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1
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Indelicato E, Delatycki MB, Farmer J, França MC, Perlman S, Rai M, Boesch S. A global perspective on research advances and future challenges in Friedreich ataxia. Nat Rev Neurol 2025; 21:204-215. [PMID: 40032987 DOI: 10.1038/s41582-025-01065-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/29/2025] [Indexed: 03/05/2025]
Abstract
Friedreich ataxia (FRDA) is a rare multisystem, life-limiting disease and is the most common early-onset inherited ataxia in populations of European, Arab and Indian descent. In recent years, substantial progress has been made in dissecting the pathogenesis and natural history of FRDA, and several clinical trials have been initiated. A particularly notable recent achievement was the approval of the nuclear factor erythroid 2-related factor 2 activator omaveloxolone as the first disease-specific therapy for FRDA. In light of these developments, we review milestones in FRDA translational and clinical research over the past 10 years, as well as the various therapeutic strategies currently in the pipeline. We also consider the lessons that have been learned from failed trials and other setbacks. We conclude by presenting a global roadmap for future research, as outlined by the recently established Friedreich's Ataxia Global Clinical Consortium, which covers North and South America, Europe, India, Australia and New Zealand.
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Affiliation(s)
- Elisabetta Indelicato
- Center for Rare Movement Disorders Innsbruck, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Martin B Delatycki
- Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Parkville, Victoria, Australia
| | | | | | | | - Myriam Rai
- Friedreich's Ataxia Research Alliance, Downingtown, PA, USA
- Laboratory of Experimental Neurology, Brussels, Belgium
| | - Sylvia Boesch
- Center for Rare Movement Disorders Innsbruck, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
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2
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Kioutchoukova IP, Foster DT, Thakkar RN, Foreman MA, Burgess BJ, Toms RM, Molina Valero EE, Lucke-Wold B. Neurologic orphan diseases: Emerging innovations and role for genetic treatments. World J Exp Med 2023; 13:59-74. [PMID: 37767543 PMCID: PMC10520757 DOI: 10.5493/wjem.v13.i4.59] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Revised: 07/16/2023] [Accepted: 08/11/2023] [Indexed: 09/15/2023] Open
Abstract
Orphan diseases are rare diseases that affect less than 200000 individuals within the United States. Most orphan diseases are of neurologic and genetic origin. With the current advances in technology, more funding has been devoted to developing therapeutic agents for patients with these conditions. In our review, we highlight emerging options for patients with neurologic orphan diseases, specifically including diseases resulting in muscular deterioration, epilepsy, seizures, neurodegenerative movement disorders, inhibited cognitive development, neuron deterioration, and tumors. After extensive literature review, gene therapy offers a promising route for the treatment of neurologic orphan diseases. The use of clustered regularly interspaced palindromic repeats/Cas9 has demonstrated positive results in experiments investigating its role in several diseases. Additionally, the use of adeno-associated viral vectors has shown improvement in survival, motor function, and developmental milestones, while also demonstrating reversal of sensory ataxia and cardiomyopathy in Friedreich ataxia patients. Antisense oligonucleotides have also been used in some neurologic orphan diseases with positive outcomes. Mammalian target of rapamycin inhibitors are currently being investigated and have reduced abnormal cell growth, proliferation, and angiogenesis. Emerging innovations and the role of genetic treatments open a new window of opportunity for the treatment of neurologic orphan diseases.
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Affiliation(s)
| | - Devon T Foster
- Florida International University Herbert Wertheim College of Medicine, Florida International University Herbert Wertheim College of Medicine, Miami, FL 33199, United States
| | - Rajvi N Thakkar
- College of Medicine, University of Florida, Gainesville, FL 32611, United States
| | - Marco A Foreman
- College of Medicine, University of Florida, Gainesville, FL 32611, United States
| | - Brandon J Burgess
- College of Medicine, University of Florida, Gainesville, FL 32611, United States
| | - Rebecca M Toms
- College of Medicine, University of Florida, Gainesville, FL 32611, United States
| | | | - Brandon Lucke-Wold
- Department of Neurosurgery, University of Florida, Gainesville, FL 32611, United States
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3
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Dionisi C, Chazalon M, Rai M, Keime C, Imbault V, Communi D, Puccio H, Schiffmann SN, Pandolfo M. Proprioceptors-enriched neuronal cultures from induced pluripotent stem cells from Friedreich ataxia patients show altered transcriptomic and proteomic profiles, abnormal neurite extension, and impaired electrophysiological properties. Brain Commun 2023; 5:fcad007. [PMID: 36865673 PMCID: PMC9972525 DOI: 10.1093/braincomms/fcad007] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 09/28/2022] [Accepted: 01/14/2023] [Indexed: 01/19/2023] Open
Abstract
Friedreich ataxia is an autosomal recessive multisystem disorder with prominent neurological manifestations and cardiac involvement. The disease is caused by large GAA expansions in the first intron of the FXN gene, encoding the mitochondrial protein frataxin, resulting in downregulation of gene expression and reduced synthesis of frataxin. The selective loss of proprioceptive neurons is a hallmark of Friedreich ataxia, but the cause of the specific vulnerability of these cells is still unknown. We herein perform an in vitro characterization of human induced pluripotent stem cell-derived sensory neuronal cultures highly enriched for primary proprioceptive neurons. We employ neurons differentiated from healthy donors, Friedreich ataxia patients and Friedreich ataxia sibling isogenic control lines. The analysis of the transcriptomic and proteomic profile suggests an impairment of cytoskeleton organization at the growth cone, neurite extension and, at later stages of maturation, synaptic plasticity. Alterations in the spiking profile of tonic neurons are also observed at the electrophysiological analysis of mature neurons. Despite the reversal of the repressive epigenetic state at the FXN locus and the restoration of FXN expression, isogenic control neurons retain many features of Friedreich ataxia neurons. Our study suggests the existence of abnormalities affecting proprioceptors in Friedreich ataxia, particularly their ability to extend towards their targets and transmit proper synaptic signals. It also highlights the need for further investigations to better understand the mechanistic link between FXN silencing and proprioceptive degeneration in Friedreich ataxia.
