Stroke-like Episodes (MELAS) and the rest with other mitochondrial disorders) showed minor effects on cycle exercise aerobic capacity and post-exercise lactate 14 . In a phase 3, randomized, double-blind, cross-over trial in children with mitochondrial diseases and documented deficiency of respiratory chain complexes or a molecular diagnosis, no statistically significant difference was documented with CoQ 10 compared to placebo in achieving the primary outcome measures; McMaster gross motor function and pediatric quality of life scales (https://clinicaltrials.gov/ct2/show/NCT00432744).

Idebenone is a CoQ 10 analogue that shares the quinone moiety with CoQ 10 but has a shorter lipophilic tail. This distinct chemical structure results in better bioavailability and allows idebenone to cross the blood-brain barrier and mitochondrial membranes more easily 15 .

Idebenone also acts as an electron carrier in the mitochondrial electron transport chain (ETC).

While its original properties were promising, the results of clinical trials using idebenone in humans have not demonstrated significant efficacy. In patients with MELAS syndrome, a phase 2a, randomized, double blind, placebo-controlled, dose finding study did not show a statistically significant difference between idebenone versus placebo on the primary outcome (mean change in cerebral lactate concentration) 16 (https://www.clinicaltrials.gov/ct2/show/NCT00887562) ( Table 1) . A randomized, double-blinded, placebo-controlled study (RHODOS) evaluating idebenone in patients with Leber hereditary optic neuropathy (LHON) did not demonstrate a statistically significant difference in recovery of visual acuity but it showed that patients with discordant visual acuities were more likely to benefit from idebenone, in whom secondary endpoints were significantly different between the idebenone and the placebo group J o u r n a l P r e -p r o o f Journal Pre-proof (https://clinicaltrials.gov/ct2/show/NCT00747487) 17 . A follow up report for this study demonstrated that the beneficial effect from idebenone persisted despite discontinuation of therapy 18 . LHON is the only mitochondrial disease for which idebenone has been recently approved by the European Medicine Agency (EMA) . An open-label interventional phase IV trial to further assesses the efficacy and safety of idebenone (Raxone) in the long-term treatment of LHON patients is currently active but not recruiting as it reached recruitment target with 197 patients enrolled (https://clinicaltrials.gov/ct2/show/NCT02774005).

Cysteamine bitartrate is an aminothiol used as an approved therapy for nephropathic cystinosis 19 . Cysteamine breaks the disulfide bond of cystine, forming cysteine-cysteamine disulfide and cysteine, the latter of which is a precursor of glutathione biosynthesis 20, 21 . Thus, a delayed release form of cysteamine bitartrate was repurposed and used as RP103 in an open label, dose-escalating study to assess its safety and efficacy in children with mitochondrial diseases. This initial study was followed by a long-term extension study that was terminated due to lack of efficacy (https://clinicaltrials.gov/ct2/show/NCT02023866 and https://clinicaltrials.gov/ct2/show/NCT02473445).

EPI-743 (Now it is PTC-743) is a para-benzoquinone analog that exerts its antioxidant effects through repletion of reduced intracellular glutathione 22 . In an open-label study in patients with a heterogeneous group of mitochondrial disorders, EPI-743 was associated with clinical improvement in most subjects treated 22 . Another open-label study in children with Leigh syndrome showed that treatment with EPI-743 was associated with reversal of disease progression 23 25 . In another open-label study, five children with a mitochondrial syndrome named RARS2 deficiency received EPI-743 during a year with an extension phase that is still ongoing.

Two children showed resolution of status epilepticus whereas the other three had a decrease in the frequency and duration of seizures 25 . EPI-743 prevented ferroptosis in cells derived from patients with mitochondrial disease-associated epilepsy 26 . Ferroptosis is a form of irondependent programmed cell death associated with glutathione depletion and production of lipid peroxides. It has been implicated in a number of disorders, including epilepsy 26 . A randomized trial to assess the efficacy and safety of EPI-743 for the treatment of mitochondrial disease subjects with refractory epilepsy is active but not recruiting yet (https://clinicaltrials.gov/ct2/show/NCT04378075).

