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Gunther K, Profeta V, Keita M, Park C, Wells M, Sharma S, Schadt K, Lynch DR. Safety Monitoring of Omaveloxolone in Friedreich Ataxia: Results from One Year of Clinical Treatment. Neurol Ther 2025; 14:1105-1114. [PMID: 40304846 PMCID: PMC12089633 DOI: 10.1007/s40120-025-00749-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Accepted: 04/04/2025] [Indexed: 05/02/2025] Open
Abstract
INTRODUCTION Omaveloxolone, the only approved medication for Friedreich ataxia (FRDA), is an NRF2 activator available since July 2023. We examined safety monitoring of omaveloxolone administration over the first 12 months of administration. METHODS We recorded baseline and follow-up serum transaminase, albumin, total bilirubin, cholesterol, and brain natriuretic peptide (BNP) values as well as adverse events over 1 year in patients initiating commercial omaveloxolone therapy. RESULTS Access to omaveloxolone was obtained in 236 of individuals for whom it was prescribed. Side effects were noted in 23.8% of patient with the most common being gastrointestinal upset, headache, and fatigue baseline. Twenty-one patients (8.9%) permanently discontinued the drug during the first year. Over the first year, 56.6% of patients had at least one transaminase value above the upper limit of normal at some point. Elevations largely occurred over the first 3 months of therapy, and after 6 months of dosing, only 8.6% of patients had elevations in transaminases. Elevations were generally < 3 × the upper limit of normal and decreased with temporary pausing of the drug or dose reduction. Few changes were noted in albumin or bilirubin, and such changes did not parallel changes in transaminases, suggesting they are independent events. BNP values were generally unchanged throughout the year, and no systematic changes in blood counts were noted. Cholesterol and low-density lipoprotein (LDL) elevations were mild. CONCLUSIONS Most patients with FRDA eventually had access to omaveloxolone, and it was generally well tolerated. Side effects were modest, and, overall, most patients remained on the drug. Abnormalities in serum liver function tests were limited to transaminases, resolved with dose pausing or reduction, and diminished markedly over time. Thus, the safety features of omaveloxolone after administration largely resemble the favorable features noted during clinical trials.
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Affiliation(s)
- Katherine Gunther
- Division of Neurology, Department of Pediatrics and Neurology, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Victoria Profeta
- Division of Neurology, Department of Pediatrics and Neurology, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Medina Keita
- Division of Neurology, Department of Pediatrics and Neurology, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Courtney Park
- Division of Neurology, Department of Pediatrics and Neurology, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - McKenzie Wells
- Division of Neurology, Department of Pediatrics and Neurology, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Sonal Sharma
- Division of Neurology, Department of Pediatrics and Neurology, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
- University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA
| | - Kimberly Schadt
- Division of Neurology, Department of Pediatrics and Neurology, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - David R Lynch
- Division of Neurology, Department of Pediatrics and Neurology, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
- University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA.
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Quatrana A, Petrillo S, Torda C, De Santis E, Bertini E, Piemonte F. Redox homeostasis and inflammation in fibroblasts of patients with Friedreich Ataxia: a possible cross talk. Front Mol Neurosci 2025; 18:1571402. [PMID: 40308559 PMCID: PMC12041223 DOI: 10.3389/fnmol.2025.1571402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Accepted: 03/25/2025] [Indexed: 05/02/2025] Open
Abstract
Redox homeostasis is impaired in Friedreich's Ataxia (FRDA), a neurodegenerative disease caused by the decreased expression of the mitochondrial protein frataxin. Nrf2, the master regulator of tissue redox balance, is defective in the disease, driving cells to ferroptosis. Neuro-inflammation is recently emerging as an additional pathological mechanism in FRDA and has to be understood in order to go deeper into the pathogenesis of the disease. As a functional cross talk between Nrf2 and NF-kB pathways has been previously reported, we wonder if inflammation may be activated in FRDA as a consequence of Nrf2 deficiency. Thus, we analyzed the expression of proteins involved in the antioxidant and inflammatory responses in fibroblasts of patients with FRDA. We found a significant activation of the TLR4/NF-kB/IL-1β axis in patients, associated to a consistent increase of the redox enzymes thioredoxin 1 (TRX1) and glutaredoxin 1 (GLRX1), which are essential to activate NF-kB under oxidative stress conditions. Furthermore, we investigated the role of 4-HNE, a by-product of lipid peroxidation, as a potential mediator between ferroptosis and inflammation in FRDA.
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Affiliation(s)
- Andrea Quatrana
- Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Sara Petrillo
- Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Caterina Torda
- Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Eleonora De Santis
- Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Enrico Bertini
- Research Unit of Neuromuscular Diseases, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Fiorella Piemonte
- Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
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Pignataro MF, Noguera ME, Herrera MG, Roman EA, Santos J. Frataxin: from the sequence to the biological role. Biophys Rev 2025; 17:449-465. [PMID: 40376404 PMCID: PMC12075029 DOI: 10.1007/s12551-025-01311-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Accepted: 03/25/2025] [Indexed: 05/18/2025] Open
Abstract
Frataxin is a small protein involved in the rare disease Friedreich's ataxia. During the last few years, significant knowledge has been gained concerning frataxin folding, structure, dynamics, and function. In eukaryotic organisms, it is located in the mitochondrial matrix, and recently, its macromolecular context was revealed. This protein is part of a decameric supercomplex consisting of six subunits required for iron-sulfur cluster assembly, where two of them alternate in a mutually exclusive manner. Regarding Frataxin, pathogenic variants were studied, and while some exhibited reduced conformational stability, others presented an altered function. In this review, we focused on different aspects concerning the biophysics and the biochemistry of frataxin and its partners, as well as on the current knowledge regarding proteostasis and post-translational modifications. The involvement of frataxin and its partners in diseases will also be addressed, including the current therapeutic approaches. Finally, a section is dedicated to understanding the phylogenetic distribution of frataxin.
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Affiliation(s)
- María Florencia Pignataro
- Departamento de Fisiología y Biología Molecular y Celular, Instituto de Biociencias, Biotecnología y Biología Traslacional (iB3), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Intendente Güiraldes, Autonomous City of Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas, Autonomous City of Buenos Aires, Argentina
| | - Martín Ezequiel Noguera
- Departamento de Fisiología y Biología Molecular y Celular, Instituto de Biociencias, Biotecnología y Biología Traslacional (iB3), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Intendente Güiraldes, Autonomous City of Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas, Autonomous City of Buenos Aires, Argentina
- Instituto de Química y Fisicoquímica Biológicas, CONICET-Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, C113AAD Autonomous City of Buenos Aires, Argentina
| | - María Georgina Herrera
- Departamento de Fisiología y Biología Molecular y Celular, Instituto de Biociencias, Biotecnología y Biología Traslacional (iB3), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Intendente Güiraldes, Autonomous City of Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas, Autonomous City of Buenos Aires, Argentina
- Molecular Cell Biology, Faculty of Medicine, Ruhr University Bochum, Universitätsstr. 150, 44801 Bochum, Germany
| | - Ernesto Andrés Roman
- Laboratorio de Ingeniería Enzimática y Nanobiotecnología, Facultad de Ciencias Exactas y Naturales, Instituto de Química Biológica de La Facultad de Ciencias Exactas y Naturales (IQUIBICEN-CONICET), Universidad de Buenos Aires and Consejo Nacional de Investigaciones Científicas y Técnicas, CP1428 Buenos Aires, Argentina
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Intendente Güiraldes, Autonomous City of Buenos Aires, Argentina
| | - Javier Santos
- Departamento de Fisiología y Biología Molecular y Celular, Instituto de Biociencias, Biotecnología y Biología Traslacional (iB3), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Intendente Güiraldes, Autonomous City of Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas, Autonomous City of Buenos Aires, Argentina
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Intendente Güiraldes, Autonomous City of Buenos Aires, Argentina
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Pepin XJH, Hynes SM, Zahir H, Walker D, Semmens LQ, Suarez‐Sharp S. Understanding the mechanisms of food effect on omaveloxolone pharmacokinetics through physiologically based biopharmaceutics modeling. CPT Pharmacometrics Syst Pharmacol 2024; 13:1771-1783. [PMID: 39219492 PMCID: PMC11494823 DOI: 10.1002/psp4.13221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 07/15/2024] [Accepted: 07/17/2024] [Indexed: 09/04/2024] Open
Abstract
Omaveloxolone is a nuclear factor (erythroid-derived 2)-like 2 activator approved in the United States and the European Union for the treatment of patients with Friedreich ataxia aged ≥16 years, with a recommended dosage of 150 mg orally once daily on an empty stomach. The effect of the US Food and Drug Administration (FDA) high-fat breakfast on the pharmacokinetic profile of omaveloxolone observed in study 408-C-1703 (NCT03664453) deviated from the usual linear correlation between fed/fasted maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) ratios reported for various oral drugs across 323 food effect studies. Here, physiologically based biopharmaceutics modeling (PBBM) was implemented to predict and explain the effect of the FDA high-fat breakfast on a 150-mg dose of omaveloxolone. The model was developed and validated based on dissolution and pharmacokinetic data available across dose-ranging, food effect, and drug-drug interaction clinical studies. PBBM predictions support clinical observations of the unique effect of a high-fat meal on omaveloxolone pharmacokinetic profile, in which the Cmax increased by 350% with only a 15% increase in the AUC. Key parameters influencing omaveloxolone pharmacokinetics in the fasted state based on a parameter sensitivity analysis included bile salt solubilization, CYP3A4 activity, drug substance particle size distribution, and permeability. Mechanistically, in vivo omaveloxolone absorption was solubility and dissolution rate limited. However, in the fed state, higher bile salt solubilization led to more rapid dissolution with predominant absorption in the upper gastrointestinal tract, resulting in increased susceptibility to first-pass gut extraction; this accounts for the lack of correlation between Cmax and AUC for omaveloxolone.
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Sanz-Alcázar A, Portillo-Carrasquer M, Delaspre F, Pazos-Gil M, Tamarit J, Ros J, Cabiscol E. Deciphering the ferroptosis pathways in dorsal root ganglia of Friedreich ataxia models. The role of LKB1/AMPK, KEAP1, and GSK3β in the impairment of the NRF2 response. Redox Biol 2024; 76:103339. [PMID: 39243573 PMCID: PMC11408871 DOI: 10.1016/j.redox.2024.103339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 09/02/2024] [Indexed: 09/09/2024] Open
Abstract
Friedreich ataxia (FA) is a rare neurodegenerative disease caused by decreased levels of the mitochondrial protein frataxin. Frataxin has been related in iron homeostasis, energy metabolism, and oxidative stress. Ferroptosis has recently been shown to be involved in FA cellular degeneration; however, its role in dorsal root ganglion (DRG) sensory neurons, the cells that are affected the most and the earliest, is mostly unknown. In this study, we used primary cultures of frataxin-deficient DRG neurons as well as DRG from the FXNI151F mouse model to study ferroptosis and its regulatory pathways. A lack of frataxin induced upregulation of transferrin receptor 1 and decreased ferritin and mitochondrial iron accumulation, a source of oxidative stress. However, there was impaired activation of NRF2, a key transcription factor involved in the antioxidant response pathway. Decreased total and nuclear NRF2 explains the downregulation of both SLC7A11 (a member of the system Xc, which transports cystine required for glutathione synthesis) and glutathione peroxidase 4, responsible for increased lipid peroxidation, the main markers of ferroptosis. Such dysregulation could be due to the increase in KEAP1 and the activation of GSK3β, which promote cytosolic localization and degradation of NRF2. Moreover, there was a deficiency in the LKB1/AMPK pathway, which would also impair NRF2 activity. AMPK acts as a positive regulator of NRF2 and it is activated by the upstream kinase LKB1. The levels of LKB1 were reduced when frataxin decreased, in agreement with reduced pAMPK (Thr172), the active form of AMPK. SIRT1, a known activator of LKB1, was also reduced when frataxin decreased. MT-6378, an AMPK activator, restored NRF2 levels, increased GPX4 levels and reduced lipid peroxidation. In conclusion, this study demonstrated that frataxin deficiency in DRG neurons disrupts iron homeostasis and the intricate regulation of molecular pathways affecting NRF2 activation and the cellular response to oxidative stress, leading to ferroptosis.
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Affiliation(s)
- Arabela Sanz-Alcázar
- Departament de Ciències Mèdiques Bàsiques, IRBLleida, Universitat de Lleida, Catalonia, Spain.
| | | | - Fabien Delaspre
- Departament de Ciències Mèdiques Bàsiques, IRBLleida, Universitat de Lleida, Catalonia, Spain.
| | - Maria Pazos-Gil
- Departament de Ciències Mèdiques Bàsiques, IRBLleida, Universitat de Lleida, Catalonia, Spain.
| | - Jordi Tamarit
- Departament de Ciències Mèdiques Bàsiques, IRBLleida, Universitat de Lleida, Catalonia, Spain.
| | - Joaquim Ros
- Departament de Ciències Mèdiques Bàsiques, IRBLleida, Universitat de Lleida, Catalonia, Spain.
| | - Elisa Cabiscol
- Departament de Ciències Mèdiques Bàsiques, IRBLleida, Universitat de Lleida, Catalonia, Spain.
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Beaudin M, Dupre N, Manto M. The importance of synthetic pharmacotherapy for recessive cerebellar ataxias. Expert Rev Neurother 2024; 24:897-912. [PMID: 38980086 DOI: 10.1080/14737175.2024.2376840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 07/02/2024] [Indexed: 07/10/2024]
Abstract
INTRODUCTION The last decade has witnessed major breakthroughs in identifying novel genetic causes of hereditary ataxias, deepening our understanding of disease mechanisms, and developing therapies for these debilitating disorders. AREAS COVERED This article reviews the currently approved and most promising candidate pharmacotherapies in relation to the known disease mechanisms of the most prevalent autosomal recessive ataxias. Omaveloxolone is an Nrf2 activator that increases antioxidant defense and was recently approved for treatment of Friedreich ataxia. Its therapeutic effect is modest, and further research is needed to find synergistic treatments that would halt or reverse disease progression. Promising approaches include upregulation of frataxin expression by epigenetic mechanisms, direct protein replacement, and gene replacement therapy. For ataxia-telangiectasia, promising approaches include splice-switching antisense oligonucleotides and small molecules targeting oxidative stress, inflammation, and mitochondrial function. Rare recessive ataxias for which disease-modifying therapies exist are also reviewed, emphasizing recently approved therapies. Evidence supporting the use of riluzole and acetyl-leucine in recessive ataxias is discussed. EXPERT OPINION Advances in genetic therapies for other neurogenetic conditions have paved the way to implement feasible approaches with potential dramatic benefits. Particularly, as we develop effective treatments for these conditions, we may need to combine therapies, consider newborn testing for pre-symptomatic treatment, and optimize non-pharmacological approaches.