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Affiliation(s)
| | | | - Myriam Rai
- Laboratory of Experimental Neurology, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium
| | - Céline Keime
- Institut de Génétique et de Biologie Moléculaire et Cellulaire UMR 7104 CNRS-UdS / INSERM U1258, Université de Strasbourg, 67404 Illkirch Cedex, Strasbourg, France
| | - Virginie Imbault
- Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium
| | - David Communi
- Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium
| | - Hélène Puccio
- Institut de Génétique et de Biologie Moléculaire et Cellulaire UMR 7104 CNRS-UdS / INSERM U1258, Université de Strasbourg, 67404 Illkirch Cedex, Strasbourg, France,Institut NeuroMyoGene (INMG) UMR5310—INSERM U1217, Faculté de Médecine, Université Claude Bernard—Lyon I, 69008 Lyon, France
| | - Serge N Schiffmann
- Laboratory of Neurophysiology, ULB-Neuroscience Institute (UNI), Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium
| | - Massimo Pandolfo
- Correspondence to: Massimo Pandolfo Department of Neurology and Neurosurgery McGill University, Montreal Neurological Institute 3801 University Street, Montreal, Quebec H3A 2B4, Canada E-mail:
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4
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Kadirvelu B, Gavriel C, Nageshwaran S, Chan JPK, Nethisinghe S, Athanasopoulos S, Ricotti V, Voit T, Giunti P, Festenstein R, Faisal AA. A wearable motion capture suit and machine learning predict disease progression in Friedreich's ataxia. Nat Med 2023; 29:86-94. [PMID: 36658420 PMCID: PMC9873563 DOI: 10.1038/s41591-022-02159-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 11/29/2022] [Indexed: 01/21/2023]
Abstract
Friedreich's ataxia (FA) is caused by a variant of the Frataxin (FXN) gene, leading to its downregulation and progressively impaired cardiac and neurological function. Current gold-standard clinical scales use simplistic behavioral assessments, which require 18- to 24-month-long trials to determine if therapies are beneficial. Here we captured full-body movement kinematics from patients with wearable sensors, enabling us to define digital behavioral features based on the data from nine FA patients (six females and three males) and nine age- and sex-matched controls, who performed the 8-m walk (8-MW) test and 9-hole peg test (9 HPT). We used machine learning to combine these features to longitudinally predict the clinical scores of the FA patients, and compared these with two standard clinical assessments, Spinocerebellar Ataxia Functional Index (SCAFI) and Scale for the Assessment and Rating of Ataxia (SARA). The digital behavioral features enabled longitudinal predictions of personal SARA and SCAFI scores 9 months into the future and were 1.7 and 4 times more precise than longitudinal predictions using only SARA and SCAFI scores, respectively. Unlike the two clinical scales, the digital behavioral features accurately predicted FXN gene expression levels for each FA patient in a cross-sectional manner. Our work demonstrates how data-derived wearable biomarkers can track personal disease trajectories and indicates the potential of such biomarkers for substantially reducing the duration or size of clinical trials testing disease-modifying therapies and for enabling behavioral transcriptomics.
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Affiliation(s)
- Balasundaram Kadirvelu
- Brain & Behaviour Lab, Department of Bioengineering, Imperial College London, London, UK
- Brain & Behaviour Lab, Department of Computing, Imperial College London, London, UK
| | - Constantinos Gavriel
- Brain & Behaviour Lab, Department of Bioengineering, Imperial College London, London, UK
- Brain & Behaviour Lab, Department of Computing, Imperial College London, London, UK
| | - Sathiji Nageshwaran
- Epigenetic Mechanisms and Disease Group, Department of Brain Sciences, Imperial College London, London, UK
| | - Jackson Ping Kei Chan
- Epigenetic Mechanisms and Disease Group, Department of Brain Sciences, Imperial College London, London, UK
| | - Suran Nethisinghe
- NIHR Great Ormond Street Hospital Biomedical Research Centre, UCL Great Ormond Street Institute of Child Health, London, UK
| | - Stavros Athanasopoulos
- Epigenetic Mechanisms and Disease Group, Department of Brain Sciences, Imperial College London, London, UK
| | - Valeria Ricotti
- NIHR Great Ormond Street Hospital Biomedical Research Centre, UCL Great Ormond Street Institute of Child Health, London, UK
- Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK
| | - Thomas Voit
- NIHR Great Ormond Street Hospital Biomedical Research Centre, UCL Great Ormond Street Institute of Child Health, London, UK
- Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK
| | - Paola Giunti
- Institute of Neurology, UCL, National Hospital for Neurology and Neurosurgery (UCLH), London, UK
| | - Richard Festenstein
- Epigenetic Mechanisms and Disease Group, Department of Brain Sciences, Imperial College London, London, UK
- Institute of Neurology, UCL, National Hospital for Neurology and Neurosurgery (UCLH), London, UK
- MRC London Institute of Medical Sciences, London, UK
| | - A Aldo Faisal
- Brain & Behaviour Lab, Department of Bioengineering, Imperial College London, London, UK.
- Brain & Behaviour Lab, Department of Computing, Imperial College London, London, UK.
- MRC London Institute of Medical Sciences, London, UK.