Elamipretide is a mitochondrial-targeted tetrapeptide that associates with cardiolipin in the inner mitochondrial membrane. It maintains mitochondrial cristae, promotes oxidative phosphorylation, and reduces production of ROS 27, 28 . A phase 3 trial to evaluate the efficacy of elamipretide in subjects with primary mitochondrial myopathy (MMPOWER-3) was recently terminated as it did not meet its primary endpoints assessing changes in the six-minute walk test and primary mitochondrial myopathy symptom assessment (PMMSA) total fatigue score One of the aims for several agents trialed in mitochondrial disorders is the enhancement of mitochondrial biogenesis. Mitochondrial biogenesis is defined as growth and division of preexisting mitochondria, thereby increasing the number, size, and mass of mitochondrial population and enhancing the mitochondrial function 32 . One of the key regulators of mitochondrial biogenesis is PGC-1α (peroxisome proliferator-activated receptor (PPAR) γ coactivator 1α). PGC-1α is a transcriptional coactivator that augments mitochondrial biogenesis through activation of different transcriptional factors among which are nuclear respiratory factor 1(Nrf1) and nuclear respiratory factor 2(Nrf2) 33, 34 . These factors in turn control the expression of nuclear-encoded mitochondrial proteins, such as the OXPHOS proteins, as well as transcription factor A mitochondrial (TFAM), which regulates mtDNA transcription and replication 35 .

PGC-1α is regulated at transcriptional and post-translational levels to meet the dynamic cellular energetic needs 36 . AMP-activated protein kinase (AMPK) is a major energy sensor that is released in response to high AMP/ATP ratio reflecting energy deficiency 37 . It helps restoring the energy balance through several mechanisms, one of which is activating PGC-1α through direct phosphorylation 38 . AMPK, through increasing cellular NAD + levels, also enhances SIRT1(NAD + -dependent deacetylase sirtuin-1) activity, thereby causing deacetylation and activation of PGC-1α 39 .

For a long time, exercise has been well known to augment mitochondrial biogenesis 40 43 . Exercise can also reduce the percentage of mutated mtDNA through mtDNA shifting 44 . Endurance and resistance exercise were found to be safe for patients with mitochondrial myopathy 45 . A trial to evaluate the effect of resistance exercise training on patients with Barth Syndrome is completed, but results are not available yet. The primary outcome measure is the change in exercise tolerance whereas secondary outcomes include change in muscle strength, quality of life, and left ventricular systolic strain (https://clinicaltrials.gov/ct2/show/NCT01629459).

Another compound that is being evaluated to promote mitochondrial biogenesis is bezafibrate.

Bezafibrate, an amphipathic carboxylic acid, is a pan-PPAR agonist and therefore it activates the PGC-1α axis 46 . In HeLa cell line, bezafibrate significantly increased PGC-1α and OXPHOS proteins levels 47 . Bezafibrate treatment in fibroblasts from a patient with DNM1L pathogenic variant resulted in normalized ATP production and oxygen consumption and it improved mitochondrial morphology 48 Besides direct effect through SIRT1 activation, RSV could also improve cellular conditioning through SIRT3 activation ,which in turn upregulates mitochondrial superoxide dismutase 56,57 . In a randomized controlled trial, exercise added to RSV treatment in elderly subjects improved mitochondrial density and muscle fatigue resistance compared to placebo and exercise treatments 58 . A randomized-controlled trial to evaluate RSV supplementation on physical ability and muscle metabolism in patients with mitochondrial myopathy and patients with VLCAD and CPTII deficiencies was recently completed but results are not available. The primary outcome was decrease in heart rate during exercise, whereas secondary outcomes included peak oxygen utilization, fatty acid oxidation, perceived exertion, and self-rated fatigue (https://clinicaltrials.gov/ct2/show/NCT03728777).