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Affiliation(s)
- Marie Beaudin
- Department of Neurology and Neurological Sciences, Stanford School of Medicine, Stanford, CA, USA
| | - Nicolas Dupre
- Neuroscience axis, CHU de Québec-Université Laval, Québec, QC, Canada
- Department of Medicine, Faculty of Medicine, Université Laval, Quebec, QC, Canada
| | - Mario Manto
- Service des Neurosciences, Université de Mons, Mons, Belgique
- Unité des Ataxies Cérébelleuses, Service de Neurologie, CHU-Charleroi, Charleroi, Belgique
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Chang KH, Chen CM. The Role of NRF2 in Trinucleotide Repeat Expansion Disorders. Antioxidants (Basel) 2024; 13:649. [PMID: 38929088 PMCID: PMC11200942 DOI: 10.3390/antiox13060649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 05/20/2024] [Accepted: 05/23/2024] [Indexed: 06/28/2024] Open
Abstract
Trinucleotide repeat expansion disorders, a diverse group of neurodegenerative diseases, are caused by abnormal expansions within specific genes. These expansions trigger a cascade of cellular damage, including protein aggregation and abnormal RNA binding. A key contributor to this damage is oxidative stress, an imbalance of reactive oxygen species that harms cellular components. This review explores the interplay between oxidative stress and the NRF2 pathway in these disorders. NRF2 acts as the master regulator of the cellular antioxidant response, orchestrating the expression of enzymes that combat oxidative stress. Trinucleotide repeat expansion disorders often exhibit impaired NRF2 signaling, resulting in inadequate responses to excessive ROS production. NRF2 activation has been shown to upregulate antioxidative gene expression, effectively alleviating oxidative stress damage. NRF2 activators, such as omaveloxolone, vatiquinone, curcumin, sulforaphane, dimethyl fumarate, and resveratrol, demonstrate neuroprotective effects by reducing oxidative stress in experimental cell and animal models of these diseases. However, translating these findings into successful clinical applications requires further research. In this article, we review the literature supporting the role of NRF2 in the pathogenesis of these diseases and the potential therapeutics of NRF2 activators.
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Affiliation(s)
- Kuo-Hsuan Chang
- Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center, Kueishan, Taoyuan 333, Taiwan;
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Chiung-Mei Chen
- Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center, Kueishan, Taoyuan 333, Taiwan;
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
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Slade L, Deane CS, Szewczyk NJ, Etheridge T, Whiteman M. Hydrogen sulfide supplementation as a potential treatment for primary mitochondrial diseases. Pharmacol Res 2024; 203:107180. [PMID: 38599468 DOI: 10.1016/j.phrs.2024.107180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 04/06/2024] [Accepted: 04/06/2024] [Indexed: 04/12/2024]
Abstract
Primary mitochondrial diseases (PMD) are amongst the most common inborn errors of metabolism causing fatal outcomes within the first decade of life. With marked heterogeneity in both inheritance patterns and physiological manifestations, these conditions present distinct challenges for targeted drug therapy, where effective therapeutic countermeasures remain elusive within the clinic. Hydrogen sulfide (H2S)-based therapeutics may offer a new option for patient treatment, having been proposed as a conserved mitochondrial substrate and post-translational regulator across species, displaying therapeutic effects in age-related mitochondrial dysfunction and neurodegenerative models of mitochondrial disease. H2S can stimulate mitochondrial respiration at sites downstream of common PMD-defective subunits, augmenting energy production, mitochondrial function and reducing cell death. Here, we highlight the primary signalling mechanisms of H2S in mitochondria relevant for PMD and outline key cytoprotective proteins/pathways amenable to post-translational restoration via H2S-mediated persulfidation. The mechanisms proposed here, combined with the advent of potent mitochondria-targeted sulfide delivery molecules, could provide a framework for H2S as a countermeasure for PMD disease progression.
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Affiliation(s)
- Luke Slade
- University of Exeter Medical School, University of Exeter, St. Luke's Campus, Exeter EX1 2LU, UK; Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V, Dortmund, Germany
| | - Colleen S Deane
- Human Development & Health, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK
| | - Nathaniel J Szewczyk
- Medical Research Council Versus Arthritis Centre for Musculoskeletal Ageing Research, Royal Derby Hospital, University of Nottingham, Derby DE22 3DT, United Kingdom; Ohio Musculoskeletal and Neurologic Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio 45701, Greece
| | - Timothy Etheridge
- Public Health and Sport Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter EX1 2LU, United Kingdom.
| | - Matthew Whiteman
- University of Exeter Medical School, University of Exeter, St. Luke's Campus, Exeter EX1 2LU, UK.
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Bakalakos A, Monda E, Elliott PM. The Diagnostic and Therapeutic Implications of Phenocopies and Mimics of Hypertrophic Cardiomyopathy. Can J Cardiol 2024; 40:754-765. [PMID: 38447917 DOI: 10.1016/j.cjca.2024.02.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 02/29/2024] [Accepted: 02/29/2024] [Indexed: 03/08/2024] Open
Abstract
Hypertrophic cardiomyopathy (HCM) is a common myocardial disease defined by increased left ventricular wall thickness unexplained by loading conditions. HCM frequently is caused by pathogenic variants in sarcomeric protein genes, but several other syndromic, metabolic, infiltrative, and neuromuscular diseases can result in HCM phenocopies. This review summarizes the current understanding of these HCM mimics, highlighting their importance across the life course. The central role of a comprehensive, multiparametric diagnostic approach and the potential of precision medicine in tailoring treatment strategies are emphasized.
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Affiliation(s)
- Athanasios Bakalakos
- Institute of Cardiovascular Science, University College London, London, United Kingdom
| | - Emanuele Monda
- Institute of Cardiovascular Science, University College London, London, United Kingdom; Department of Translational Medical Sciences, Inherited and Rare Cardiovascular Diseases, University of Campania "Luigi Vanvitelli," Naples, Italy
| | - Perry Mark Elliott
- Institute of Cardiovascular Science, University College London, London, United Kingdom.
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Gunther K, Lynch DR. Pharmacotherapeutic strategies for Friedreich Ataxia: a review of the available data. Expert Opin Pharmacother 2024; 25:529-539. [PMID: 38622054 DOI: 10.1080/14656566.2024.2343782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 04/12/2024] [Indexed: 04/17/2024]
Abstract
INTRODUCTION Friedreich ataxia (FRDA) is a rare autosomal recessive disease, marked by loss of coordination as well as impaired neurological, endocrine, orthopedic, and cardiac function. There are many symptomatic medications for FRDA, and many clinical trials have been performed, but only one FDA-approved medication exists. AREAS COVERED The relative absence of the frataxin protein (FXN) in FRDA causes mitochondrial dysfunction, resulting in clinical manifestations. Currently, the only approved treatment for FRDA is an Nrf2 activator called omaveloxolone (Skyclarys). Patients with FRDA also rely on various symptomatic medications for treatment. Because there is only one approved medication for FRDA, clinical trials continue to advance in FRDA. Although some trials have not met their endpoints, many current and upcoming clinical trials provide exciting possibilities for the treatment of FRDA. EXPERT OPINION The approval of omaveloxolone provides a major advance in FRDA therapeutics. Although well tolerated, it is not curative. Reversal of deficient frataxin levels with gene therapy, protein replacement, or epigenetic approaches provides the most likely prospect for enduring, disease-modifying therapy in the future.
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Affiliation(s)
- Katherine Gunther
- Friedreich Ataxia Program, Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - David R Lynch
- Friedreich Ataxia Program, Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
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Pilotto F, Chellapandi DM, Puccio H. Omaveloxolone: a groundbreaking milestone as the first FDA-approved drug for Friedreich ataxia. Trends Mol Med 2024; 30:117-125. [PMID: 38272714 DOI: 10.1016/j.molmed.2023.12.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 12/01/2023] [Accepted: 12/04/2023] [Indexed: 01/27/2024]
Abstract
Friedreich ataxia (FA) is an inherited autosomal recessive neurodegenerative disease (NDD) characterized primarily by progressive sensory and spinocerebellar ataxia associated with hypertrophic cardiomyopathy. FA is due to an intronic GAA repeat expansion within the frataxin gene (FXN) leading to reduced levels of frataxin (FXN) which causes mitochondrial dysfunction, production of reactive oxygen species (ROS), and altered iron metabolism. To date there is no resolutive cure for FA; however, the FDA has recently approved omaveloxolone - a potent activator of nuclear factor erythroid 2-related factor 2 (NRF2) - as the first treatment for FA. We discuss herein the urgency to find a resolutive cure for NDDs that will most probably be achieved via combinatorial therapy targeting multiple disease pathways, and how omavaloxolone serves as an example for future treatments.
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Affiliation(s)
- Federica Pilotto
- Institut NeuroMyoGène (INMG), Unité Physiopathologie et Génétique du Neurone et du Muscle, Université Claude Bernard Lyon 1 CNRS UMR 5261, Inserm U1315, Lyon, France
| | - Deepika M Chellapandi
- Institut NeuroMyoGène (INMG), Unité Physiopathologie et Génétique du Neurone et du Muscle, Université Claude Bernard Lyon 1 CNRS UMR 5261, Inserm U1315, Lyon, France
| | - Hélène Puccio
- Institut NeuroMyoGène (INMG), Unité Physiopathologie et Génétique du Neurone et du Muscle, Université Claude Bernard Lyon 1 CNRS UMR 5261, Inserm U1315, Lyon, France.
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Smith FM, Kosman DJ. Loss of filamentous actin, tight junction protein expression, and paracellular barrier integrity in frataxin-deficient human brain microvascular endothelial cells-implications for blood-brain barrier physiology in Friedreich's ataxia. Front Mol Biosci 2024; 10:1299201. [PMID: 38274097 PMCID: PMC10808331 DOI: 10.3389/fmolb.2023.1299201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 12/22/2023] [Indexed: 01/27/2024] Open
Abstract
Introduction: Friedreich's Ataxia (FRDA) is the most prevalent inherited ataxia. FRDA results from loss of Frataxin (FXN), an essential mitochondrial iron trafficking protein. FRDA starts with an early burst of neurodegeneration of the dorsal root ganglion and cerebellar dentate nuclei, followed by progressive brain iron accumulation in the latter. End stage disease includes cardiac fibrosis that contributes to hypertrophic cardiomyopathy. The microvasculature plays an essential barrier role in both brain and heart homeostasis, thus an investigation of this tissue system in FRDA is essential to the delineation of the cellular dysfunction in this genetic disorder. Previous reports have identified cytoskeletal alterations in non-barrier forming FRDA cell models, but physiological consequences are limited. Methods: We investigated brain microvascular endothelial cell integrity in FRDA in a model of the blood-brain barrier (BBB). We have knocked down FXN in immortalized human brain microvascular endothelial cells (hBMVEC), which compose the microcapillaries of the BBB, by using shRNA. We confirmed known cellular pathophysiologies of FXN-knockdown including decreased energy metabolism, markers of oxidative stress, and increased cell size. Results: We investigated cytoskeletal architecture, identifying decreased filamentous actin and Occludin and Claudin-5 tight junction protein expression in shFXN hBMVECs. This was consistent with decreased transendothelial electrical resistance (TEER) and increased paracellular tracer flux during early barrier formation. shFXN hBMVEC start with only 67% barrier integrity of the controls, and flux a paracellular tracer at 800% of physiological levels. Discussion: We identified that insufficient FXN levels in the hBMVEC BBB model causes changes in cytoskeletal architecture and tight junction protein abundance, co-incident with increased barrier permeability. Changes in the integrity of the BBB may be related to patient brain iron accumulation, neuroinflammation, neurodegeneration, and stroke. Furthermore, our findings implicate other barrier cells, e.g., the cardiac microvasculature, loci of disease pathology in FRDA.
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Affiliation(s)
- Frances M. Smith
- Jacobs School of Medicine and Biomedical Sciences, Department of Biochemistry, The State University of New York at Buffalo, Buffalo, NY, United States
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13
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Saydi A, Behpoor N, Khamis Abadi F, Jung F, Kordi N. Modulation of pulmonary oxidative status in methamphetamine-withdrawn rats, comparing the effects of continuous training and NBS superfood supplementation. Clin Hemorheol Microcirc 2024; 88:373-384. [PMID: 39031345 DOI: 10.3233/ch-242306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/22/2024]
Abstract
OBJECTIVE This study aimed to investigate the effects of six weeks of continuous training and Nutrition Bio-shield (NBS) Superfood Supplementation on the state of oxidative stress by the expression of Nrf2, NOX4, superoxide dismutase, and malondialdehyde genes in the lungs of rats after methamphetamine withdrawal. METHODS Forty male Wistar rats were randomly divided into five groups (n = 8, per group), undergoing methamphetamine administration (six weeks, 5 mg/kg ip, and once per day) followed by a 21-day withdrawal period. The rats were supplemented NBS superfood at a dosage of 25 g/kg per day for six weeks. The training protocol was 30 minutes of daily continuous training (treadmill running), five days a week for six weeks. The regimen escalated from a pace of 3 m/min for the initial 5 minutes, to 5 m/min for the following 5 minutes, culminating at 8 m/min for the remainder of the session, all at a 0° incline. A one-way analysis of variance was performed to analyze the gene expression of Nrf2, NOX4, MDA, and SOD in the lungs tissue of rats. RESULTS The results indicated that, in the experimental groups which underwent continuous training and NBS Superfood supplementation, the expression of the Nrf2 gene exhibited a significant elevation compared to the control group (P < 0.05), while the NOX4, MDA, and SOD genes expression exhibited a significant decline in comparison to the control group (P < 0.05). CONCLUSION In general, both exercise interventions and NBS superfood supplementation, when employed separately or in combination after methamphetamine withdrawal, can enhance the state of oxidative stress in the lung.