- Behaviour Analytics Lab, Data Science Institute, Imperial College London, London, UK.
- Brain & Behaviour Lab, Institute for Artificial and Human Intelligence, University of Bayreuth, Bayreuth, Germany.
- Chair in Digital Health, Faculty of Life Sciences, University of Bayreuth, Bayreuth, Germany.
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5
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Joers JM, Adanyeguh IM, Deelchand DK, Hutter DH, Eberly LE, Iltis I, Bushara KO, Lenglet C, Henry PG. Spinal cord magnetic resonance imaging and spectroscopy detect early-stage alterations and disease progression in Friedreich ataxia. Brain Commun 2022; 4:fcac246. [PMID: 36300142 PMCID: PMC9581897 DOI: 10.1093/braincomms/fcac246] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 06/04/2022] [Accepted: 09/23/2022] [Indexed: 02/01/2023] Open
Abstract
Friedreich ataxia is the most common hereditary ataxia. Atrophy of the spinal cord is one of the hallmarks of the disease. MRI and magnetic resonance spectroscopy are powerful and non-invasive tools to investigate pathological changes in the spinal cord. A handful of studies have reported cross-sectional alterations in Friedreich ataxia using MRI and diffusion MRI. However, to our knowledge no longitudinal MRI, diffusion MRI or MRS results have been reported in the spinal cord. Here, we investigated early-stage cross-sectional alterations and longitudinal changes in the cervical spinal cord in Friedreich ataxia, using a multimodal magnetic resonance protocol comprising morphometric (anatomical MRI), microstructural (diffusion MRI), and neurochemical (1H-MRS) assessments.We enrolled 28 early-stage individuals with Friedreich ataxia and 20 age- and gender-matched controls (cross-sectional study). Disease duration at baseline was 5.5 ± 4.0 years and Friedreich Ataxia Rating Scale total neurological score at baseline was 42.7 ± 13.6. Twenty-one Friedreich ataxia participants returned for 1-year follow-up, and 19 of those for 2-year follow-up (cohort study). Each visit consisted in clinical assessments and magnetic resonance scans. Controls were scanned at baseline only. At baseline, individuals with Friedreich ataxia had significantly lower spinal cord cross-sectional area (-31%, P = 8 × 10-17), higher eccentricity (+10%, P = 5 × 10-7), lower total N-acetyl-aspartate (tNAA) (-36%, P = 6 × 10-9) and higher myo-inositol (mIns) (+37%, P = 2 × 10-6) corresponding to a lower ratio tNAA/mIns (-52%, P = 2 × 10-13), lower fractional anisotropy (-24%, P = 10-9), as well as higher radial diffusivity (+56%, P = 2 × 10-9), mean diffusivity (+35%, P = 10-8) and axial diffusivity (+17%, P = 4 × 10-5) relative to controls. Longitudinally, spinal cord cross-sectional area decreased by 2.4% per year relative to baseline (P = 4 × 10-4), the ratio tNAA/mIns decreased by 5.8% per year (P = 0.03), and fractional anisotropy showed a trend to decrease (-3.2% per year, P = 0.08). Spinal cord cross-sectional area correlated strongly with clinical measures, with the strongest correlation coefficients found between cross-sectional area and Scale for the Assessment and Rating of Ataxia (R = -0.55, P = 7 × 10-6) and between cross-sectional area and Friedreich ataxia Rating Scale total neurological score (R = -0.60, P = 4 × 10-7). Less strong but still significant correlations were found for fractional anisotropy and tNAA/mIns. We report here the first quantitative longitudinal magnetic resonance results in the spinal cord in Friedreich ataxia. The largest longitudinal effect size was found for spinal cord cross-sectional area, followed by tNAA/mIns and fractional anisotropy. Our results provide direct evidence that abnormalities in the spinal cord result not solely from hypoplasia, but also from neurodegeneration, and show that disease progression can be monitored non-invasively in the spinal cord.
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Affiliation(s)
- James M Joers
- Center for Magnetic Resonance Research and Department of Radiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Isaac M Adanyeguh
- Center for Magnetic Resonance Research and Department of Radiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Dinesh K Deelchand
- Center for Magnetic Resonance Research and Department of Radiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Diane H Hutter
- Center for Magnetic Resonance Research and Department of Radiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Lynn E Eberly
- Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN 55455, USA
| | - Isabelle Iltis
- Center for Magnetic Resonance Research and Department of Radiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Khalaf O Bushara
- Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Christophe Lenglet
- Center for Magnetic Resonance Research and Department of Radiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Pierre-Gilles Henry
- Center for Magnetic Resonance Research and Department of Radiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
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6
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Huin V, Coarelli G, Guemy C, Boluda S, Debs R, Mochel F, Stojkovic T, Grabli D, Maisonobe T, Gaymard B, Lenglet T, Tard C, Davion JB, Sablonnière B, Monin ML, Ewenczyk C, Viala K, Charles P, Le Ber I, Reilly MM, Houlden H, Cortese A, Seilhean D, Brice A, Durr A. Motor neuron pathology in CANVAS due to RFC1 expansions. Brain 2021; 145:2121-2132. [DOI: 10.1093/brain/awab449] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 11/03/2021] [Accepted: 11/18/2021] [Indexed: 11/14/2022] Open
Abstract
Abstract
CANVAS caused by RFC1 biallelic expansions is a major cause of inherited sensory neuronopathy. Detection of RFC1 expansion is challenging and CANVAS can be associated with atypical features.
We clinically and genetically characterized 50 patients, selected based on the presence of sensory neuronopathy confirmed by EMG. We screened RFC1 expansion by PCR, repeat-primed PCR, and Southern blotting of long-range PCR products, a newly developed method. Neuropathological characterization was performed on the brain and spinal cord of one patient.