AICAR (5-aminoimidazole-4-carboxamide ribonucleotide), an adenosine analog, is a known activator of AMPK 59 , making it a potential therapeutic target in mitochondrial disorders. Studies J o u r n a l P r e -p r o o f in animal models and human cells though revealed inconsistent effects of AICAR treatment on mitochondrial biogenesis and function 60-64 . Epicatechin is a naturally occurring molecule that belongs to flavonoids family. It is found in high concentrations in cocoa 65 . Mice fed with (-)epicatechin showed increased mitochondrial biogenesis in hindlimb and heart muscles and better exercise performance 66 . In a randomized-controlled trial, dark chocolate (epicatechin rich cocoa) intake in sedentary subjects was associated with better exercise performance and mitochondrial biogenesis 67 . Mitochondrial biogenesis augmentation was attributed to increase concentration of upstream inducers like AMPK 67,68 and nitric oxide synthase 69 . Moreover, Moreno-Ulloa et al.

showed that treatment of mouse skeletal muscle cells with (-)-epicatechin stimulated mitochondrial biogenesis through activation of G-protein coupled estrogen receptor (GPER1) 70 .

No human trials in mitochondrial disorders have been conducted so far with AICAR or epicatechin.

Omaveloxolone (RTA 408) is a semi-synthetic triterpenoid that prevents ubiquitination of Nrf2 and therefore potentiates it action 71, 72 . In neural cells from mouse models and fibroblasts from patients with FA, omaveloxolone restored substrate availability and complex I activity and was able to protect the cells against oxidative stress 73 . Recently, the results of the MOTOR trial were published. Fifty-three patients with mitochondrial myopathy caused by known nuclear or mitochondrial DNA pathogenic variants participated in a double-blind study and were randomized to either 12 weeks of escalating doses of omaveloxolone or placebo. Overall, omaveloxolone was well tolerated. No statistically significant differences in peak cycling exercise workload (primary outcome) or in 6-minute walk test (secondary outcome) were observed after treatment. However, treatment resulted in reduced heart rate and lactate levels during submaximal exercise, indicating improved mitochondrial function and submaximal J o u r n a l P r e -p r o o f exercise tolerance. The authors suggested further studies need to be conducted with a more homogenous population, and a larger number of patients 74 (https://clinicaltrials.gov/ct2/show/NCT02255422). NAD + (nicotinamide adenine dinucleotide) is a cofactor for SIRT1, which then activates PGC-1α and mitochondrial biogenesis 75 . The NAD + /NADH ratio is also essential for several metabolic pathways including citric acid cycle and fatty acid oxidation 75 79 . KL1333 is an NAD+ modulator that increases intracellular NAD + levels via NADH oxidation and was shown to improve mitochondrial dysfunction in MELAS fibroblasts 80 . There is an ongoing phase one study to assess safety and tolerability of KL1333 in healthy subjects and patients with primary mitochondrial disease (https://clinicaltrials.gov/ct2/show/NCT03888716).

Taurine is a sulfur-containing amino acid that can augment mitochondrial biogenesis via PGC-1α activation and it is also essential for mitochondrial protein synthesis through modifications of taurine-containing uridines of the anticodon in a subset of mitochondrial tRNAs 81, 82 . This taurine modification is defective in patients with MELAS syndrome and some other mitochondrial

disorder. An open-label, phase III trial was conducted to evaluate taurine supplementation over 52 weeks in 10 patients with MELAS and recurrent stroke-like episodes. 60% of patients had complete prevention of stroke-like episodes during the evaluation period and taurine reduced the annual relapse rate of stroke-like episodes from 2.22 to 0.72 (P=0.001) 83 .

Finally, REN001 is a recently developed drug that works as PPAR-δ agonist. It was found to be safe and well tolerated in 23 adult patients with primary mitochondrial myopathies in a 12- week open label trial. A multicenter placebo controlled clinical trial is expected to start in 2021 (https://clinicaltrials.gov/ct2/show/NCT03862846). Urolithin A is a gut microbiota-generated small metabolite that can induce mitophagy 88 . In a recent trial, Urolithin A was evaluated in healthy, sedentary elderly individuals. It was found to be safe and also it modulated plasma acylcarnitines and skeletal muscle mitochondrial gene expression with improved mitochondrial and cellular health 89 . No human trials in mitochondrial disorders have been conducted so far using this compound.