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Affiliation(s)
- Ali Saydi
- Department of Exercise Physiology, Faculty of Sport Sciences, Razi University, Kermanshah, Iran
| | - Naser Behpoor
- Department of Exercise Physiology, Faculty of Sport Sciences, Razi University, Kermanshah, Iran
| | - Fatemeh Khamis Abadi
- Department of Sport Physiology, Faculty of Human Sciences, Borujerd Branch, Islamic Azad University, Borujerd, Iran
| | - Friedrich Jung
- Faculty of Health Sciences Brandenburg, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg, Germany
| | - Negin Kordi
- Department of Exercise Physiology, Faculty of Sport Sciences, Razi University, Kermanshah, Iran
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Lenahan A, Yano S, Graham B, Sen K. Omaveloxolone approved for patients aged 16 years and older with Friedreich ataxia (FRDA): A therapeutics bulletin of the American College of Medical Genetics and Genomics (ACMG). GENETICS IN MEDICINE OPEN 2023; 1:100832. [PMID: 39669230 PMCID: PMC11613714 DOI: 10.1016/j.gimo.2023.100832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 08/31/2023] [Indexed: 12/14/2024]
Affiliation(s)
- Arthur Lenahan
- Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA
| | - Sho Yano
- Section of Pediatric Neurology, Department of Pediatrics, University of Chicago, Chicago, IL
| | - Brett Graham
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN
| | - Kuntal Sen
- Division of Neurogenetics and Neurodevelopmental Pediatrics, Center for Neuroscience and Behavioral Medicine, Children's National Hospital, Washington, DC
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Pensabene KM, LaMorte J, Allender AE, Wehr J, Kaur P, Savage M, Eggler AL. Acute Oxidative Stress Can Paradoxically Suppress Human NRF2 Protein Synthesis by Inhibiting Global Protein Translation. Antioxidants (Basel) 2023; 12:1735. [PMID: 37760038 PMCID: PMC10525356 DOI: 10.3390/antiox12091735] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/28/2023] [Accepted: 09/03/2023] [Indexed: 09/29/2023] Open
Abstract
The NRF2 transcription factor is a master regulator of the cellular oxidant/electrophile response and a drug target for the prevention/treatment of chronic diseases. A major mechanism of NRF2 activation is its escape from rapid degradation, and newly synthesized NRF2 induces cytoprotective protein expression through its cognate antioxidant response elements (AREs). However, oxidative stress can also inhibit global protein translation, thereby potentially inhibiting NRF2 protein accumulation. H2O2 has been shown to be a relatively weak inducer of NRF2 in comparison with electrophiles. In the current study, we evaluated whether levels of H2O2 that activate the NRF2/ARE pathway inhibit NRF2 protein synthesis in HaCaT keratinocytes. A weak maximum induction was observed for H2O2 in comparison with electrophiles, both for NRF2 protein accumulation and ARE reporter activation (~10-fold compared to ≥100-fold activation). At similar H2O2 concentrations, both NRF2 protein synthesis and global protein synthesis were inhibited. The manganese porphyrin antioxidant MnTMPyP rescued both global protein synthesis and NRF2 protein synthesis from H2O2 inhibition and increased ARE reporter activation. Similar results were observed for the diphenol di-tert-butylhydroquinone (dtBHQ). In conclusion, induction of the NRF2/ARE pathway by H2O2 and dtBHQ-derived oxidative species can be limited by inhibition of NRF2 protein synthesis, likely by arrest of global protein synthesis.
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Affiliation(s)
| | | | | | | | | | | | - Aimee L. Eggler
- Department of Chemistry, Villanova University, Villanova, PA 19085, USA
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16
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Monda E, Bakalakos A, Rubino M, Verrillo F, Diana G, De Michele G, Altobelli I, Lioncino M, Perna A, Falco L, Palmiero G, Elliott PM, Limongelli G. Targeted Therapies in Pediatric and Adult Patients With Hypertrophic Heart Disease: From Molecular Pathophysiology to Personalized Medicine. Circ Heart Fail 2023; 16:e010687. [PMID: 37477018 DOI: 10.1161/circheartfailure.123.010687] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 06/06/2023] [Indexed: 07/22/2023]
Abstract
Hypertrophic cardiomyopathy is a myocardial disease defined by an increased left ventricular wall thickness not solely explained by abnormal loading conditions. It is often genetically determined, with sarcomeric gene mutations accounting for around 50% of cases. Several conditions, including syndromic, metabolic, infiltrative, and neuromuscular diseases, may present with left ventricular hypertrophy, mimicking the hypertrophic cardiomyopathy phenotype but showing a different pathophysiology, clinical course, and outcome. Despite being rare, they are collectively responsible for a large proportion of patients presenting with hypertrophic heart disease, and their timely diagnosis can significantly impact patients' management. The understanding of disease pathophysiology has advanced over the last few years, and several therapeutic targets have been identified, leading to a new era of tailored treatments applying to different etiologies associated with left ventricular hypertrophy. This review aims to provide an overview of the existing and emerging therapies for the principal causes of hypertrophic heart disease, discussing the potential impact on patients' management and clinical outcome.
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Affiliation(s)
- Emanuele Monda
- Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli," Naples, Italy (E.M., M.R., F.V., G.D., G.D.M., I.A., M.L., A.P., L.F., G.P., G.L.)
- Institute of Cardiovascular Sciences, University College London, United Kingdom (E.M., A.B., P.M.E., G.L.)
| | - Athanasios Bakalakos
- Institute of Cardiovascular Sciences, University College London, United Kingdom (E.M., A.B., P.M.E., G.L.)
| | - Marta Rubino
- Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli," Naples, Italy (E.M., M.R., F.V., G.D., G.D.M., I.A., M.L., A.P., L.F., G.P., G.L.)
| | - Federica Verrillo
- Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli," Naples, Italy (E.M., M.R., F.V., G.D., G.D.M., I.A., M.L., A.P., L.F., G.P., G.L.)
| | - Gaetano Diana
- Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli," Naples, Italy (E.M., M.R., F.V., G.D., G.D.M., I.A., M.L., A.P., L.F., G.P., G.L.)
| | - Gianantonio De Michele
- Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli," Naples, Italy (E.M., M.R., F.V., G.D., G.D.M., I.A., M.L., A.P., L.F., G.P., G.L.)
| | - Ippolita Altobelli
- Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli," Naples, Italy (E.M., M.R., F.V., G.D., G.D.M., I.A., M.L., A.P., L.F., G.P., G.L.)
| | - Michele Lioncino
- Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli," Naples, Italy (E.M., M.R., F.V., G.D., G.D.M., I.A., M.L., A.P., L.F., G.P., G.L.)
| | - Alessia Perna
- Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli," Naples, Italy (E.M., M.R., F.V., G.D., G.D.M., I.A., M.L., A.P., L.F., G.P., G.L.)
| | - Luigi Falco
- Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli," Naples, Italy (E.M., M.R., F.V., G.D., G.D.M., I.A., M.L., A.P., L.F., G.P., G.L.)
| | - Giuseppe Palmiero
- Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli," Naples, Italy (E.M., M.R., F.V., G.D., G.D.M., I.A., M.L., A.P., L.F., G.P., G.L.)
| | - Perry M Elliott
- Institute of Cardiovascular Sciences, University College London, United Kingdom (E.M., A.B., P.M.E., G.L.)
| | - Giuseppe Limongelli
- Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences, University of Campania "Luigi Vanvitelli," Naples, Italy (E.M., M.R., F.V., G.D., G.D.M., I.A., M.L., A.P., L.F., G.P., G.L.)
- Institute of Cardiovascular Sciences, University College London, United Kingdom (E.M., A.B., P.M.E., G.L.)
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Tiberi J, Segatto M, Fiorenza MT, La Rosa P. Apparent Opportunities and Hidden Pitfalls: The Conflicting Results of Restoring NRF2-Regulated Redox Metabolism in Friedreich's Ataxia Pre-Clinical Models and Clinical Trials. Biomedicines 2023; 11:biomedicines11051293. [PMID: 37238963 DOI: 10.3390/biomedicines11051293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 04/18/2023] [Accepted: 04/22/2023] [Indexed: 05/28/2023] Open
Abstract
Friedreich's ataxia (FRDA) is an autosomal, recessive, inherited neurodegenerative disease caused by the loss of activity of the mitochondrial protein frataxin (FXN), which primarily affects dorsal root ganglia, cerebellum, and spinal cord neurons. The genetic defect consists of the trinucleotide GAA expansion in the first intron of FXN gene, which impedes its transcription. The resulting FXN deficiency perturbs iron homeostasis and metabolism, determining mitochondrial dysfunctions and leading to reduced ATP production, increased reactive oxygen species (ROS) formation, and lipid peroxidation. These alterations are exacerbated by the defective functionality of the nuclear factor erythroid 2-related factor 2 (NRF2), a transcription factor acting as a key mediator of the cellular redox signalling and antioxidant response. Because oxidative stress represents a major pathophysiological contributor to FRDA onset and progression, a great effort has been dedicated to the attempt to restore the NRF2 signalling axis. Despite this, the beneficial effects of antioxidant therapies in clinical trials only partly reflect the promising results obtained in preclinical studies conducted in cell cultures and animal models. For these reasons, in this critical review, we overview the outcomes obtained with the administration of various antioxidant compounds and critically analyse the aspects that may have contributed to the conflicting results of preclinical and clinical studies.
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Affiliation(s)
- Jessica Tiberi
- Division of Neuroscience, Department of Psychology, Sapienza University of Rome, Via dei Marsi 78, 00185 Rome, Italy
- PhD Program in Behavioral Neuroscience, Sapienza University of Rome, Via dei Marsi 78, 00185 Rome, Italy
| | - Marco Segatto
- Department of Bioscience and Territory, University of Molise, Contrada Fonte Lappone, 86090 Pesche, Italy
| | - Maria Teresa Fiorenza
- Division of Neuroscience, Department of Psychology, Sapienza University of Rome, Via dei Marsi 78, 00185 Rome, Italy
- European Center for Brain Research, IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano 64, 00179 Rome, Italy
| | - Piergiorgio La Rosa
- Division of Neuroscience, Department of Psychology, Sapienza University of Rome, Via dei Marsi 78, 00185 Rome, Italy
- European Center for Brain Research, IRCCS Fondazione Santa Lucia, Via del Fosso di Fiorano 64, 00179 Rome, Italy
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18
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Smith FM, Kosman DJ. Frataxin-deficient human brain microvascular endothelial cells lose polymerized actin and are paracellularly permeable -implications for blood-brain barrier integrity in Friedreich's Ataxia. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.02.09.527936. [PMID: 36798283 PMCID: PMC9934603 DOI: 10.1101/2023.02.09.527936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
Abstract
Background Friedreich's Ataxia (FRDA) is the most prevalent inherited ataxia; the disease results from loss of Frataxin, an essential mitochondrial iron trafficking protein. FRDA presents as neurodegeneration of the dorsal root ganglion and cerebellar dentate nuclei, followed by brain iron accumulation in the latter. End stage disease includes cardiac fibrosis that contributes to hypertrophic cardiomyopathy. The microvasculature plays an essential barrier role in both the brain and heart, thus an investigation of this tissue system in FRDA is essential to the delineation of the cellular dysfunction in this genetic disorder. Here, we investigate brain microvascular endothelial cell integrity in FRDA in a model of the blood-brain barrier (BBB). Methods We used lentiviral mediated shRNA delivery to generate a novel FRDA model in immortalized human brain microvascular endothelial cells (hBMVEC) that compose the microcapillaries of the BBB. We verified known cellular pathophysiologies of FXN knockdown including increased oxidative stress, loss of energy metabolism, and increased cell size. Furthermore, we investigated cytoskeletal architecture including the abundance and organization of filamentous actin, and barrier physiology via transendothelial electrical resistance and fluorescent tracer flux. Results shFXN hBMVEC display the known FRDA cell morbidity including increased oxidative stress, decreased energy metabolism, and an increase in cell size. We demonstrate that shFXN hBMVEC have less overall filamentous actin, and that filamentous actin is lost at the cell membrane and cortical actin ring. Consistent with loss of cytoskeletal structure and anchorage, we found decreased barrier strength and increased paracellular tracer flux in the shFXN hBMVEC transwell model. Conclusion We identified that insufficient FXN levels in the hBMVEC BBB model causes changes in cytoskeletal architecture and increased barrier permeability, cell pathologies that may be related to patient brain iron accumulation, neuroinflammation, neurodegeneration, and stroke. Our findings implicate other barrier cells, e.g., the cardiac microvasculature, likely contributory also to disease pathology in FRDA.