Most patients (88%) carried a biallelic (AAGGG)n expansion in RFC1. In addition to the core CANVAS phenotype (sensory neuronopathy, cerebellar syndrome, and vestibular impairment), we observed chronic cough (97%), oculomotor signs (85%), motor neuron involvement (55%), dysautonomia (50%), and parkinsonism (10%). Motor neuron involvement was found for 24 of 38 patients (63.1%). First motor neuron signs, such as brisk reflexes, extensor plantar responses, and/or spasticity, were present in 29% of patients, second motor neuron signs, such as fasciculations, wasting, weakness, or a neurogenic pattern on EMG in 18%, and both in 16%. Mixed motor and sensory neuronopathy was observed in 19% of patients. Among six non-RFC1 patients, one carried a heterozygous AAGGG expansion and a pathogenic variant in GRM1. Neuropathological examination of one RFC1 patient with an enriched phenotype, including parkinsonism, dysautonomia, and cognitive decline, showed posterior column and lumbar posterior root atrophy. Degeneration of the vestibulospinal and spinocerebellar tracts was mild. We observed marked astrocytic gliosis and axonal swelling of the synapse between first and second motor neurons in the anterior horn at the lumbar level. The cerebellum showed mild depletion of Purkinje cells, with empty baskets, torpedoes, and astrogliosis characterized by a disorganization of the Bergmann's radial glia. We found neuronal loss in the vagal nucleus. The pars compacta of the substantia nigra was depleted, with widespread Lewy bodies in the locus coeruleus, substantia nigra, hippocampus, entorhinal cortex, and amygdala.
We propose new guidelines for the screening of RFC1 expansion, considering different expansion motifs. Here, we developed a new method to more easily detect pathogenic RFC1 expansions. We report frequent motor neuron involvement and different neuronopathy subtypes. Parkinsonism was more prevalent in this cohort than in the general population, 10% versus the expected 1% (p < 0.001). We describe, for the first time, the spinal cord pathology in CANVAS, showing the alteration of posterior columns and roots, astrocytic gliosis and axonal swelling, suggesting motor neuron synaptic dysfunction.
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Affiliation(s)
- Vincent Huin
- Sorbonne Université, Paris Brain Institute, APHP, INSERM, CNRS, Paris, France
- Univ. Lille, Inserm, CHU Lille, U1172 - LilNCog (JPARC) - Lille Neuroscience & Cognition, F-59000 Lille, France
| | - Giulia Coarelli
- Sorbonne Université, Paris Brain Institute, APHP, INSERM, CNRS, Paris, France
- AP-HP, Pitié Salpêtrière University Hospital, Genetics Department, Sorbonne University, Paris, France
| | - Clément Guemy
- Sorbonne Université, Paris Brain Institute, APHP, INSERM, CNRS, Paris, France
| | - Susana Boluda
- Sorbonne Université, Paris Brain Institute, APHP, INSERM, CNRS, Paris, France
- Laboratoire Neuropathologie Raymond Escourolle, AP-HP, Pitié Salpêtrière University Hospital, Sorbonne University, Paris, France
| | - Rabab Debs
- AP-HP, Pitié Salpêtrière University Hospital, Department of Neurology, Sorbonne University, Paris, France
| | - Fanny Mochel
- Sorbonne Université, Paris Brain Institute, APHP, INSERM, CNRS, Paris, France
- AP-HP, Pitié Salpêtrière University Hospital, Genetics Department, Sorbonne University, Paris, France
| | - Tanya Stojkovic
- Institut de Myologie, Centre de Référence de Pathologie Neuromusculaire Paris-Est, AP-HP, Pitié Salpêtrière University Hospital, Sorbonne University, Paris, France
| | - David Grabli
- AP-HP, Pitié Salpêtrière University Hospital, Department of Neurology, Sorbonne University, Paris, France
| | - Thierry Maisonobe
- Institut de Myologie, Centre de Référence de Pathologie Neuromusculaire Paris-Est, AP-HP, Pitié Salpêtrière University Hospital, Sorbonne University, Paris, France
| | - Bertrand Gaymard
- AP-HP, Pitié Salpêtrière University Hospital, Department of Neurophysiology, Sorbonne University, Paris, France
| | - Timothée Lenglet
- AP-HP, Pitié Salpêtrière University Hospital, Department of Neurophysiology, Sorbonne University, Paris, France
| | - Céline Tard
- Univ. Lille, Inserm, CHU Lille, U1172 - LilNCog (JPARC) - Lille Neuroscience & Cognition, F-59000 Lille, France
- Centre de Référence des Maladies Neuromusculaires, CHU Lille, F-59000 Lille, France
| | - Jean-Baptiste Davion
- Univ. Lille, Inserm, CHU Lille, U1172 - LilNCog (JPARC) - Lille Neuroscience & Cognition, F-59000 Lille, France
- Centre de Référence des Maladies Neuromusculaires, CHU Lille, F-59000 Lille, France
| | - Bernard Sablonnière
- Univ. Lille, Inserm, CHU Lille, U1172 - LilNCog (JPARC) - Lille Neuroscience & Cognition, F-59000 Lille, France
| | | | - Claire Ewenczyk
- Sorbonne Université, Paris Brain Institute, APHP, INSERM, CNRS, Paris, France
- AP-HP, Pitié Salpêtrière University Hospital, Genetics Department, Sorbonne University, Paris, France
| | - Karine Viala
- Institut de Myologie, Centre de Référence de Pathologie Neuromusculaire Paris-Est, AP-HP, Pitié Salpêtrière University Hospital, Sorbonne University, Paris, France
| | - Perrine Charles
- Sorbonne Université, Paris Brain Institute, APHP, INSERM, CNRS, Paris, France
- AP-HP, Pitié Salpêtrière University Hospital, Genetics Department, Sorbonne University, Paris, France
| | - Isabelle Le Ber
- Sorbonne Université, Paris Brain Institute, APHP, INSERM, CNRS, Paris, France
- AP-HP, National Reference Center for “Rare and Young Dementia”, IM2A, Pitié-Salpêtrière University Hospital, Sorbonne University, Paris, France
| | - Mary M Reilly
- Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK
| | - Henry Houlden
- Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK
| | - Andrea Cortese
- Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK
| | - Danielle Seilhean
- Sorbonne Université, Paris Brain Institute, APHP, INSERM, CNRS, Paris, France
- Laboratoire Neuropathologie Raymond Escourolle, AP-HP, Pitié Salpêtrière University Hospital, Sorbonne University, Paris, France
| | - Alexis Brice
- Sorbonne Université, Paris Brain Institute, APHP, INSERM, CNRS, Paris, France
| | - Alexandra Durr
- Sorbonne Université, Paris Brain Institute, APHP, INSERM, CNRS, Paris, France
- AP-HP, Pitié Salpêtrière University Hospital, Genetics Department, Sorbonne University, Paris, France
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7