Nitric oxide (NO) is produced by vascular endothelial cells and it relaxes vascular smooth muscles and maintains patency of small blood vessels and blood flow through microvasculature 90, 91 . NO deficiency in mitochondrial diseases can contribute to the pathogenesis of several complications observed in these conditions including stroke-like episodes, myopathy, and lactic acidosis 3,92,93 . J o u r n a l P r e -p r o o f NO is formed from arginine via the enzyme NO synthase, which catalyzes the conversion of arginine to citrulline. Citrulline can be converted back to arginine via argininosuccinate synthase and argininosuccinate lyase 94 . Both NO production impairment and postproduction sequestration cause the deficiency in mitochondrial disorders. NO production can be reduced because of NO synthase inhibition and decreased intracellular availability of NO precursors arginine and citrulline. Postproduction NO sequestration occurs due to NO shunting into reactive nitrogen species formation and binding to cytochrome C oxidase 93 .

The administration of intravenous arginine to subjects with MELAS syndrome during strokelike episodes was shown to improve the clinical symptoms associated with these episodes, and oral arginine supplementation at the interictal phase was shown to decrease frequency and severity stroke-like episodes [95] [96] [97] . The use of arginine intravenously during stroke-like episodes and orally as maintenance therapy has been recommend in treating individuals with MELAS syndrome 98 . In a recent report, a trough plasma arginine level of ≥168 micromoles/L was found to be optimal for prevention of stroke like episodes 99 .

Stable isotope studies have demonstrated that arginine and citrulline supplementation can increase NO production in children and adults with MELAS syndrome 100, 101 . These studies also found that citrulline supplementation induced a greater increase in NO synthesis rate than arginine supplementation indicating that citrulline is a more effective NO precursor, and therefore may have a better therapeutic effect, than arginine. This can be due to the superiority of citrulline in raising plasma and intracellular arginine levels, leading to more arginine availability for NO synthesis 93 Many of the physiological functions of NO are mediated through its primary receptor, soluble guanylyl cyclase (SGC) 103 . Following a dose determination study in healthy volunteers, a phase 2a study to assess safety and tolerability of a CNS penetrant-SGC stimulator (IW-6463) in patients with MELAS is planned to start, but no recruiting yet (https://clinicaltrials.gov/ct2/show/NCT04475549).

Gene therapy for mitochondrial disorders is challenging. The mitochondria are under dual genome control and they contain their own DNA (mtDNA); however, most of the mitochondrial proteins are encoded by nuclear genes 104 . Most mitochondrial disorders have clinical features consistent with multi-organ disease, and therefore for a gene therapy trial to be successful, the vector should be expressed throughout the body and should be able to cross the blood-brain barrier 105 

The maintenance of mtDNA depends on a number of nuclear DNA-encoded proteins that play roles in either mtDNA synthesis or in the provision of a constant and balanced supply of nucleotides. The latter is achieved by nucleotide recycling inside the mitochondria and nucleotide import from the cytosol. Mitochondrial DNA maintenance defects are a group of diseases caused by mutations in the nuclear genes involved in mtDNA maintenance resulting in impaired mtDNA synthesis leading to quantitative (mtDNA depletion) and qualitative (multiple mtDNA deletions) defects in mtDNA 125 .

As a constant and balanced supply of nucleotides is crucial for mtDNA maintenance, mtDNA maintenance defects associated with nucleotide metabolism defects can be amenable to J o u r n a l P r e -p r o o f therapeutic administration of nucleotides. This approach aims to restore the imbalanced mitochondrial nucleotide pools which can improve mtDNA maintenance and the clinical manifestations associated with these diseases including the deficiencies of thymidine kinase 2 and thymidine phosphorylase 126 .