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Affiliation(s)
- Frances M Smith
- Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, The University of New York at Buffalo
| | - Daniel J Kosman
- Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, The University of New York at Buffalo
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Lynch DR, Chin MP, Boesch S, Delatycki MB, Giunti P, Goldsberry A, Hoyle JC, Mariotti C, Mathews KD, Nachbauer W, O'Grady M, Perlman S, Subramony SH, Wilmot G, Zesiewicz T, Meyer CJ. Efficacy of Omaveloxolone in Friedreich's Ataxia: Delayed-Start Analysis of the MOXIe Extension. Mov Disord 2023; 38:313-320. [PMID: 36444905 DOI: 10.1002/mds.29286] [Citation(s) in RCA: 52] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 09/29/2022] [Accepted: 10/24/2022] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND MOXIe was a two-part study evaluating the safety and efficacy of omaveloxolone in patients with Friedreich's ataxia, a rare, progressive neurological disease with no proven therapy. MOXIe part 2, a randomized double-blind placebo-controlled trial, showed omaveloxolone significantly improved modified Friedreich's Ataxia Rating Scale (mFARS) scores relative to placebo. Patients who completed part 1 or 2 were eligible to receive omaveloxolone in an open-label extension study. OBJECTIVE The delayed-start study compared mFARS scores at the end of MOXIe part 2 with those at 72 weeks in the open-label extension period (up to 144 weeks) for patients initially randomized to omaveloxolone versus those initially randomized to placebo. METHODS We performed a noninferiority test to compare the difference between treatment groups (placebo to omaveloxolone versus omaveloxolone to omaveloxolone) using a single mixed model repeated measures (MMRM) model. In addition, slopes of the change in mFARS scores were compared between both groups in the open-label extension. RESULTS The noninferiority testing demonstrated that the difference in mFARS between omaveloxolone and placebo observed at the end of placebo-controlled MOXIe part 2 (-2.17 ± 1.09 points) was preserved after 72 weeks in the extension (-2.91 ± 1.44 points). In addition, patients previously randomized to omaveloxolone in MOXIe part 2 continued to show no worsening in mFARS relative to their extension baseline through 144 weeks. CONCLUSIONS These results support the positive results of MOXIe part 2 and indicate a persistent benefit of omaveloxolone treatment on disease course in Friedreich's ataxia. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Affiliation(s)
- David R Lynch
- Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | | | - Sylvia Boesch
- Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
| | - Martin B Delatycki
- Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Victoria, Australia
| | - Paola Giunti
- University College London Hospital, London, United Kingdom
| | | | - J Chad Hoyle
- Department of Neurology, Ohio State University College of Medicine, Columbus, Ohio, USA
| | | | - Katherine D Mathews
- Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
| | - Wolfgang Nachbauer
- Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
| | | | - Susan Perlman
- Department of Neurology, University of California Los Angeles, Los Angeles, California, USA
| | - S H Subramony
- Department of Neurology, McKnight Brain Institute, University of Florida Health System, Gainesville, Florida, USA
| | - George Wilmot
- Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Theresa Zesiewicz
- Department of Neurology, University of South Florida Ataxia Research Center, Tampa, Florida, USA
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Keita M, McIntyre K, Rodden LN, Schadt K, Lynch DR. Friedreich ataxia: clinical features and new developments. Neurodegener Dis Manag 2022; 12:267-283. [PMID: 35766110 PMCID: PMC9517959 DOI: 10.2217/nmt-2022-0011] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 06/15/2022] [Indexed: 11/21/2022] Open
Abstract
Friedreich's ataxia (FRDA), a neurodegenerative disease characterized by ataxia and other neurological features, affects 1 in 50,000-100,000 individuals in the USA. However, FRDA also includes cardiac, orthopedic and endocrine dysfunction, giving rise to many secondary disease characteristics. The multifaceted approach for clinical care has necessitated the development of disease-specific clinical care guidelines. New developments in FRDA include the advancement of clinical drug trials targeting the NRF2 pathway and frataxin restoration. Additionally, a novel understanding of gene silencing in FRDA, reflecting a variegated silencing pattern, will have applications to current and future therapeutic interventions. Finally, new perspectives on the neuroanatomy of FRDA and its developmental features will refine the time course and anatomical targeting of novel approaches.
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Affiliation(s)
- Medina Keita
- Departments of Pediatrics & Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Kellie McIntyre
- Departments of Pediatrics & Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Layne N Rodden
- Departments of Pediatrics & Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Kim Schadt
- Departments of Pediatrics & Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - David R Lynch
- Departments of Pediatrics & Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Liu JJ, Xu Y, Chen S, Hao CF, Liang J, Li ZL. The mechanism of Yinchenhao decoction in treating obstructive-jaundice-induced liver injury based on Nrf2 signaling pathway. World J Gastroenterol 2022; 28:4635-4648. [PMID: 36157920 PMCID: PMC9476870 DOI: 10.3748/wjg.v28.i32.4635] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 06/08/2022] [Accepted: 06/24/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Obstructive jaundice (OJ) is caused by bile excretion disorder after partial or complete bile duct obstruction. It may cause liver injury through various mechanisms. Traditional Chinese medicine (TCM) has a lot of advantages in treating OJ. The recovery of liver function can be accelerated by combining Chinese medicine treatment with existing clinical practice. Yinchenhao decoction (YCHD), a TCM formula, has been used to treat jaundice. Although much progress has been made in recent years in understanding the mechanism of YCHD in treating OJ-induced liver injury, it is still not clear. AIM To investigate chemical components of YCHD that are effective in the treatment of OJ and predict the mechanism of YCHD. METHODS The active components and putative targets of YCHD were predicted using a network pharmacology approach. Gene Ontology biological process and Kyoto Encyclopedia of Genes and Genomes path enrichment analysis were carried out by cluster profile. We predicted the biological processes, possible targets, and associated signaling pathways that YCHD may involve in the treatment of OJ. Thirty male Sprague-Dawley rats were randomly divided into three groups, each consisting of 10 rats: the sham group (Group S), the OJ model group (Group M), and the YCHD-treated group (Group Y). The sham group only received laparotomy. The OJ model was established by ligating the common bile duct twice in Groups M and Y. For 1 wk, rats in Group Y were given a gavage of YCHD (3.6 mL/kg) twice daily, whereas rats in Groups S and M were given the same amount of physiological saline after intragastric administration daily. After 7 d, all rats were killed, and the liver and blood samples were collected for histopathological and biochemical examinations. Total bilirubin (TBIL), direct bilirubin (DBIL), alanine aminotransferase (ALT), and aspartate transaminase (AST) levels in the blood samples were detected. The gene expression levels of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS), and the nucleus positive rate of NF-E2 related factor 2 (Nrf2) protein were measured. Western blot analyses were used to detect the protein and gene expression levels of Nrf2, Kelch-like ECH-associated protein 1, NAD(P)H quinone dehydrogenase 1 (NQO1), and glutathione-S-transferase (GST) in the liver tissues. One-way analysis of variance was used to evaluate the statistical differences using the statistical package for the social sciences 23.0 software. Intergroup comparisons were followed by the least significant difference test and Dunnett's test. RESULTS The effects of YCHD on OJ involve biological processes such as DNA transcription factor binding, RNA polymerase II specific regulation, DNA binding transcriptional activator activity, and nuclear receptor activity. The protective effects of YCHD against OJ were closely related to 20 pathways, including the hepatitis-B, the mitogen-activated protein kinase, the phosphatidylinositol 3-kinase/protein kinase B, and tumor necrosis factor signaling pathways. YCHD alleviated the swelling and necrosis of hepatocytes. Following YCHD treatment, the serum levels of TBIL (176.39 ± 17.03 μmol/L vs 132.23 ± 13.88 μmol/L, P < 0.01), DBIL (141.41 ± 14.66 μmol/L vs 106.43 ± 10.88 μmol/L, P < 0.01), ALT (332.07 ± 34.34 U/L vs 269.97 ± 24.78 U/L, P < 0.05), and AST (411.44 ± 47.64 U/L vs 305.47 ± 29.36 U/L, P < 0.01) decreased. YCHD promoted the translocation of Nrf2 into the nucleus (12.78 ± 0.99 % vs 60.77 ± 1.90 %, P < 0.001). After YCHD treatment, we found a decrease in iNOS (0.30 ± 0.02 vs 0.20 ± 0.02, P < 0.001) and an increase in eNOS (0.18 ± 0.02 vs 0.32 ± 0.02, P < 0.001). Meanwhile, in OJ rats, YCHD increased the expressions of Nrf2 (0.57 ± 0.03 vs 1.18 ± 0.10, P < 0.001), NQO1 (0.13 ± 0.09 vs 1.19 ± 0.07, P < 0.001), and GST (0.12 ± 0.02 vs 0.50 ± 0.05, P < 0.001), implying that the potential mechanism of YCHD against OJ-induced liver injury was the upregulation of the Nrf2 signaling pathway. CONCLUSION OJ-induced liver injury is associated with the Nrf2 signaling pathway. YCHD can reduce liver injury and oxidative damage by upregulating the Nrf2 pathway.
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Affiliation(s)
- Jun-Jian Liu
- The Second Department of Hepatobiliary and Pancreatic Surgery, Tianjin Medical University NanKai Hospital, Tianjin 300102, China
| | - Yan Xu
- Graduate School, Tianjin Medical University, Tianjin 3000070, China
| | - Shuai Chen
- Department of Thoracic Surgery, Xuzhou City Hospital of Traditional Chinese Medicine, Xuzhou 221000, Jiangsu Province, China
| | - Cheng-Fei Hao
- The Second Department of Hepatobiliary and Pancreatic Surgery, Tianjin Medical University NanKai Hospital, Tianjin 300102, China
| | - Jing Liang
- School of Foreign Languages, Chengdu University of Traditional Chinese Medicine, Chengdu 610000, Sichuan Province, China
| | - Zhong-Lian Li
- The Second Department of Hepatobiliary and Pancreatic Surgery, Tianjin Medical University NanKai Hospital, Tianjin 300102, China
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22
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Hackett PT, Jia X, Li L, Ward DM. Posttranslational regulation of mitochondrial frataxin and identification of compounds that increase frataxin levels in Friedreich's ataxia. J Biol Chem 2022; 298:101982. [PMID: 35472330 PMCID: PMC9127368 DOI: 10.1016/j.jbc.2022.101982] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Revised: 04/18/2022] [Accepted: 04/19/2022] [Indexed: 11/18/2022] Open
Abstract
Friedreich's ataxia (FRDA) is a degenerative disease caused by a decrease in the mitochondrial protein frataxin (Fxn), which is involved in iron-sulfur cluster (ISC) synthesis. Diminutions in Fxn result in decreased ISC synthesis, increased mitochondrial iron accumulation, and impaired mitochondrial function. Here, we show that conditions that result in increased mitochondrial reactive oxygen species in yeast or mammalian cell culture give rise to increased turnover of Fxn but not of other ISC synthesis proteins. We demonstrate that the mitochondrial Lon protease is involved in Fxn degradation and that iron export through the mitochondrial metal transporter Mmt1 protects yeast Fxn from degradation. We also determined that when FRDA fibroblasts were grown in media containing elevated iron, mitochondrial reactive oxygen species increased and Fxn decreased compared to WT fibroblasts. Furthermore, we screened a library of FDA-approved compounds and identified 38 compounds that increased yeast Fxn levels, including the azole bifonazole, antiparasitic fipronil, antitumor compound dibenzoylmethane, antihypertensive 4-hydroxychalcone, and a nonspecific anion channel inhibitor 4,4-diisothiocyanostilbene-2,2-sulfonic acid. We show that top hits 4-hydroxychalcone and dibenzoylmethane increased mRNA levels of transcription factor nuclear factor erythroid 2-related factor 2 in FRDA patient-derived fibroblasts, as well as downstream antioxidant targets thioredoxin, glutathione reductase, and superoxide dismutase 2. Taken together, these findings reveal that FRDA progression may be in part due to oxidant-mediated decreases in Fxn and that some approved compounds may be effective in increasing mitochondrial Fxn in FRDA, delaying disease progression.
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Affiliation(s)
- Peter T Hackett
- Department of Pathology, Division of Microbiology and Immunology, University of Utah School of Medicine, Salt Lake City, Utah, USA
| | - Xuan Jia
- Department of Pathology, Division of Microbiology and Immunology, University of Utah School of Medicine, Salt Lake City, Utah, USA
| | - Liangtao Li
- Department of Pathology, Division of Microbiology and Immunology, University of Utah School of Medicine, Salt Lake City, Utah, USA
| | - Diane M Ward
- Department of Pathology, Division of Microbiology and Immunology, University of Utah School of Medicine, Salt Lake City, Utah, USA.
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23
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Vicente-Acosta A, Giménez-Cassina A, Díaz-Nido J, Loria F. The smoothened agonist SAG reduces mitochondrial dysfunction and neurotoxicity of frataxin-deficient astrocytes. J Neuroinflammation 2022; 19:93. [PMID: 35413853 PMCID: PMC9006607 DOI: 10.1186/s12974-022-02442-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 03/24/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Friedreich's ataxia is a rare hereditary neurodegenerative disease caused by decreased levels of the mitochondrial protein frataxin. Similar to other neurodegenerative pathologies, previous studies suggested that astrocytes might contribute to the progression of the disease. To fully understand the mechanisms underlying neurodegeneration in Friedreich's ataxia, we investigated the reactivity status and functioning of cultured human astrocytes after frataxin depletion using an RNA interference-based approach and tested the effect of pharmacologically modulating the SHH pathway as a novel neuroprotective strategy. RESULTS We observed loss of cell viability, mitochondrial alterations, increased autophagy and lipid accumulation in cultured astrocytes upon frataxin depletion. Besides, frataxin-deficient cells show higher expression of several A1-reactivity markers and release of pro-inflammatory cytokines. Interestingly, most of these defects were prevented by chronically treating the cells with the smoothened agonist SAG. Furthermore, in vitro culture of neurons with conditioned medium from frataxin-deficient astrocytes results in a reduction of neuronal survival, neurite length and synapse formation. However, when frataxin-deficient astrocytes were chronically treated with SAG, we did not observe these alterations in neurons. CONCLUSIONS Our results demonstrate that the pharmacological activation of the SHH pathway could be used as a target to modulate astrocyte reactivity and neuron-glia interactions to prevent neurodegeneration in Friedreich's ataxia.