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Straub S, Mangesius S, Emmerich J, Indelicato E, Nachbauer W, Degenhardt KS, Ladd ME, Boesch S, Gizewski ER. Toward quantitative neuroimaging biomarkers for Friedreich's ataxia at 7 Tesla: Susceptibility mapping, diffusion imaging, R 2 and R 1 relaxometry. J Neurosci Res 2020; 98:2219-2231. [PMID: 32731306 PMCID: PMC7590084 DOI: 10.1002/jnr.24701] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 06/12/2020] [Accepted: 07/08/2020] [Indexed: 01/21/2023]
Abstract
Friedreich's ataxia (FRDA) is a rare genetic disorder leading to degenerative processes. So far, no effective treatment has been found. Therefore, it is important to assist the development of medication with imaging biomarkers reflecting disease status and progress. Ten FRDA patients (mean age 37 ± 14 years; four female) and 10 age- and sex-matched controls were included. Acquisition of magnetic resonance imaging (MRI) data for quantitative susceptibility mapping, R1 , R2 relaxometry and diffusion imaging was performed at 7 Tesla. Results of volume of interest (VOI)-based analyses of the quantitative data were compared with a voxel-based morphometry (VBM) evaluation. Differences between patients and controls were assessed using the analysis of covariance (ANCOVA; p < 0.01) with age and sex as covariates, effect size of group differences, and correlations with disease characteristics with Spearman correlation coefficient. For the VBM analysis, a statistical threshold of 0.001 for uncorrected and 0.05 for corrected p-values was used. Statistically significant differences between FRDA patients and controls were found in five out of twelve investigated structures, and statistically significant correlations with disease characteristics were revealed. Moreover, VBM revealed significant white matter atrophy within regions of the brainstem, and the cerebellum. These regions overlapped partially with brain regions for which significant differences between healthy controls and patients were found in the VOI-based quantitative MRI evaluation. It was shown that two independent analyses provided overlapping results. Moreover, positive results on correlations with disease characteristics were found, indicating that these quantitative MRI parameters could provide more detailed information and assist the search for effective treatments.
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Affiliation(s)
- Sina Straub
- Division of Medical Physics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Stephanie Mangesius
- Department of Neuroradiology, Medical University of Innsbruck, Innsbruck, Austria.,Neuroimaging Core Facility, Medical University of Innsbruck, Innsbruck, Austria
| | - Julian Emmerich
- Division of Medical Physics, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Faculty of Physics and Astronomy, Heidelberg University, Heidelberg, Germany
| | | | - Wolfgang Nachbauer
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Katja S Degenhardt
- Division of Medical Physics, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Faculty of Physics and Astronomy, Heidelberg University, Heidelberg, Germany
| | - Mark E Ladd
- Division of Medical Physics, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Faculty of Physics and Astronomy, Heidelberg University, Heidelberg, Germany.,Faculty of Medicine, Heidelberg University, Heidelberg, Germany
| | - Sylvia Boesch
- Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
| | - Elke R Gizewski
- Department of Neuroradiology, Medical University of Innsbruck, Innsbruck, Austria.,Neuroimaging Core Facility, Medical University of Innsbruck, Innsbruck, Austria
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8
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LEW SY, YOW YY, LIM LW, WONG KH. Antioxidant-mediated protective role of Hericium erinaceus (Bull.: Fr.) Pers. against oxidative damage in fibroblasts from Friedreich’s ataxia patient. FOOD SCIENCE AND TECHNOLOGY 2020. [DOI: 10.1590/fst.09919] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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9
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Llorens JV, Soriano S, Calap-Quintana P, Gonzalez-Cabo P, Moltó MD. The Role of Iron in Friedreich's Ataxia: Insights From Studies in Human Tissues and Cellular and Animal Models. Front Neurosci 2019; 13:75. [PMID: 30833885 PMCID: PMC6387962 DOI: 10.3389/fnins.2019.00075] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 01/23/2019] [Indexed: 12/12/2022] Open
Abstract
Friedreich's ataxia (FRDA) is a rare early-onset degenerative disease that affects both the central and peripheral nervous systems, and other extraneural tissues, mainly the heart and endocrine pancreas. This disorder progresses as a mixed sensory and cerebellar ataxia, primarily disturbing the proprioceptive pathways in the spinal cord, peripheral nerves and nuclei of the cerebellum. FRDA is an inherited disease with an autosomal recessive pattern caused by an insufficient amount of the nuclear-encoded mitochondrial protein frataxin, which is an essential and highly evolutionary conserved protein whose deficit results in iron metabolism dysregulation and mitochondrial dysfunction. The first experimental evidence connecting frataxin with iron homeostasis came from Saccharomyces cerevisiae; iron accumulates in the mitochondria of yeast with deletion of the frataxin ortholog gene. This finding was soon linked to previous observations of iron deposits in the hearts of FRDA patients and was later reported in animal models of the disease. Despite advances made in the understanding of FRDA pathophysiology, the role of iron in this disease has not yet been completely clarified. Some of the questions still unresolved include the molecular mechanisms responsible for the iron accumulation and iron-mediated toxicity. Here, we review the contribution of the cellular and animal models of FRDA and relevance of the studies using FRDA patient samples to gain knowledge about these issues. Mechanisms of mitochondrial iron overload are discussed considering the potential roles of frataxin in the major mitochondrial metabolic pathways that use iron. We also analyzed the effect of iron toxicity on neuronal degeneration in FRDA by reactive oxygen species (ROS)-dependent and ROS-independent mechanisms. Finally, therapeutic strategies based on the control of iron toxicity are considered.