Thymidine kinase 2 (TK2) is a key enzyme in the mitochondrial pyrimidine nucleotide salvage pathway. TK2 deficiency causes a depletion of mitochondrial nucleotides leading to impairment of mtDNA synthesis and a myopathic mtDNA depletion syndrome 127 . In Tk2 deficient mice, the administration of deoxythymidine(dT) and deoxycytidine(dC) was found to delay the onset of disease, prolong the life span of Tk2-deficient mice, and restore mtDNA content as well as ETC complexes activities and levels 128 

Jain et al. performed a genome-wide, Cas9-mediated screen to identify factors that could protect against ETC inhibition and identified Von Hippel-Lindau (VHL) to be the most effective genetic suppressor of mitochondrial disease. This effect stems from the important role of VHL in degrading hypoxia inducible transcription factors (HIF) and therefore, suppression of VHL allows for continues activation of the HIF 133 . The protective effect of hypoxia was further explored in vhl-null zebrafish which had better survival when exposed to ETC inhibitors like antimycin compared to heterozygous and wild-type controls. Furthermore, chronic hypoxia was found to prevent or even reverse neurological dysfunction in Ndufs4 knockout mice 133, 134 . In a subsequent study, the same group showed that interventions that normalize brain tissue hyperoxia, rather than those that activate HIF, reverse the neurological disease, indicating that unused oxygen could be the likely culprit in the disease pathology 135 

Allogenic hematopoietic stem cell transplant (AHSCT) has been tried as a measure to restore thymidine phosphorylase (TP) activity in MNGIE patients 144 . In a retrospective review of 24 patients with MNGIE who had AHSCT, only 9 (37.5%) were alive at last follow-up.

Death was attributed to transplant (9/15) and to the primary disease (6/15). In all survivors, TP activity normalized after transplant. Survival was found to be associated with human leukocyte antigen match 10/10; and absence of liver disease, history of gastrointestinal pseudoobstruction or both 145 . Currently, there is an active trial to assess the safety of AHSCT in patients with MNGIE (https://clinicaltrials.gov/ct2/show/NCT02427178).

Due to the multi-organ nature of mitochondrial disorders, the options for organs and stem cell transplantation are limited. The 5-year survival rate post orthotopic liver transplantation (OLT) in 14 patients with hepatocerebral mitochondrial DNA depletion syndrome due to deoxyguanosine kinase (DGUOK) deficiency transplanted in infancy was 36% 146 . In the presence of abnormal neurological features in DGUOK deficiency, liver transplantation was not associated with increased survival and therefore should not be considered 147 . In 6 patients with MNGIE, including one child, OLT was associated with 100% survival, significant J o u r n a l P r e -p r o o f improvement in nucleosides levels, and stabilization of clinical course with short term follow up [148] [149] [150] . OLT also led to clinical and biochemical improvement in three patients with ethylmalonic encephalopathy 151, 152 . Cardiac transplantation has been performed in some patients with Barth syndrome 153 . The outcomes of solid organ transplant in subjects with mitochondrial diseases could be comparable with those with non-mitochondrial disease provided there is good selection and preparation of patient 154 .

Mitochondrial diseases caused by defects in nuclear mitochondrial genes follow Mendelian inheritance and prevention in these disorders can be achieved through prenatal testing or preimplantation genetic testing (PGT) 2 . The situation is more daunting in mtDNA-related disorders in which counseling and prevention are complicated by maternal inheritance of mtDNA, heteroplasmy, and the presence of mitochondrial genetic bottleneck. PGT can be used in these situations to select embryos with low level heteroplasmy 155 . This option is not suitable in mothers with homoplasmic mutations or those unable to produce embryos with low mutation load 156 . Mitochondrial donation or mitochondrial replacement therapy is a method in which the nuclear DNA from a mother with mtDNA mutation is transferred to oocyte or zygote that contains normal mtDNA from a healthy donor 156 

In this review, we discuss the various modalities used in treatment of mitochondrial disorders and we focus on the recent and the ongoing clinical trials. While the treatment of mitochondrial disorders still lags behind in comparison to the advances in the diagnosis of these disorders, recent efforts in this field to provide a more targeted approach are promising. The better understating of the pathophysiologic mechanisms in mitochondrial disorders, recently acquired knowledge of the epidemiology and natural history of these disorders, and the establishment of collaborative, multi-center consortia, will allow for the design of more efficient clinical trials.

The use of metabolomics in mitochondrial disorders may also help in identifying disease specific biomarkers that could potentially be used to monitor the effects of investigational drugs. 