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Affiliation(s)
- Andrés Vicente-Acosta
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Nicolás Cabrera 1, 28049 Madrid, Spain
- Departamento de Biología Molecular, Universidad Autónoma de Madrid, Francisco Tomás y Valiente, 7, Ciudad Universitaria de Cantoblanco, 28049 Madrid, Spain
- Instituto de Investigación Sanitaria Puerta de Hierro, Segovia de Arana, Hospital Universitario Puerta de Hierro, Joaquín Rodrigo 1, Majadahonda, 28222 Madrid, Spain
- Program in Molecular Biosciences, Doctoral School, Universidad Autónoma de Madrid, Madrid, Spain
| | - Alfredo Giménez-Cassina
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Nicolás Cabrera 1, 28049 Madrid, Spain
- Departamento de Biología Molecular, Universidad Autónoma de Madrid, Francisco Tomás y Valiente, 7, Ciudad Universitaria de Cantoblanco, 28049 Madrid, Spain
| | - Javier Díaz-Nido
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Nicolás Cabrera 1, 28049 Madrid, Spain
- Departamento de Biología Molecular, Universidad Autónoma de Madrid, Francisco Tomás y Valiente, 7, Ciudad Universitaria de Cantoblanco, 28049 Madrid, Spain
- Instituto de Investigación Sanitaria Puerta de Hierro, Segovia de Arana, Hospital Universitario Puerta de Hierro, Joaquín Rodrigo 1, Majadahonda, 28222 Madrid, Spain
| | - Frida Loria
- Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Nicolás Cabrera 1, 28049 Madrid, Spain
- Departamento de Biología Molecular, Universidad Autónoma de Madrid, Francisco Tomás y Valiente, 7, Ciudad Universitaria de Cantoblanco, 28049 Madrid, Spain
- Laboratorio de Apoyo a la Investigación, Hospital Universitario Fundación Alcorcón, Budapest 1, Alcorcón, 28922 Madrid, Spain
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24
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Recessive cerebellar and afferent ataxias - clinical challenges and future directions. Nat Rev Neurol 2022; 18:257-272. [PMID: 35332317 DOI: 10.1038/s41582-022-00634-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/17/2022] [Indexed: 02/07/2023]
Abstract
Cerebellar and afferent ataxias present with a characteristic gait disorder that reflects cerebellar motor dysfunction and sensory loss. These disorders are a diagnostic challenge for clinicians because of the large number of acquired and inherited diseases that cause cerebellar and sensory neuron damage. Among such conditions that are recessively inherited, Friedreich ataxia and RFC1-associated cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) include the characteristic clinical, neuropathological and imaging features of ganglionopathies, a distinctive non-length-dependent type of sensory involvement. In this Review, we discuss the typical and atypical phenotypes of Friedreich ataxia and CANVAS, along with the features of other recessive ataxias that present with a ganglionopathy or polyneuropathy, with an emphasis on recently described clinical features, natural history and genotype-phenotype correlations. We review the main developments in understanding the complex pathology that affects the sensory neurons and cerebellum, which seem to be most vulnerable to disorders that affect mitochondrial function and DNA repair mechanisms. Finally, we discuss disease-modifying therapeutic advances in Friedreich ataxia, highlighting the most promising candidate molecules and lessons learned from previous clinical trials.
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25
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Rufini A, Malisan F, Condò I, Testi R. Drug Repositioning in Friedreich Ataxia. Front Neurosci 2022; 16:814445. [PMID: 35221903 PMCID: PMC8863941 DOI: 10.3389/fnins.2022.814445] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Accepted: 01/07/2022] [Indexed: 12/14/2022] Open
Abstract
Friedreich ataxia is a rare neurodegenerative disorder caused by insufficient levels of the essential mitochondrial protein frataxin. It is a severely debilitating disease that significantly impacts the quality of life of affected patients and reduces their life expectancy, however, an adequate cure is not yet available for patients. Frataxin function, although not thoroughly elucidated, is associated with assembly of iron-sulfur cluster and iron metabolism, therefore insufficient frataxin levels lead to reduced activity of many mitochondrial enzymes involved in the electron transport chain, impaired mitochondrial metabolism, reduced ATP production and inefficient anti-oxidant response. As a consequence, neurons progressively die and patients progressively lose their ability to coordinate movement and perform daily activities. Therapeutic strategies aim at restoring sufficient frataxin levels or at correcting some of the downstream consequences of frataxin deficiency. However, the classical pathways of drug discovery are challenging, require a significant amount of resources and time to reach the final approval, and present a high failure rate. Drug repositioning represents a viable alternative to boost the identification of a therapy, particularly for rare diseases where resources are often limited. In this review we will describe recent efforts aimed at the identification of a therapy for Friedreich ataxia through drug repositioning, and discuss the limitation of such strategies.
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Affiliation(s)
- Alessandra Rufini
- Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy
- Fratagene Therapeutics, Rome, Italy
- Saint Camillus International University of Health and Medical Sciences, Rome, Italy
- *Correspondence: Alessandra Rufini,
| | - Florence Malisan
- Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy
| | - Ivano Condò
- Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy
| | - Roberto Testi
- Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy
- Fratagene Therapeutics, Rome, Italy
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26
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Shah S, Dooms MM, Amaral-Garcia S, Igoillo-Esteve M. Current Drug Repurposing Strategies for Rare Neurodegenerative Disorders. Front Pharmacol 2022; 12:768023. [PMID: 34992533 PMCID: PMC8724568 DOI: 10.3389/fphar.2021.768023] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 11/10/2021] [Indexed: 12/12/2022] Open
Abstract
Rare diseases are life-threatening or chronically debilitating low-prevalent disorders caused by pathogenic mutations or particular environmental insults. Due to their high complexity and low frequency, important gaps still exist in their prevention, diagnosis, and treatment. Since new drug discovery is a very costly and time-consuming process, leading pharmaceutical companies show relatively low interest in orphan drug research and development due to the high cost of investments compared to the low market return of the product. Drug repurposing–based approaches appear then as cost- and time-saving strategies for the development of therapeutic opportunities for rare diseases. In this article, we discuss the scientific, regulatory, and economic aspects of the development of repurposed drugs for the treatment of rare neurodegenerative disorders with a particular focus on Huntington’s disease, Friedreich’s ataxia, Wolfram syndrome, and amyotrophic lateral sclerosis. The role of academia, pharmaceutical companies, patient associations, and foundations in the identification of candidate compounds and their preclinical and clinical evaluation will also be discussed.
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Affiliation(s)
- Sweta Shah
- Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium
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27
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Cheng R, Dhorajia VV, Kim J, Kim Y. Mitochondrial iron metabolism and neurodegenerative diseases. Neurotoxicology 2022; 88:88-101. [PMID: 34748789 PMCID: PMC8748425 DOI: 10.1016/j.neuro.2021.11.003] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 11/01/2021] [Accepted: 11/03/2021] [Indexed: 01/03/2023]
Abstract
Iron is a key element for mitochondrial function and homeostasis, which is also crucial for maintaining the neuronal system, but too much iron promotes oxidative stress. A large body of evidence has indicated that abnormal iron accumulation in the brain is associated with various neurodegenerative diseases such as Huntington's disease, Alzheimer's disease, Parkinson's disease, and Friedreich's ataxia. However, it is still unclear how irregular iron status contributes to the development of neuronal disorders. Hence, the current review provides an update on the causal effects of iron overload in the development and progression of neurodegenerative diseases and discusses important roles of mitochondrial iron homeostasis in these disease conditions. Furthermore, this review discusses potential therapeutic targets for the treatments of iron overload-linked neurodegenerative diseases.
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Affiliation(s)
- Ruiying Cheng
- Department of Biomedical and Nutritional Sciences, University of Massachusetts Lowell, USA
| | | | - Jonghan Kim
- Department of Biomedical and Nutritional Sciences, University of Massachusetts Lowell, USA.
| | - Yuho Kim
- Department of Physical Therapy and Kinesiology, University of Massachusetts Lowell, USA.
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28
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Motley W, Chaudry V, Lloyd TE. Treatment and Management of Hereditary Neuropathies. Neuromuscul Disord 2022. [DOI: 10.1016/b978-0-323-71317-7.00014-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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29
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Seminotti B, Grings M, Tucci P, Leipnitz G, Saso L. Nuclear Factor Erythroid-2-Related Factor 2 Signaling in the Neuropathophysiology of Inherited Metabolic Disorders. Front Cell Neurosci 2021; 15:785057. [PMID: 34955754 PMCID: PMC8693715 DOI: 10.3389/fncel.2021.785057] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 11/05/2021] [Indexed: 01/14/2023] Open
Abstract
Inherited metabolic disorders (IMDs) are rare genetic conditions that affect multiple organs, predominantly the central nervous system. Since treatment for a large number of IMDs is limited, there is an urgent need to find novel therapeutical targets. Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor that has a key role in controlling the intracellular redox environment by regulating the expression of antioxidant enzymes and several important genes related to redox homeostasis. Considering that oxidative stress along with antioxidant system alterations is a mechanism involved in the neuropathophysiology of many IMDs, this review focuses on the current knowledge about Nrf2 signaling dysregulation observed in this group of disorders characterized by neurological dysfunction. We review here Nrf2 signaling alterations observed in X-linked adrenoleukodystrophy, glutaric acidemia type I, hyperhomocysteinemia, and Friedreich’s ataxia. Additionally, beneficial effects of different Nrf2 activators are shown, identifying a promising target for treatment of patients with these disorders. We expect that this article stimulates research into the investigation of Nrf2 pathway involvement in IMDs and the use of potential pharmacological modulators of this transcription factor to counteract oxidative stress and exert neuroprotection.
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Affiliation(s)
- Bianca Seminotti
- Postgraduate Program in Biological Sciences: Biochemistry, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Mateus Grings
- Postgraduate Program in Biological Sciences: Biochemistry, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Paolo Tucci
- Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
| | - Guilhian Leipnitz
- Postgraduate Program in Biological Sciences: Biochemistry, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.,Department of Biochemistry, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.,Postgraduate Program in Biological Sciences: Physiology, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Luciano Saso
- Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, Rome, Italy
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30
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Jiménez-Villegas J, Ferraiuolo L, Mead RJ, Shaw PJ, Cuadrado A, Rojo AI. NRF2 as a therapeutic opportunity to impact in the molecular roadmap of ALS. Free Radic Biol Med 2021; 173:125-141. [PMID: 34314817 DOI: 10.1016/j.freeradbiomed.2021.07.022] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 06/12/2021] [Accepted: 07/15/2021] [Indexed: 12/18/2022]
Abstract
Amyotrophic Lateral Sclerosis (ALS) is a devastating heterogeneous disease with still no convincing therapy. To identify the most strategically significant hallmarks for therapeutic intervention, we have performed a comprehensive transcriptomics analysis of dysregulated pathways, comparing datasets from ALS patients and healthy donors. We have identified crucial alterations in RNA metabolism, intracellular transport, vascular system, redox homeostasis, proteostasis and inflammatory responses. Interestingly, the transcription factor NRF2 (nuclear factor (erythroid-derived 2)-like 2) has significant effects in modulating these pathways. NRF2 has been classically considered as the master regulator of the antioxidant cellular response, although it is currently considered as a key component of the transduction machinery to maintain coordinated control of protein quality, inflammation, and redox homeostasis. Herein, we will summarize the data from NRF2 activators in ALS pre-clinical models as well as those that are being studied in clinical trials. As we will discuss, NRF2 is a promising target to build a coordinated transcriptional response to motor neuron injury, highlighting its therapeutic potential to combat ALS.
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Affiliation(s)
- J Jiménez-Villegas
- Department of Biochemistry, Medical College, Autonomous University of Madrid (UAM), Madrid, Spain; Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), Madrid, Spain; Instituto de Investigación Sanitaria La Paz (IdiPaz), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - L Ferraiuolo
- Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK
| | - R J Mead
- Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK
| | - P J Shaw
- Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK
| | - A Cuadrado
- Department of Biochemistry, Medical College, Autonomous University of Madrid (UAM), Madrid, Spain; Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), Madrid, Spain; Instituto de Investigación Sanitaria La Paz (IdiPaz), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - A I Rojo
- Department of Biochemistry, Medical College, Autonomous University of Madrid (UAM), Madrid, Spain; Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), Madrid, Spain; Instituto de Investigación Sanitaria La Paz (IdiPaz), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
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31
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Petrillo S, Santoro M, La Rosa P, Perna A, Gallo MG, Bertini ES, Silvestri G, Piemonte F. Nuclear Factor Erythroid 2-Related Factor 2 Activation Might Mitigate Clinical Symptoms in Friedreich's Ataxia: Clues of an "Out-Brain Origin" of the Disease From a Family Study. Front Neurosci 2021; 15:638810. [PMID: 33708070 PMCID: PMC7940825 DOI: 10.3389/fnins.2021.638810] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 01/22/2021] [Indexed: 11/25/2022] Open
Abstract
Friedreich’s ataxia (FRDA) is the most frequent autosomal recessive ataxia in western countries, with a mean age of onset at 10–15 years. Patients manifest progressive cerebellar and sensory ataxia, dysarthria, lower limb pyramidal weakness, and other systemic manifestations. Previously, we described a family displaying two expanded GAA alleles not only in the proband affected by late-onset FRDA but also in the two asymptomatic family members: the mother and the younger sister. Both of them showed a significant reduction of frataxin levels, without any disease manifestation. Here, we analyzed if a protective mechanism might contribute to modulate the phenotype in this family. We particularly focused on the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), the first line of antioxidant defense in cells, and on the glutathione (GSH) system, an index of reactive oxygen species (ROS) detoxification ability. Our findings show a great reactivity of the GSH system to the frataxin deficiency, particularly in the asymptomatic mother, where the genes of GSH synthesis [glutamate–cysteine ligase (GCL)] and GSSG detoxification [GSH S-reductase (GSR)] were highly responsive. The GSR was activated even in the asymptomatic sister and in the proband, reflecting the need of buffering the GSSG increase. Furthermore, and contrasting the NRF2 expression documented in FRDA tissues, NRF2 was highly activated in the mother and in the younger sister, while it was constitutively low in the proband. This suggests that, also under frataxin depletion, the endogenous stimulation of NRF2 in asymptomatic FRDA subjects may contribute to protect against the progressive oxidative damage, helping to prevent the onset of neurological symptoms and highlighting an “out-brain origin” of the disease.
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Affiliation(s)
- Sara Petrillo
- Unit of Muscular and Neurodegenerative Diseases, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy
| | | | - Piergiorgio La Rosa
- Division of Neuroscience, Department of Psychology, Sapienza University of Rome, Rome, Italy
| | - Alessia Perna
- Department of Neurosciences, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Maria Giovanna Gallo
- Unit of Muscular and Neurodegenerative Diseases, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy
| | - Enrico Silvio Bertini
- Unit of Muscular and Neurodegenerative Diseases, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy
| | - Gabriella Silvestri
- Department of Neurosciences, Università Cattolica del Sacro Cuore, Rome, Italy.,UOC of Neurology, Area of Neuroscience, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Fiorella Piemonte
- Unit of Muscular and Neurodegenerative Diseases, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy
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32
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Frataxins Emerge as New Players of the Intracellular Antioxidant Machinery. Antioxidants (Basel) 2021; 10:antiox10020315. [PMID: 33672495 PMCID: PMC7923443 DOI: 10.3390/antiox10020315] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/17/2021] [Accepted: 02/18/2021] [Indexed: 12/30/2022] Open
Abstract
Frataxin is a mitochondrial protein which deficiency causes Friedreich's ataxia, a cardio-neurodegenerative disease. The lack of frataxin induces the dysregulation of mitochondrial iron homeostasis and oxidative stress, which finally causes the neuronal death. The mechanism through which frataxin regulates the oxidative stress balance is rather complex and poorly understood. While the absence of human (Hfra) and yeast (Yfh1) frataxins turn out cells sensitive to oxidative stress, this does not occur when the frataxin gene is knocked-out in E. coli. To better understand the biological roles of Hfra and Yfh1 as endogenous antioxidants, we have studied their ability to inhibit the formation of reactive oxygen species (ROS) from Cu2+- and Fe3+-catalyzed degradation of ascorbic acid. Both proteins drastically reduce the formation of ROS, and during this process they are not oxidized. In addition, we have also demonstrated that merely the presence of Yfh1 or Hfra is enough to protect a highly oxidation-prone protein such as α-synuclein. This unspecific intervention (without a direct binding) suggests that frataxins could act as a shield to prevent the oxidation of a broad set of intracellular proteins, and reinforces that idea that frataxin can be used to prevent neurological pathologies linked to an enhanced oxidative stress.