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Affiliation(s)
- José Vicente Llorens
- Department of Genetics, Faculty of Biological Sciences, University of Valencia, Valencia, Spain
- Unit for Psychiatry and Neurodegenerative Diseases, Biomedical Research Institute INCLIVA, Valencia, Spain
| | - Sirena Soriano
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
- Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, United States
| | - Pablo Calap-Quintana
- Department of Genetics, Faculty of Biological Sciences, University of Valencia, Valencia, Spain
- Unit for Psychiatry and Neurodegenerative Diseases, Biomedical Research Institute INCLIVA, Valencia, Spain
| | - Pilar Gonzalez-Cabo
- Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, Valencia, Spain
- Center of Biomedical Network Research on Rare Diseases CIBERER, Valencia, Spain
- Associated Unit for Rare Diseases INCLIVA-CIPF, Biomedical Research Institute INCLIVA, Valencia, Spain
| | - María Dolores Moltó
- Department of Genetics, Faculty of Biological Sciences, University of Valencia, Valencia, Spain
- Unit for Psychiatry and Neurodegenerative Diseases, Biomedical Research Institute INCLIVA, Valencia, Spain
- Center of Biomedical Network Research on Mental Health CIBERSAM, Valencia, Spain
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10
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Castro IH, Pignataro MF, Sewell KE, Espeche LD, Herrera MG, Noguera ME, Dain L, Nadra AD, Aran M, Smal C, Gallo M, Santos J. Frataxin Structure and Function. Subcell Biochem 2019; 93:393-438. [PMID: 31939159 DOI: 10.1007/978-3-030-28151-9_13] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Mammalian frataxin is a small mitochondrial protein involved in iron sulfur cluster assembly. Frataxin deficiency causes the neurodegenerative disease Friedreich's Ataxia. Valuable knowledge has been gained on the structural dynamics of frataxin, metal-ion-protein interactions, as well as on the effect of mutations on protein conformation, stability and internal motions. Additionally, laborious studies concerning the enzymatic reactions involved have allowed for understanding the capability of frataxin to modulate Fe-S cluster assembly function. Remarkably, frataxin biological function depends on its interaction with some proteins to form a supercomplex, among them NFS1 desulfurase and ISCU, the scaffolding protein. By combining multiple experimental tools including high resolution techniques like NMR and X-ray, but also SAXS, crosslinking and mass-spectrometry, it was possible to build a reliable model of the structure of the desulfurase supercomplex NFS1/ACP-ISD11/ISCU/frataxin. In this chapter, we explore these issues showing how the scientific view concerning frataxin structure-function relationships has evolved over the last years.
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Affiliation(s)
- Ignacio Hugo Castro
- Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencia Exactas y Naturales, Instituto de Biociencias, Biotecnología y Biomedicina (iB3), Universidad de Buenos Aires, Intendente Güiraldes 2160-Ciudad Universitaria, 1428EGA, C.A.B.A, Argentina
- Intituto de Química y Fisicoquímica Biológicas, Dr. Alejandro Paladini Universidad de Buenos Aires, CONICET, Junín 956, 1113AAD, C.A.B.A, Argentina
| | - María Florencia Pignataro
- Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencia Exactas y Naturales, Instituto de Biociencias, Biotecnología y Biomedicina (iB3), Universidad de Buenos Aires, Intendente Güiraldes 2160-Ciudad Universitaria, 1428EGA, C.A.B.A, Argentina
- Intituto de Química y Fisicoquímica Biológicas, Dr. Alejandro Paladini Universidad de Buenos Aires, CONICET, Junín 956, 1113AAD, C.A.B.A, Argentina
| | - Karl Ellioth Sewell
- Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencia Exactas y Naturales, Instituto de Biociencias, Biotecnología y Biomedicina (iB3), Universidad de Buenos Aires, Intendente Güiraldes 2160-Ciudad Universitaria, 1428EGA, C.A.B.A, Argentina
- Intituto de Química y Fisicoquímica Biológicas, Dr. Alejandro Paladini Universidad de Buenos Aires, CONICET, Junín 956, 1113AAD, C.A.B.A, Argentina
| | - Lucía Daniela Espeche
- Departamento de Diagnóstico Genético, Centro Nacional de Genética Médica "Dr. Eduardo E. Castilla"-A.N.L.I.S, Av. Las Heras 2670, C1425ASQ, C.A.B.A, Argentina
| | - María Georgina Herrera
- Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencia Exactas y Naturales, Instituto de Biociencias, Biotecnología y Biomedicina (iB3), Universidad de Buenos Aires, Intendente Güiraldes 2160-Ciudad Universitaria, 1428EGA, C.A.B.A, Argentina
| | - Martín Ezequiel Noguera
- Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencia Exactas y Naturales, Instituto de Biociencias, Biotecnología y Biomedicina (iB3), Universidad de Buenos Aires, Intendente Güiraldes 2160-Ciudad Universitaria, 1428EGA, C.A.B.A, Argentina
- Intituto de Química y Fisicoquímica Biológicas, Dr. Alejandro Paladini Universidad de Buenos Aires, CONICET, Junín 956, 1113AAD, C.A.B.A, Argentina
- Departamento de Ciencia y Tecnología, Universidad Nacional de Quilmes, Roque Sáenz Peña 352, B1876BXD, Bernal, Provincia de Buenos Aires, Argentina
| | - Liliana Dain
- Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencia Exactas y Naturales, Instituto de Biociencias, Biotecnología y Biomedicina (iB3), Universidad de Buenos Aires, Intendente Güiraldes 2160-Ciudad Universitaria, 1428EGA, C.A.B.A, Argentina
- Departamento de Diagnóstico Genético, Centro Nacional de Genética Médica "Dr. Eduardo E. Castilla"-A.N.L.I.S, Av. Las Heras 2670, C1425ASQ, C.A.B.A, Argentina
| | - Alejandro Daniel Nadra
- Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencia Exactas y Naturales, Instituto de Biociencias, Biotecnología y Biomedicina (iB3), Universidad de Buenos Aires, Intendente Güiraldes 2160-Ciudad Universitaria, 1428EGA, C.A.B.A, Argentina
- Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina
| | - Martín Aran
- Fundación Instituto Leloir E IIBBA-CONICET, Av. Patricias Argentinas 435, C1405BWE, Buenos Aires, Argentina
| | - Clara Smal
- Fundación Instituto Leloir E IIBBA-CONICET, Av. Patricias Argentinas 435, C1405BWE, Buenos Aires, Argentina
| | - Mariana Gallo
- IRBM Science Park S.p.A, Via Pontina km 30,600, 00071, Pomezia, RM, Italy
| | - Javier Santos
- Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencia Exactas y Naturales, Instituto de Biociencias, Biotecnología y Biomedicina (iB3), Universidad de Buenos Aires, Intendente Güiraldes 2160-Ciudad Universitaria, 1428EGA, C.A.B.A, Argentina.
- Intituto de Química y Fisicoquímica Biológicas, Dr. Alejandro Paladini Universidad de Buenos Aires, CONICET, Junín 956, 1113AAD, C.A.B.A, Argentina.
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11
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Mollá B, Muñoz-Lasso DC, Riveiro F, Bolinches-Amorós A, Pallardó FV, Fernandez-Vilata A, de la Iglesia-Vaya M, Palau F, Gonzalez-Cabo P. Reversible Axonal Dystrophy by Calcium Modulation in Frataxin-Deficient Sensory Neurons of YG8R Mice. Front Mol Neurosci 2017; 10:264. [PMID: 28912677 PMCID: PMC5583981 DOI: 10.3389/fnmol.2017.00264] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Accepted: 08/04/2017] [Indexed: 11/13/2022] Open
Abstract
Friedreich’s ataxia (FRDA) is a peripheral neuropathy involving a loss of proprioceptive sensory neurons. Studies of biopsies from patients suggest that axonal dysfunction precedes the death of proprioceptive neurons in a dying-back process. We observed that the deficiency of frataxin in sensory neurons of dorsal root ganglia (DRG) of the YG8R mouse model causes the formation of axonal spheroids which retain dysfunctional mitochondria, shows alterations in the cytoskeleton and it produces impairment of axonal transport and autophagic flux. The homogenous distribution of axonal spheroids along the neurites supports the existence of continues focal damages. This lead us to propose for FRDA a model of distal axonopathy based on axonal focal damages. In addition, we observed the involvement of oxidative stress and dyshomeostasis of calcium in axonal spheroid formation generating axonal injury as a primary cause of pathophysiology. Axonal spheroids may be a consequence of calcium imbalance, thus we propose the quenching or removal extracellular Ca2+ to prevent spheroids formation. In our neuronal model, treatments with BAPTA and o-phenanthroline reverted the axonal dystrophy and the mitochondrial dysmorphic parameters. These results support the hypothesis that axonal pathology is reversible in FRDA by pharmacological manipulation of intracellular Ca2+ with Ca2+ chelators or metalloprotease inhibitors, preventing Ca2+-mediated axonal injury. Thus, the modulation of Ca2+ levels may be a relevant therapeutic target to develop early axonal protection and prevent dying-back neurodegeneration.