Inherited Neuromuscular Diseases: Translation from Pathomechanisms to Therapies

Mitochondrial diseases

Mitochondrial cytopathies

A proposed nosology of inborn errors of metabolism

Mitochondrial diseases in North America: An analysis of the NAMDC Registry

Towards a therapy for mitochondrial disease: an update

A modern approach to the treatment of mitochondrial disease

Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society

Oxidative Stress in Inherited Mitochondrial Diseases

Oxidative stress: the mitochondria-dependent and mitochondria-independent pathways of apoptosis

Coenzyme Q10: Absorption, tissue uptake, metabolism and pharmacokinetics

Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects

Primary and secondary coenzyme Q10 deficiency: the role of therapeutic supplementation

A randomized trial of coenzyme Q10 in mitochondrial disorders

Emerging Therapies for Mitochondrial Diseases

A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy

Persistence of the treatment effect of idebenone in Leber's hereditary optic neuropathy

Effects of long-term cysteamine treatment in patients with cystinosis

Cysteamine restores glutathione redox status in cultured cystinotic proximal tubular epithelial cells

Pre-clinical evaluation of cysteamine bitartrate as a therapeutic agent for mitochondrial respiratory chain disease

Initial experience in the treatment of inherited mitochondrial disease with EPI-743

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

Effect of EPI-743 on the Clinical Course of the Mitochondrial Disease Leber Hereditary Optic Neuropathy

Clinical Trials in Mitochondrial Disease: An Update on EPI-743 and RP103

Targeting ferroptosis: A novel therapeutic strategy for the treatment of mitochondrial disease-related epilepsy

First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics

Serendipity and the Discovery of Novel Compounds That Restore Mitochondrial Plasticity

Elamipretide in Patients with Barth Syndrome: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial Followed by 36-Week Open-Label Extension

KH176 Safeguards Mitochondrial Diseased Cells from Redox Stress-Induced Cell Death by Interacting with the Thioredoxin System/Peroxiredoxin Enzyme Machinery

The KHENERGY Study: Safety and Efficacy of KH176 in Mitochondrial m.3243A>G Spectrum Disorders

Regulation of mitochondrial biogenesis

Metabolic control through the PGC-1 family of transcription coactivators

Transcriptional control of mitochondrial biogenesis: the central role of PGC-1alpha

Mitochondrial biogenesis through activation of nuclear signaling proteins

Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis

AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance

AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha

AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity

Cyclophorase system. XXIII. Correlation of cyclophorase activity and mitochondrial density in striated muscle

Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1

Role of PGC-1α signaling in skeletal muscle health and disease

PGC-1α is dispensable for exerciseinduced mitochondrial biogenesis in skeletal muscle

Mitochondrial DNA shifting in older adults following resistance exercise training

Exercise as a therapeutic strategy for primary mitochondrial cytopathies

Bezafibrate at Clinically Relevant Doses Decreases Serum/Liver Triglycerides via Down-Regulation of Sterol Regulatory Element-Binding Protein-1c in Mice: A Novel Peroxisome Proliferator-Activated Receptor α-Independent Mechanism

Defining the action spectrum of potential PGC-1α activators on a mitochondrial and cellular level in vivo

Bezafibrate Improves Mitochondrial Fission and Function in DNM1L-Deficient Patient Cells

Effect of bezafibrate treatment on late-onset mitochondrial myopathy in mice

Long-term bezafibrate treatment improves skin and spleen phenotypes of the mtDNA mutator mouse

Metabolic effects of bezafibrate in mitochondrial disease

Epicatechin enhances fatigue resistance and oxidative capacity in mouse muscle

Beneficial effects of dark chocolate on exercise capacity in sedentary subjects: underlying mechanisms. A double blind, randomized, placebo controlled trial

Increase in AMPK brought about by cocoa is renoprotective in experimental diabetes mellitus by reducing NOX4/TGFβ-1 signaling

Cell membrane mediated (-)-epicatechin effects on upstream endothelial cell signaling: evidence for a surface receptor