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Lynch DR, Chin MP, Delatycki MB, Subramony SH, Corti M, Hoyle JC, Boesch S, Nachbauer W, Mariotti C, Mathews KD, Giunti P, Wilmot G, Zesiewicz T, Perlman S, Goldsberry A, O'Grady M, Meyer CJ. Safety and Efficacy of Omaveloxolone in Friedreich Ataxia (MOXIe Study). Ann Neurol 2021; 89:212-225. [PMID: 33068037 PMCID: PMC7894504 DOI: 10.1002/ana.25934] [Citation(s) in RCA: 160] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 10/13/2020] [Accepted: 10/14/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Friedreich ataxia (FA) is a progressive genetic neurodegenerative disorder with no approved treatment. Omaveloxolone, an Nrf2 activator, improves mitochondrial function, restores redox balance, and reduces inflammation in models of FA. We investigated the safety and efficacy of omaveloxolone in patients with FA. METHODS We conducted an international, double-blind, randomized, placebo-controlled, parallel-group, registrational phase 2 trial at 11 institutions in the United States, Europe, and Australia (NCT02255435, EudraCT2015-002762-23). Eligible patients, 16 to 40 years of age with genetically confirmed FA and baseline modified Friedreich's Ataxia Rating Scale (mFARS) scores between 20 and 80, were randomized 1:1 to placebo or 150mg per day of omaveloxolone. The primary outcome was change from baseline in the mFARS score in those treated with omaveloxolone compared with those on placebo at 48 weeks. RESULTS One hundred fifty-five patients were screened, and 103 were randomly assigned to receive omaveloxolone (n = 51) or placebo (n = 52), with 40 omaveloxolone patients and 42 placebo patients analyzed in the full analysis set. Changes from baseline in mFARS scores in omaveloxolone (-1.55 ± 0.69) and placebo (0.85 ± 0.64) patients showed a difference between treatment groups of -2.40 ± 0.96 (p = 0.014). Transient reversible increases in aminotransferase levels were observed with omaveloxolone without increases in total bilirubin or other signs of liver injury. Headache, nausea, and fatigue were also more common among patients receiving omaveloxolone. INTERPRETATION In the MOXIe trial, omaveloxolone significantly improved neurological function compared to placebo and was generally safe and well tolerated. It represents a potential therapeutic agent in FA. ANN NEUROL 2021;89:212-225.
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Affiliation(s)
- David R. Lynch
- Division of NeurologyChildren's Hospital of PhiladelphiaPhiladelphiaPAUSA
| | | | - Martin B. Delatycki
- Victorian Clinical Genetics Services, Murdoch Children's Research InstituteParkvilleVictoriaAustralia
| | - S. H. Subramony
- Department of NeurologyMcKnight Brain Institute, University of Florida Health SystemGainesvilleFLUSA
| | - Manuela Corti
- Department of PediatricsUniversity of Florida Health SystemGainesvilleFLUSA
| | - J. Chad Hoyle
- Department of NeurologyOhio State University College of MedicineColumbusOHUSA
| | - Sylvia Boesch
- Department of NeurologyMedical University InnsbruckInnsbruckAustria
| | | | - Caterina Mariotti
- Istituto di Ricovero e Cura a Carattere Scientifico–Carlo Besta Neurological InstituteMilanItaly
| | - Katherine D. Mathews
- Department of NeurologyUniversity of Iowa Carver College of MedicineIowa CityIAUSA
| | - Paola Giunti
- University College London HospitalLondonUnited Kingdom
| | - George Wilmot
- Department of NeurologyEmory University School of MedicineAtlantaGAUSA
| | - Theresa Zesiewicz
- Department of NeurologyUniversity of South Florida Ataxia Research CenterTampaFLUSA
| | - Susan Perlman
- Department of NeurologyUniversity of California, Los AngelesLos AngelesCAUSA
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Lynch DR, Johnson J. Omaveloxolone: potential new agent for Friedreich ataxia. Neurodegener Dis Manag 2021; 11:91-98. [PMID: 33430645 DOI: 10.2217/nmt-2020-0057] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Friedreich ataxia is a slowly progressive neurodegenerative disorder leading to ataxia, dyscoordination, dysarthria and in many individuals vision and hearing loss. It is associated with cardiomyopathy, the leading cause of death in Friedreich ataxia (FRDA), diabetes and scoliosis. There are no approved therapies, but elucidation of the pathophysiology of FRDA suggest that agents that increase the activity of the transcription factor Nrf2 may provide a mechanism for ameliorating disease progression or severity. In this work, we review the evidence for use of omaveloxolone in FRDA from recent clinical trials. Though not at present approved for any indication, the present data suggest that this agent acting though increases in Nrf2 activity may provide a novel therapy for FRDA.
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Affiliation(s)
- David R Lynch
- Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.,Department of Neurology & Pediatrics, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Joseph Johnson
- Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.,Department of Systems Pharmacology & Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA
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Kahroba H, Ramezani B, Maadi H, Sadeghi MR, Jaberie H, Ramezani F. The role of Nrf2 in neural stem/progenitors cells: From maintaining stemness and self-renewal to promoting differentiation capability and facilitating therapeutic application in neurodegenerative disease. Ageing Res Rev 2021; 65:101211. [PMID: 33186670 DOI: 10.1016/j.arr.2020.101211] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 11/05/2020] [Accepted: 11/07/2020] [Indexed: 02/07/2023]
Abstract
Neurodegenerative diseases (NDs) cause progressive loss of neurons in nervous system. NDs are categorized as acute NDs such as stroke and head injury, besides chronic NDs including Alzheimer's, Parkinson's, Huntington's diseases, Friedreich's Ataxia, Multiple Sclerosis. The exact etiology of NDs is not understood but oxidative stress, inflammation and synaptic dysfunction are main hallmarks. Oxidative stress leads to free radical attack on neural cells which contributes to protein misfolding, glia cell activation, mitochondrial dysfunction, impairment of DNA repair system and subsequently cellular death. Neural stem cells (NSCs) support adult neurogenesis in nervous system during injuries which is limited to certain regions in brain. NSCs can differentiate into the neurons, astrocytes or oligodendrocytes. Impaired neurogenesis and inadequate induction of neurogenesis are the main obstacles in treatment of NDs. Protection of neural cells from oxidative damages and supporting neurogenesis are promising strategies to treat NDs. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a transcriptional master regulator that maintains the redox homeostasis in cells by provoking expression of antioxidant, anti-inflammatory and cytoprotective genes. Nrf2 can strongly influence the NSCs function and fate determination by reducing levels of reactive oxygen species in benefit of NSC survival and neurogenesis. In this review we will summarize the role of Nrf2 in NSC function, and exogenous and endogenous therapeutic strategies in treatment of NDs.
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Affiliation(s)
- Houman Kahroba
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Bahman Ramezani
- Department of Chemistry, Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | - Hamid Maadi
- Department of Medical Genetics, and Signal Transduction Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
| | - Mohammad Reza Sadeghi
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hajar Jaberie
- Department of Biochemistry, Faculty of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Fatemeh Ramezani
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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Seco-Cervera M, González-Cabo P, Pallardó FV, Romá-Mateo C, García-Giménez JL. Thioredoxin and Glutaredoxin Systems as Potential Targets for the Development of New Treatments in Friedreich's Ataxia. Antioxidants (Basel) 2020; 9:antiox9121257. [PMID: 33321938 PMCID: PMC7763308 DOI: 10.3390/antiox9121257] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/04/2020] [Accepted: 12/07/2020] [Indexed: 12/11/2022] Open
Abstract
The thioredoxin family consists of a small group of redox proteins present in all organisms and composed of thioredoxins (TRXs), glutaredoxins (GLRXs) and peroxiredoxins (PRDXs) which are found in the extracellular fluid, the cytoplasm, the mitochondria and in the nucleus with functions that include antioxidation, signaling and transcriptional control, among others. The importance of thioredoxin family proteins in neurodegenerative diseases is gaining relevance because some of these proteins have demonstrated an important role in the central nervous system by mediating neuroprotection against oxidative stress, contributing to mitochondrial function and regulating gene expression. Specifically, in the context of Friedreich’s ataxia (FRDA), thioredoxin family proteins may have a special role in the regulation of Nrf2 expression and function, in Fe-S cluster metabolism, controlling the expression of genes located at the iron-response element (IRE) and probably regulating ferroptosis. Therefore, comprehension of the mechanisms that closely link thioredoxin family proteins with cellular processes affected in FRDA will serve as a cornerstone to design improved therapeutic strategies.
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Affiliation(s)
- Marta Seco-Cervera
- Centre for Biomedical Research on Rare Diseases (CIBERER), 46010 Valencia, Spain; (M.S.-C.); (P.G.-C.); (F.V.P.)
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València (UV), 46010 Valencia, Spain
- Biomedical Research Institute INCLIVA, 46010 Valencia, Spain
| | - Pilar González-Cabo
- Centre for Biomedical Research on Rare Diseases (CIBERER), 46010 Valencia, Spain; (M.S.-C.); (P.G.-C.); (F.V.P.)
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València (UV), 46010 Valencia, Spain
- Biomedical Research Institute INCLIVA, 46010 Valencia, Spain
| | - Federico V. Pallardó
- Centre for Biomedical Research on Rare Diseases (CIBERER), 46010 Valencia, Spain; (M.S.-C.); (P.G.-C.); (F.V.P.)
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València (UV), 46010 Valencia, Spain
- Biomedical Research Institute INCLIVA, 46010 Valencia, Spain
| | - Carlos Romá-Mateo
- Centre for Biomedical Research on Rare Diseases (CIBERER), 46010 Valencia, Spain; (M.S.-C.); (P.G.-C.); (F.V.P.)
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València (UV), 46010 Valencia, Spain
- Biomedical Research Institute INCLIVA, 46010 Valencia, Spain
- Correspondence: (C.R.-M.); (J.L.G.-G.); Tel.: +34-963-864-646 (C.R.-M. & J.L.G.-G.)
| | - José Luis García-Giménez
- Centre for Biomedical Research on Rare Diseases (CIBERER), 46010 Valencia, Spain; (M.S.-C.); (P.G.-C.); (F.V.P.)
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València (UV), 46010 Valencia, Spain
- Biomedical Research Institute INCLIVA, 46010 Valencia, Spain
- Correspondence: (C.R.-M.); (J.L.G.-G.); Tel.: +34-963-864-646 (C.R.-M. & J.L.G.-G.)
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La Rosa P, Petrillo S, Fiorenza MT, Bertini ES, Piemonte F. Ferroptosis in Friedreich's Ataxia: A Metal-Induced Neurodegenerative Disease. Biomolecules 2020; 10:biom10111551. [PMID: 33202971 PMCID: PMC7696618 DOI: 10.3390/biom10111551] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 11/05/2020] [Accepted: 11/09/2020] [Indexed: 02/07/2023] Open
Abstract
Ferroptosis is an iron-dependent form of regulated cell death, arising from the accumulation of lipid-based reactive oxygen species when glutathione-dependent repair systems are compromised. Lipid peroxidation, mitochondrial impairment and iron dyshomeostasis are the hallmark of ferroptosis, which is emerging as a crucial player in neurodegeneration. This review provides an analysis of the most recent advances in ferroptosis, with a special focus on Friedreich's Ataxia (FA), the most common autosomal recessive neurodegenerative disease, caused by reduced levels of frataxin, a mitochondrial protein involved in iron-sulfur cluster synthesis and antioxidant defenses. The hypothesis is that the iron-induced oxidative damage accumulates over time in FA, lowering the ferroptosis threshold and leading to neuronal cell death and, at last, to cardiac failure. The use of anti-ferroptosis drugs combined with treatments able to activate the antioxidant response will be of paramount importance in FA therapy, such as in many other neurodegenerative diseases triggered by oxidative stress.
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Affiliation(s)
- Piergiorgio La Rosa
- Department of Psychology, Division of Neuroscience, Sapienza University of Rome, 00185 Rome, Italy; (P.L.R.); (M.T.F.)
| | - Sara Petrillo
- Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy; (S.P.); (E.S.B.)
| | - Maria Teresa Fiorenza
- Department of Psychology, Division of Neuroscience, Sapienza University of Rome, 00185 Rome, Italy; (P.L.R.); (M.T.F.)
| | - Enrico Silvio Bertini
- Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy; (S.P.); (E.S.B.)
| | - Fiorella Piemonte
- Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy; (S.P.); (E.S.B.)
- Correspondence: ; Tel.: +39-06-6859-2102
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The Nrf2 induction prevents ferroptosis in Friedreich's Ataxia. Redox Biol 2020; 38:101791. [PMID: 33197769 PMCID: PMC7677700 DOI: 10.1016/j.redox.2020.101791] [Citation(s) in RCA: 108] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 10/14/2020] [Accepted: 11/02/2020] [Indexed: 12/12/2022] Open
Abstract
Ferroptosis is an iron-dependent cell death caused by impaired glutathione metabolism, lipid peroxidation and mitochondrial failure. Emerging evidences report a role for ferroptosis in Friedreich's Ataxia (FRDA), a neurodegenerative disease caused by the decreased expression of the mitochondrial protein frataxin. Nrf2 signalling is implicated in many molecular aspects of ferroptosis, by upstream regulating glutathione homeostasis, mitochondrial function and lipid metabolism. As Nrf2 is down-regulated in FRDA, targeting Nrf2-mediated ferroptosis in FRDA may be an attractive option to counteract neurodegeneration in such disease, thus paving the way to new therapeutic opportunities. In this study, we evaluated ferroptosis hallmarks in frataxin-silenced mouse myoblasts, in hearts of a frataxin Knockin/Knockout (KIKO) mouse model, in skin fibroblasts and blood of patients, particularly focusing on ferroptosis-driven gene expression, mitochondrial impairment and lipid peroxidation. The efficacy of Nrf2 inducers to neutralize ferroptosis has been also evaluated.