Epicatechin stimulates mitochondrial biogenesis and cell growth in C2C12 myotubes via the G-protein coupled estrogen receptor

Topical application of the synthetic triterpenoid RTA 408 activates Nrf2 and induces cytoprotective genes in rat skin

Safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia

Novel Nrf2-Inducer Prevents Mitochondrial Defects and Oxidative Stress in Friedreich's Ataxia Models

Safety and efficacy of omaveloxolone in patients with mitochondrial myopathy: MOTOR trial

Emerging therapeutic roles for NAD(+) metabolism in mitochondrial and agerelated disorders

Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3

NAD(+)-dependent activation of Sirt1 corrects the phenotype in a mouse model of mitochondrial disease

Niacin Cures Systemic NAD+ Deficiency and Improves Muscle Performance in Adult-Onset Mitochondrial Myopathy

Mitochondrial Diseases: Hope for the Future

Defective Mitochondrial tRNA Taurine Modification Activates Global Proteostress and Leads to Mitochondrial Disease

Taurine as a constituent of mitochondrial tRNAs: new insights into the functions of taurine and human mitochondrial diseases

Taurine supplementation for prevention of stroke-like episodes in MELAS: a multicentre, open-label, 52-week phase III trial

Minireview: Selective Degradation of Mitochondria by Mitophagy

mTOR Inhibition Alleviates Mitochondrial Disease in a Mouse Model of Leigh Syndrome

Rapamycin rescues mitochondrial myopathy via coordinated activation of autophagy and lysosomal biogenesis

Exploring mTOR inhibition as treatment for mitochondrial disease

Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents

The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans

Effect of exercise training on endotheliumderived nitric oxide function in humans

The pharmacology of nitric oxide in the peripheral nervous system of blood vessels

Glucose metabolism derangements in adults with the MELAS m.3243A>G mutation

Citrulline and arginine utility in treating nitric oxide deficiency in mitochondrial disorders

Endothelial nitric oxide production is tightly coupled to the citrulline-NO cycle

Endothelial dysfunction in MELAS improved by l-arginine supplementation

L-arginine improves the symptoms of strokelike episodes in MELAS

Recommendations for the Management of Strokelike Episodes in Patients With Mitochondrial Encephalomyopathy, Lactic Acidosis, and Strokelike Episodes

Arginine therapy in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes

Impaired nitric oxide production in children with MELAS syndrome and the effect of arginine and citrulline supplementation

Restoration of impaired nitric oxide production in MELAS syndrome with citrulline and arginine supplementation

Endothelial Dysfunction and the Effect of Arginine and Citrulline Supplementation in Children and Adolescents With Mitochondrial Diseases

Mechanism of NO binding to soluble guanylyl cyclase: implication for the second NO binding to the heme proximal site

Mitochondrial DNA replication: clinical syndromes

The special considerations of gene therapy for mitochondrial diseases

Effective AAVmediated gene therapy in a mouse model of ethylmalonic encephalopathy

Gene therapy using a livertargeted AAV vector restores nucleoside and nucleotide homeostasis in a murine model of MNGIE

Long-Term Sustained Effect of Liver-Targeted Adeno-Associated Virus Gene Therapy for Mitochondrial Neurogastrointestinal Encephalomyopathy

Targeting nucleic acids into mitochondria: progress and prospects

Efficiency and safety of AAV-mediated gene delivery of the human ND4 complex I subunit in the mouse visual system

Nuclear expression of a mitochondrial DNA gene: mitochondrial targeting of allotopically expressed mutant ATP6 in transgenic mice

Optimized allotopic expression of the human mitochondrial ND4 prevents blindness in a rat model of mitochondrial dysfunction

The optimized allotopic expression of ND1 or ND4 genes restores respiratory chain complex I activity in fibroblasts harboring mutations in these genes

What limits the allotopic expression of nucleus-encoded mitochondrial genes? The case of the chimeric Cox3 and Atp6 genes

Gene Therapy for Leber Hereditary Optic Neuropathy: Low-and Medium-Dose Visual Results

Long-term outcomes of gene therapy for the treatment of Leber's hereditary optic neuropathy

Bilateral Visual Improvement with Unilateral Gene Therapy for Leber Hereditary Optic Neuropathy (LHON)

Heteroplasmy Shifting as Therapy for Mitochondrial Disorders

Therapeutic Manipulation of mtDNA Heteroplasmy: A Shifting Perspective

Selective elimination of mutant mitochondrial genomes as therapeutic strategy for the treatment of NARP and MILS syndromes

Genome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo

Mitochondrially targeted ZFNs for selective degradation of pathogenic mitochondrial genomes bearing large-scale deletions or point mutations

Targeted elimination of mutant mitochondrial DNA in MELAS-iPSCs by mitoTALENs

Selective elimination of mitochondrial mutations in the germline by genome editing

Mitochondrial DNA maintenance defects

Insights into deoxyribonucleoside therapy for mitochondrial TK2 deficient mtDNA depletion

TK2-Related Mitochondrial DNA Maintenance Defect, Myopathic Form

Deoxycytidine and Deoxythymidine Treatment for Thymidine Kinase 2 Deficiency

Deoxynucleoside Therapy for Thymidine Kinase 2-Deficient Myopathy

Zogenix Presents Positive Clinical Study Results for Investigational Treatment for TK2 Deficiency -Zogenix, Inc. Accessed

Limited dCTP availability accounts for mitochondrial DNA depletion in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)

Administration of deoxyribonucleosides or inhibition of their catabolism as a pharmacological approach for mitochondrial DNA depletion syndrome

Hypoxia as a Therapy for Mitochondrial Disease

Hypoxia treatment reverses neurodegenerative disease in a mouse model of Leigh syndrome

Syndrome Mouse Model Can Be Rescued by Interventions that Normalize Brain Hyperoxia, but Not HIF Activation

Clinical and biochemical improvements in a patient with MNGIE following enzyme replacement

Mesenchymal stem cells and their mitochondrial transfer: a double-edged sword

Mesenchymal Stem Cells Shift Mitochondrial Dynamics and Enhance Oxidative Phosphorylation in Recipient Cells

Miro1 regulates intercellular mitochondrial transport & enhances mesenchymal stem cell rescue efficacy

Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury

Mitochondria transfer from mesenchymal stem cells structurally and functionally repairs renal proximal tubular epithelial cells in diabetic nephropathy in vivo

First-in-Human Mitochondrial Augmentation of Hematopoietic Stem Cells in Pearson Syndrome

Promising Results for Kearns-Sayre Syndrome of First in Man Treatment by Mitochondrial Augmentation Therapy (457)

Allogeneic stem cell transplantation corrects biochemical derangements in MNGIE

Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy

Long-term outcomes after liver transplantation for deoxyguanosine kinase deficiency: a single-center experience and a review of the literature

Abnormal neurological features predict poor survival and should preclude liver transplantation in patients with deoxyguanosine kinase deficiency

Liver transplantation for mitochondrial neurogastrointestinal encephalomyopathy

Liver transplant reverses biochemical imbalance in mitochondrial neurogastrointestinal encephalomyopathy

Successful liver transplantation in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)

Liver transplant in ethylmalonic encephalopathy: a new treatment for an otherwise fatal disease

Improved clinical outcome following liver transplant in patients with ethylmalonic encephalopathy

Clinical Characteristics and Outcomes of Cardiomyopathy in Barth Syndrome: The UK Experience

Solid organ transplantation in primary mitochondrial disease: Proceed with caution

Concise Reviews: Assisted Reproductive Technologies to Prevent Transmission of Mitochondrial DNA Disease

Advances in methods for reducing mitochondrial DNA disease by replacing or manipulating the mitochondrial genome

Mitochondrial Replacement Therapy in Reproductive Medicine

Mitochondrial donation: from test tube to clinic

Title: Clinical Trials in Mitochondrial disorders, an Update

Section of Medical Genetics, Children's Hospital, King Fahad Medical City

Resveratrol supplementation in patients with mitochondrial myopathies and skeletal muscle fatty acid oxidation disorders: A double-blind, placebocontrolled, cross over study (NCT03728777) Decrease in heart rate during constant loa exercise (