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Chiang S, Huang MLH, Park KC, Richardson DR. Antioxidant defense mechanisms and its dysfunctional regulation in the mitochondrial disease, Friedreich's ataxia. Free Radic Biol Med 2020; 159:177-188. [PMID: 32739593 DOI: 10.1016/j.freeradbiomed.2020.07.019] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 07/12/2020] [Accepted: 07/13/2020] [Indexed: 02/06/2023]
Abstract
Redox stress is associated with the pathogenesis of a wide variety of disease states. This can be amplified potentially through redox active iron deposits in oxidatively active organelles such as the mitochondrion. There are a number of disease states, including Friedreich's ataxia (FA) and sideroblastic anemia, where iron metabolism is dysregulated and leads to mitochondrial iron accumulation. Considering FA, which is due to the decreased expression of the mitochondrial protein, frataxin, this iron accumulation does not occur within protective storage proteins such as mitochondrial ferritin. Instead, it forms unbound biomineral aggregates composed of high spin iron(III), phosphorous and sulfur, which probably contributes to the observed redox stress. There is also a dysregulated response to the ensuing redox assault, as the master regulator of oxidative stress, nuclear factor erythroid 2-related factor-2 (Nrf2), demonstrates marked down-regulation. The dysfunctional response of Nrf2 in FA is due to multiple mechanisms including: (1) up-regulation of Keap1 that is involved in Nrf2 degradation; (2) activation of the nuclear Nrf2 export/degradation machinery via glycogen synthase kinase-3β (Gsk3β) signaling; and (3) inhibited nuclear translocation of Nrf2. More recently, increased microRNA (miRNA) 144 expression has been demonstrated to down-regulate Nrf2 in several disease states, including an animal model of FA. Other miRNAs have also demonstrated to be dysregulated upon frataxin depletion in vivo in humans and animal models of FA. Collectively, frataxin depletion results in multiple, complex responses that lead to detrimental redox effects that could contribute to the mechanisms involved in the pathogenesis of FA.
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Affiliation(s)
- S Chiang
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Medical Foundation Building (K25), University of Sydney, Sydney, New South Wales, 2006, Australia
| | - M L H Huang
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Medical Foundation Building (K25), University of Sydney, Sydney, New South Wales, 2006, Australia
| | - K C Park
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Medical Foundation Building (K25), University of Sydney, Sydney, New South Wales, 2006, Australia
| | - D R Richardson
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Medical Foundation Building (K25), University of Sydney, Sydney, New South Wales, 2006, Australia; Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan; Centre for Cancer Cell Biology, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland, 4111, Australia.
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Chiang S, Huang MLH, Richardson DR. Treatment of dilated cardiomyopathy in a mouse model of Friedreich's ataxia using N-acetylcysteine and identification of alterations in microRNA expression that could be involved in its pathogenesis. Pharmacol Res 2020; 159:104994. [PMID: 32534099 DOI: 10.1016/j.phrs.2020.104994] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 06/01/2020] [Accepted: 06/01/2020] [Indexed: 01/01/2023]
Abstract
Deficient expression of the mitochondrial protein, frataxin, leads to a deadly cardiomyopathy. Our laboratory reported the master regulator of oxidative stress, nuclear factor erythroid 2-related factor-2 (Nrf2), demonstrates marked down-regulation after frataxin deletion in the heart. This was due, in part, to a pronounced increase in Keap1. To assess if this can be therapeutically targeted, cells were incubated with N-acetylcysteine (NAC), or buthionine sulfoximine (BSO), which increases or decreases glutathione (GSH), respectively, or the NRF2-inducer, sulforaphane (SFN). While SFN significantly (p < 0.05) induced NRF2, KEAP1 and BACH1, NAC attenuated SFN-induced NRF2, KEAP1 and BACH1. The down-regulation of KEAP1 by NAC was of interest, as Keap1 is markedly increased in the MCK conditional frataxin knockout (MCK KO) mouse model and this could lead to the decreased Nrf2 levels. Considering this, MCK KO mice were treated with i.p. NAC (500- or 1500-mg/kg, 5 days/week for 5-weeks) and demonstrated slightly less (p > 0.05) body weight loss versus the vehicle-treated KO. However, NAC did not rescue the cardiomyopathy. To additionally examine the dys-regulation of Nrf2 upon frataxin deletion, studies assessed the role of microRNA (miRNA) in this process. In MCK KO mice, miR-144 was up-regulated, which down-regulates Nrf2. Furthermore, miRNA screening in MCK KO mice demonstrated 23 miRNAs from 756 screened were significantly (p < 0.05) altered in KOs versus WT littermates. Of these, miR-21*, miR-34c*, and miR-200c, demonstrated marked alterations, with functional clustering analysis showing they regulate genes linked to cardiac hypertrophy, cardiomyopathy, and oxidative stress, respectively.
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MESH Headings
- Acetylcysteine/pharmacology
- Animals
- Basic-Leucine Zipper Transcription Factors/metabolism
- Cardiomyopathy, Dilated/drug therapy
- Cardiomyopathy, Dilated/etiology
- Cardiomyopathy, Dilated/genetics
- Cardiomyopathy, Dilated/metabolism
- Cell Line, Tumor
- Disease Models, Animal
- Friedreich Ataxia/complications
- Friedreich Ataxia/genetics
- Gene Expression Regulation
- Humans
- Iron-Binding Proteins/genetics
- Iron-Binding Proteins/metabolism
- Isothiocyanates/pharmacology
- Kelch-Like ECH-Associated Protein 1/metabolism
- Mice, Knockout
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/pathology
- NF-E2-Related Factor 2/genetics
- NF-E2-Related Factor 2/metabolism
- Sulfoxides/pharmacology
- Frataxin
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Affiliation(s)
- S Chiang
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Medical Foundation Building (K25), University of Sydney, Sydney, New South Wales, 2006 Australia
| | - M L H Huang
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Medical Foundation Building (K25), University of Sydney, Sydney, New South Wales, 2006 Australia
| | - D R Richardson
- Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Medical Foundation Building (K25), University of Sydney, Sydney, New South Wales, 2006 Australia; Centre for Cancer Cell Biology, Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, 4111, Queensland, Australia.
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Rodríguez LR, Lapeña T, Calap-Quintana P, Moltó MD, Gonzalez-Cabo P, Navarro Langa JA. Antioxidant Therapies and Oxidative Stress in Friedreich´s Ataxia: The Right Path or Just a Diversion? Antioxidants (Basel) 2020; 9:E664. [PMID: 32722309 PMCID: PMC7465446 DOI: 10.3390/antiox9080664] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 07/17/2020] [Accepted: 07/19/2020] [Indexed: 12/12/2022] Open
Abstract
Friedreich´s ataxia is the commonest autosomal recessive ataxia among population of European descent. Despite the huge advances performed in the last decades, a cure still remains elusive. One of the most studied hallmarks of the disease is the increased production of oxidative stress markers in patients and models. This feature has been the motivation to develop treatments that aim to counteract such boost of free radicals and to enhance the production of antioxidant defenses. In this work, we present and critically review those "antioxidant" drugs that went beyond the disease´s models and were approved for its application in clinical trials. The evaluation of these trials highlights some crucial aspects of the FRDA research. On the one hand, the analysis contributes to elucidate whether oxidative stress plays a central role or whether it is only an epiphenomenon. On the other hand, it comments on some limitations in the current trials that complicate the analysis and interpretation of their outcome. We also include some suggestions that will be interesting to implement in future studies and clinical trials.
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Affiliation(s)
- Laura R. Rodríguez
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València-INCLIVA, 46010 Valencia, Spain; (L.R.R.); (T.L.); (P.C.-Q.)
- Associated Unit for Rare Diseases INCLIVA-CIPF, 46010 Valencia, Spain
| | - Tamara Lapeña
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València-INCLIVA, 46010 Valencia, Spain; (L.R.R.); (T.L.); (P.C.-Q.)
- Associated Unit for Rare Diseases INCLIVA-CIPF, 46010 Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 46010 Valencia, Spain
| | - Pablo Calap-Quintana
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València-INCLIVA, 46010 Valencia, Spain; (L.R.R.); (T.L.); (P.C.-Q.)
- Associated Unit for Rare Diseases INCLIVA-CIPF, 46010 Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 46010 Valencia, Spain
| | - María Dolores Moltó
- Department of Genetics, Universitat de València-INCLIVA, 46100 Valencia, Spain;
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), 46100 Valencia, Spain
| | - Pilar Gonzalez-Cabo
- Department of Physiology, Faculty of Medicine and Dentistry, Universitat de València-INCLIVA, 46010 Valencia, Spain; (L.R.R.); (T.L.); (P.C.-Q.)
- Associated Unit for Rare Diseases INCLIVA-CIPF, 46010 Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 46010 Valencia, Spain
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La Rosa P, Petrillo S, Bertini ES, Piemonte F. Oxidative Stress in DNA Repeat Expansion Disorders: A Focus on NRF2 Signaling Involvement. Biomolecules 2020; 10:biom10050702. [PMID: 32369911 PMCID: PMC7277112 DOI: 10.3390/biom10050702] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 04/24/2020] [Accepted: 04/27/2020] [Indexed: 12/13/2022] Open
Abstract
DNA repeat expansion disorders are a group of neuromuscular and neurodegenerative diseases that arise from the inheritance of long tracts of nucleotide repetitions, located in the regulatory region, introns, or inside the coding sequence of a gene. Although loss of protein expression and/or the gain of function of its transcribed mRNA or translated product represent the major pathogenic effect of these pathologies, mitochondrial dysfunction and imbalance in redox homeostasis are reported as common features in these disorders, deeply affecting their severity and progression. In this review, we examine the role that the redox imbalance plays in the pathological mechanisms of DNA expansion disorders and the recent advances on antioxidant treatments, particularly focusing on the expression and the activity of the transcription factor NRF2, the main cellular regulator of the antioxidant response.
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Kasai S, Shimizu S, Tatara Y, Mimura J, Itoh K. Regulation of Nrf2 by Mitochondrial Reactive Oxygen Species in Physiology and Pathology. Biomolecules 2020; 10:biom10020320. [PMID: 32079324 PMCID: PMC7072240 DOI: 10.3390/biom10020320] [Citation(s) in RCA: 343] [Impact Index Per Article: 68.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 02/13/2020] [Accepted: 02/13/2020] [Indexed: 02/06/2023] Open
Abstract
Reactive oxygen species (ROS) are byproducts of aerobic respiration and signaling molecules that control various cellular functions. Nrf2 governs the gene expression of endogenous antioxidant synthesis and ROS-eliminating enzymes in response to various electrophilic compounds that inactivate the negative regulator Keap1. Accumulating evidence has shown that mitochondrial ROS (mtROS) activate Nrf2, often mediated by certain protein kinases, and induce the expression of antioxidant genes and genes involved in mitochondrial quality/quantity control. Mild physiological stress, such as caloric restriction and exercise, elicits beneficial effects through a process known as “mitohormesis”. Exercise induces NOX4 expression in the heart, which activates Nrf2 and increases endurance capacity. Mice transiently depleted of SOD2 or overexpressing skeletal muscle-specific UCP1 exhibit Nrf2-mediated antioxidant gene expression and PGC1α-mediated mitochondrial biogenesis. ATF4 activation may induce a transcriptional program that enhances NADPH synthesis in the mitochondria and might cooperate with the Nrf2 antioxidant system. In response to severe oxidative stress, Nrf2 induces Klf9 expression, which represses mtROS-eliminating enzymes to enhance cell death. Nrf2 is inactivated in certain pathological conditions, such as diabetes, but Keap1 down-regulation or mtROS elimination rescues Nrf2 expression and improves the pathology. These reports aid us in understanding the roles of Nrf2 in pathophysiological alterations involving mtROS.
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Affiliation(s)
- Shuya Kasai
- Department of Stress Response Science, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan; (S.K.); (S.S.); (J.M.)
| | - Sunao Shimizu
- Department of Stress Response Science, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan; (S.K.); (S.S.); (J.M.)
- Department of Nature & Wellness Research, Innovation Division, Kagome Co., Ltd. Nasushiobara, Tochigi 329-2762, Japan
| | - Yota Tatara
- Department of Glycotechnology, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan;
| | - Junsei Mimura
- Department of Stress Response Science, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan; (S.K.); (S.S.); (J.M.)
| | - Ken Itoh
- Department of Stress Response Science, Center for Advanced Medical Research, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan; (S.K.); (S.S.); (J.M.)
- Correspondence: ; Tel.: +81-172-39-5158
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Igoillo-Esteve M, Oliveira AF, Cosentino C, Fantuzzi F, Demarez C, Toivonen S, Hu A, Chintawar S, Lopes M, Pachera N, Cai Y, Abdulkarim B, Rai M, Marselli L, Marchetti P, Tariq M, Jonas JC, Boscolo M, Pandolfo M, Eizirik DL, Cnop M. Exenatide induces frataxin expression and improves mitochondrial function in Friedreich ataxia. JCI Insight 2020; 5:134221. [PMID: 31877117 PMCID: PMC7098728 DOI: 10.1172/jci.insight.134221] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 12/18/2019] [Indexed: 12/26/2022] Open
Abstract
Friedreich ataxia is an autosomal recessive neurodegenerative disease associated with a high diabetes prevalence. No treatment is available to prevent or delay disease progression. Friedreich ataxia is caused by intronic GAA trinucleotide repeat expansions in the frataxin-encoding FXN gene that reduce frataxin expression, impair iron-sulfur cluster biogenesis, cause oxidative stress, and result in mitochondrial dysfunction and apoptosis. Here we examined the metabolic, neuroprotective, and frataxin-inducing effects of glucagon-like peptide-1 (GLP-1) analogs in in vivo and in vitro models and in patients with Friedreich ataxia. The GLP-1 analog exenatide improved glucose homeostasis of frataxin-deficient mice through enhanced insulin content and secretion in pancreatic β cells. Exenatide induced frataxin and iron-sulfur cluster-containing proteins in β cells and brain and was protective to sensory neurons in dorsal root ganglia. GLP-1 analogs also induced frataxin expression, reduced oxidative stress, and improved mitochondrial function in Friedreich ataxia patients' induced pluripotent stem cell-derived β cells and sensory neurons. The frataxin-inducing effect of exenatide was confirmed in a pilot trial in Friedreich ataxia patients, showing modest frataxin induction in platelets over a 5-week treatment course. Taken together, GLP-1 analogs improve mitochondrial function in frataxin-deficient cells and induce frataxin expression. Our findings identify incretin receptors as a therapeutic target in Friedreich ataxia.
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Affiliation(s)
| | | | | | - Federica Fantuzzi
- ULB Center for Diabetes Research and
- Endocrinology and Metabolism, Department of Medicine and Surgery, University of Parma, Parma, Italy
| | | | | | - Amélie Hu
- Laboratory of Experimental Neurology, Université Libre de Bruxelles, Brussels, Belgium
| | - Satyan Chintawar
- Laboratory of Experimental Neurology, Université Libre de Bruxelles, Brussels, Belgium
| | | | | | - Ying Cai
- ULB Center for Diabetes Research and
| | | | - Myriam Rai
- Laboratory of Experimental Neurology, Université Libre de Bruxelles, Brussels, Belgium
| | - Lorella Marselli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Piero Marchetti
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Mohammad Tariq
- Pole of Endocrinology, Diabetes and Nutrition, Institute of Experimental and Clinical Research, Université Catholique de Louvain, Brussels, Belgium
| | - Jean-Christophe Jonas
- Pole of Endocrinology, Diabetes and Nutrition, Institute of Experimental and Clinical Research, Université Catholique de Louvain, Brussels, Belgium
| | - Marina Boscolo
- Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Massimo Pandolfo
- Laboratory of Experimental Neurology, Université Libre de Bruxelles, Brussels, Belgium
| | - Décio L. Eizirik
- ULB Center for Diabetes Research and
- Indiana Biosciences Research Institute, Indianapolis, Indiana, USA
| | - Miriam Cnop
- ULB Center for Diabetes Research and
- Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium
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45
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The NRF2 Signaling Network Defines Clinical Biomarkers and Therapeutic Opportunity in Friedreich's Ataxia. Int J Mol Sci 2020; 21:ijms21030916. [PMID: 32019240 PMCID: PMC7037688 DOI: 10.3390/ijms21030916] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 01/27/2020] [Accepted: 01/29/2020] [Indexed: 02/06/2023] Open
Abstract
Friedreich’s ataxia (FA) is a trinucleotide repeats expansion neurodegenerative disorder, for which no cure or approved therapies are present. In most cases, GAA trinucleotide repetitions in the first intron of the FXN gene are the genetic trigger of FA, determining a strong reduction of frataxin, a mitochondrial protein involved in iron homeostasis. Frataxin depletion impairs iron–sulfur cluster biosynthesis and determines iron accumulation in the mitochondria. Mounting evidence suggests that these defects increase oxidative stress susceptibility and reactive oxygen species production in FA, where the pathologic picture is worsened by a defective regulation of the expression and signaling pathway modulation of the transcription factor NF-E2 p45-related factor 2 (NRF2), one of the fundamental mediators of the cellular antioxidant response. NRF2 protein downregulation and impairment of its nuclear translocation can compromise the adequate cellular response to the frataxin depletion-dependent redox imbalance. As NRF2 stability, expression, and activation can be modulated by diverse natural and synthetic compounds, efforts have been made in recent years to understand if regulating NRF2 signaling might ameliorate the pathologic defects in FA. Here we provide an analysis of the pharmaceutical interventions aimed at restoring the NRF2 signaling network in FA, elucidating specific biomarkers useful for monitoring therapeutic effectiveness, and developing new therapeutic tools.
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46
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Petrillo S, Schirinzi T, Di Lazzaro G, D'Amico J, Colona VL, Bertini E, Pierantozzi M, Mari L, Mercuri NB, Piemonte F, Pisani A. Systemic Activation of Nrf2 Pathway in Parkinson's Disease. Mov Disord 2019; 35:180-184. [DOI: 10.1002/mds.27878] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 09/09/2019] [Accepted: 09/12/2019] [Indexed: 12/16/2022] Open
Affiliation(s)
- Sara Petrillo
- Unit of Muscular and Neurodegenerative Diseases Children's Hospital and Research Institute Bambino Gesù, Istituto di Ricovero e Cura a Carattere Scientifico(I.R.C.C.S.) Rome Italy
| | - Tommaso Schirinzi
- Unit of Muscular and Neurodegenerative Diseases Children's Hospital and Research Institute Bambino Gesù, Istituto di Ricovero e Cura a Carattere Scientifico(I.R.C.C.S.) Rome Italy
- Neurology, Department of Systems Medicine University of Rome Tor Vergata Rome Italy
| | - Giulia Di Lazzaro
- Neurology, Department of Systems Medicine University of Rome Tor Vergata Rome Italy
| | - Jessica D'Amico
- Unit of Muscular and Neurodegenerative Diseases Children's Hospital and Research Institute Bambino Gesù, Istituto di Ricovero e Cura a Carattere Scientifico(I.R.C.C.S.) Rome Italy
| | - Vito L. Colona
- Neurology, Department of Systems Medicine University of Rome Tor Vergata Rome Italy
| | - Enrico Bertini
- Unit of Muscular and Neurodegenerative Diseases Children's Hospital and Research Institute Bambino Gesù, Istituto di Ricovero e Cura a Carattere Scientifico(I.R.C.C.S.) Rome Italy
| | | | - Luisa Mari
- Neurology, Department of Systems Medicine University of Rome Tor Vergata Rome Italy
| | - Nicola B. Mercuri
- Neurology, Department of Systems Medicine University of Rome Tor Vergata Rome Italy
- Fondazione Santa Lucia I.R.C.C.S Rome Italy
| | - Fiorella Piemonte
- Unit of Muscular and Neurodegenerative Diseases Children's Hospital and Research Institute Bambino Gesù, Istituto di Ricovero e Cura a Carattere Scientifico(I.R.C.C.S.) Rome Italy
| | - Antonio Pisani
- Neurology, Department of Systems Medicine University of Rome Tor Vergata Rome Italy
- Fondazione Santa Lucia I.R.C.C.S Rome Italy
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47
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Petrillo S, D'Amico J, La Rosa P, Bertini ES, Piemonte F. Targeting NRF2 for the Treatment of Friedreich's Ataxia: A Comparison among Drugs. Int J Mol Sci 2019; 20:E5211. [PMID: 31640150 PMCID: PMC6829337 DOI: 10.3390/ijms20205211] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 10/17/2019] [Accepted: 10/17/2019] [Indexed: 12/31/2022] Open
Abstract
NRF2 (Nuclear factor Erythroid 2-related Factor 2) signaling is impaired in Friedreich's Ataxia (FRDA), an autosomal recessive disease characterized by progressive nervous system damage and degeneration of nerve fibers in the spinal cord and peripheral nerves. The loss of frataxin in patients results in iron sulfur cluster deficiency and iron accumulation in the mitochondria, making FRDA a fatal and debilitating condition. There are no currently approved therapies for the treatment of FRDA and molecules able to activate NRF2 have the potential to induce clinical benefits in patients. In this study, we compared the efficacy of six redox-active drugs, some already adopted in clinical trials, targeting NRF2 activation and frataxin expression in fibroblasts obtained from skin biopsies of FRDA patients. All of these drugs consistently increased NRF2 expression, but differential profiles of NRF2 downstream genes were activated. The Sulforaphane and N-acetylcysteine were particularly effective on genes involved in preventing inflammation and maintaining glutathione homeostasis, the dimethyl fumarate, omaxevolone, and EPI-743 in counteracting toxic products accumulation, the idebenone in mitochondrial protection. This study may contribute to develop synergic therapies, based on a combination of treatment molecules.
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Affiliation(s)
- Sara Petrillo
- Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital, IRCCS, 00146 Rome, Italy.
| | - Jessica D'Amico
- Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital, IRCCS, 00146 Rome, Italy.
| | - Piergiorgio La Rosa
- Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital, IRCCS, 00146 Rome, Italy.
| | - Enrico Silvio Bertini
- Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital, IRCCS, 00146 Rome, Italy.
| | - Fiorella Piemonte
- Unit of Muscular and Neurodegenerative Diseases, Bambino Gesù Children's Hospital, IRCCS, 00146 Rome, Italy.
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48
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Gottesfeld JM. Molecular Mechanisms and Therapeutics for the GAA·TTC Expansion Disease Friedreich Ataxia. Neurotherapeutics 2019; 16:1032-1049. [PMID: 31317428 PMCID: PMC6985418 DOI: 10.1007/s13311-019-00764-x] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Friedreich ataxia (FRDA), the most common inherited ataxia, is caused by transcriptional silencing of the nuclear FXN gene, encoding the essential mitochondrial protein frataxin. Currently, there is no approved therapy for this fatal disorder. Gene silencing in FRDA is due to hyperexpansion of the triplet repeat sequence GAA·TTC in the first intron of the FXN gene, which results in chromatin histone modifications consistent with heterochromatin formation. Frataxin is involved in mitochondrial iron homeostasis and the assembly and transfer of iron-sulfur clusters to various mitochondrial enzymes and components of the electron transport chain. Frataxin insufficiency leads to progressive spinocerebellar neurodegeneration, causing symptoms of gait and limb ataxia, slurred speech, muscle weakness, sensory loss, and cardiomyopathy in many patients, resulting in death in early adulthood. Numerous approaches are being taken to find a treatment for FRDA, including excision or correction of the repeats by genome engineering methods, gene activation with small molecules or artificial transcription factors, delivery of frataxin to affected cells by protein replacement therapy, gene therapy, or small molecules to increase frataxin protein levels, and therapies aimed at countering the cellular consequences of reduced frataxin. This review will summarize the mechanisms involved in repeat-mediated gene silencing and recent efforts aimed at development of therapeutics.
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Affiliation(s)
- Joel M Gottesfeld
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, 92037, USA.
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49
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Galiè M, Covi V, Tabaracci G, Malatesta M. The Role of Nrf2 in the Antioxidant Cellular Response to Medical Ozone Exposure. Int J Mol Sci 2019; 20:E4009. [PMID: 31426459 PMCID: PMC6720777 DOI: 10.3390/ijms20164009] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Revised: 08/15/2019] [Accepted: 08/15/2019] [Indexed: 02/07/2023] Open
Abstract
Ozone (O3) is a natural, highly unstable atmospheric gas that rapidly decomposes to oxygen. Although not being a radical molecule, O3 is a very strong oxidant and therefore it is potentially toxic for living organisms. However, scientific evidence proved that the effects of O3 exposure are dose-dependent: high dosages stimulate severe oxidative stress resulting in inflammatory response and tissue injury, whereas low O3 concentrations induce a moderate oxidative eustress activating antioxidant pathways. These properties make O3 a powerful medical tool, which can be used as either a disinfectant or an adjuvant agent in the therapy of numerous diseases. In this paper, the cellular mechanisms involved in the antioxidant response to O3 exposure will be reviewed with special reference to the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its role in the efficacy of ozone therapy.
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Affiliation(s)
- Mirco Galiè
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Strada Le Grazie 8, I-37134 Verona, Italy
| | - Viviana Covi
- San Rocco Clinic, Via Monsignor G. V. Moreni 95, I-25018 Montichiari (BS), Italy
| | - Gabriele Tabaracci
- San Rocco Clinic, Via Monsignor G. V. Moreni 95, I-25018 Montichiari (BS), Italy
| | - Manuela Malatesta
- Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Strada Le Grazie 8, I-37134 Verona, Italy.
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50
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Fang YJ, Mei SH, Lu JN, Chen YK, Chai ZH, Dong X, Araujo C, Reis C, Zhang JM, Chen S. New risk score of the early period after spontaneous subarachnoid hemorrhage: For the prediction of delayed cerebral ischemia. CNS Neurosci Ther 2019; 25:1173-1181. [PMID: 31407513 PMCID: PMC6776741 DOI: 10.1111/cns.13202] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 07/11/2019] [Accepted: 07/12/2019] [Indexed: 01/09/2023] Open
Abstract
Background and Purpose The aim of this study is to identify the early predictors for delayed cerebral ischemia (DCI) and develop a risk stratification score by focusing on the early change after aneurysmal subarachnoid hemorrhage (aSAH). Methods The study retrospectively reviewed aSAH patients between 2014 and 2015. Risk factors within 72 hours after aSAH were included into univariable and multivariable logistic regression analysis to screen the independent predictors for DCI and to design a risk stratification score. Results We analyzed 702 aSAH patients; four predictors were retained from the final multivariable analysis: World Federation of Neurosurgical Societies scale (WFNS; OR = 4.057, P < .001), modified Fisher Scale (mFS; OR = 2.623, P < .001), Subarachnoid Hemorrhage Early Brain Edema Score (SEBES; OR = 1.539, P = .036), and intraventricular hemorrhage (IVH; OR = 1.932, P = .002). According to the regression coefficient, we created a risk stratification score ranging from 0 to 7 (WFNS = 3, mFS = 2, SEBES = 1, and IVH = 1). The new score showed a significantly higher area under curve (0.785) compared with other scores (P < .001). Conclusion The early DCI score provides a practical method at the early 72 hours after aSAH to predict DCI.
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Affiliation(s)
- Yuan-Jian Fang
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Shu-Hao Mei
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jia-Nan Lu
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yi-Ke Chen
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhao-Hui Chai
- Department of Neurosurgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiao Dong
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Camila Araujo
- Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Cesar Reis
- Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Jian-Min Zhang
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Brain Research Institute, Zhejiang University, Hangzhou, China.,Collaborative Innovation Center for Brain Science, Zhejiang University, Hangzhou, China
| | - Sheng Chen
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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