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Affiliation(s)
- Belén Mollá
- CIBER de Enfermedades Raras (CIBERER)Valencia, Spain.,Instituto de Biomedicina de Valencia (IBV), CSICValencia, Spain
| | - Diana C Muñoz-Lasso
- CIBER de Enfermedades Raras (CIBERER)Valencia, Spain.,Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia-Instituto de Investigación Sanitaria (INCLIVA)Valencia, Spain.,Associated Unit for Rare Diseases INCLIVA-CIPFValencia, Spain.,VEDAS Corporación de Investigación e Innovación, VEDASCIIMedellín, Colombia
| | - Fátima Riveiro
- CIBER de Enfermedades Raras (CIBERER)Valencia, Spain.,Fundacion Publica Galega de Medicina Xenomica (FPGMX)-SERGAS, Grupo de Medicina Xenomica, Hospital Clínico UniversitarioSantiago de Compostela, Spain
| | - Arantxa Bolinches-Amorós
- CIBER de Enfermedades Raras (CIBERER)Valencia, Spain.,Cell Therapy Program, Prince Felipe Research Centre (CIPF)Valencia, Spain
| | - Federico V Pallardó
- CIBER de Enfermedades Raras (CIBERER)Valencia, Spain.,Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia-Instituto de Investigación Sanitaria (INCLIVA)Valencia, Spain.,Associated Unit for Rare Diseases INCLIVA-CIPFValencia, Spain
| | | | - María de la Iglesia-Vaya
- Regional Ministry of Health in Valencia, Hospital Sagunto (CEIB-CSUSP)Valencia, Spain.,Brain Connectivity Laboratory, Joint Unit FISABIO & Prince Felipe Research Centre (CIPF)Valencia, Spain.,CIBER de Salud Mental (CIBERSAM)Valencia, Spain
| | - Francesc Palau
- CIBER de Enfermedades Raras (CIBERER)Valencia, Spain.,Department of Genetic and Molecular Medicine, Institut de Recerca Sant Joan de Déu, Hospital Sant Joan de DéuBarcelona, Spain.,Department of Pediatrics, University of Barcelona School of MedicineBarcelona, Spain
| | - Pilar Gonzalez-Cabo
- CIBER de Enfermedades Raras (CIBERER)Valencia, Spain.,Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia-Instituto de Investigación Sanitaria (INCLIVA)Valencia, Spain.,Associated Unit for Rare Diseases INCLIVA-CIPFValencia, Spain
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12
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Nabhan JF, Wood KM, Rao VP, Morin J, Bhamidipaty S, LaBranche TP, Gooch RL, Bozal F, Bulawa CE, Guild BC. Intrathecal delivery of frataxin mRNA encapsulated in lipid nanoparticles to dorsal root ganglia as a potential therapeutic for Friedreich's ataxia. Sci Rep 2016; 6:20019. [PMID: 26883577 PMCID: PMC4756688 DOI: 10.1038/srep20019] [Citation(s) in RCA: 107] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Accepted: 12/04/2015] [Indexed: 12/18/2022] Open
Abstract
In Friedreich's ataxia (FRDA) patients, diminished frataxin (FXN) in sensory neurons is thought to yield the predominant pathology associated with disease. In this study, we demonstrate successful usage of RNA transcript therapy (RTT) as an exogenous human FXN supplementation strategy in vitro and in vivo, specifically to dorsal root ganglia (DRG). Initially, 293 T cells were transfected with codon optimized human FXN mRNA, which was translated to yield FXN protein. Importantly, FXN was rapidly processed into the mature functional form of FXN (mFXN). Next, FXN mRNA, in the form of lipid nanoparticles (LNPs), was administered intravenously in adult mice. Examination of liver homogenates demonstrated efficient FXN LNP uptake in hepatocytes and revealed that the mitochondrial maturation machinery had efficiently processed all FXN protein to mFXN in ~24 h in vivo. Remarkably, greater than 50% mFXN protein derived from LNPs was detected seven days after intravenous administration of FXN LNPs, suggesting that the half-life of mFXN in vivo exceeds one week. Moreover, when FXN LNPs were delivered by intrathecal administration, we detected recombinant human FXN protein in DRG. These observations provide the first demonstration that RTT can be used for the delivery of therapeutic mRNA to DRG.
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Affiliation(s)
- Joseph F. Nabhan
- Rare Disease Research Unit, Pfizer, 610 Main Street, Cambridge, MA 02139, USA
| | - Kristy M. Wood
- Global Biotherapeutics, Pfizer, 610 Main Street, Cambridge, MA 02139, USA
| | - Varada P. Rao
- Comparative Medicine, Pfizer, 1 Burtt Rd, Andover, MA 01810, USA
| | - Jeffrey Morin
- Comparative Medicine, Pfizer, 1 Burtt Rd, Andover, MA 01810, USA
| | - Surya Bhamidipaty
- Drug Safety Research and Development, Pfizer, 1 Burtt Rd, Andover, MA 01810, USA
| | - Timothy P. LaBranche
- Drug Safety Research and Development, Pfizer, 1 Burtt Rd, Andover, MA 01810, USA
| | - Renea L. Gooch
- Rare Disease Research Unit, Pfizer, 610 Main Street, Cambridge, MA 02139, USA
| | - Fazli Bozal
- Rare Disease Research Unit, Pfizer, 610 Main Street, Cambridge, MA 02139, USA
| | - Christine E. Bulawa
- Rare Disease Research Unit, Pfizer, 610 Main Street, Cambridge, MA 02139, USA
| | - Braydon C. Guild
- Global Biotherapeutics, Pfizer, 610 Main Street, Cambridge, MA 02139, USA
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13
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Friedreich's footprint. Lancet Neurol 2015; 14:141. [DOI: 10.1016/s1474-4422(15)70005-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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14
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Al-Mahdawi S, Virmouni SA, Pook MA. The emerging role of 5-hydroxymethylcytosine in neurodegenerative diseases. Front Neurosci 2014; 8:397. [PMID: 25538551 PMCID: PMC4256999 DOI: 10.3389/fnins.2014.00397] [Citation(s) in RCA: 81] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Accepted: 11/18/2014] [Indexed: 12/12/2022] Open
Abstract
DNA methylation primarily occurs within human cells as a 5-methylcytosine (5mC) modification of the cytosine bases in CpG dinucleotides. 5mC has proven to be an important epigenetic mark that is involved in the control of gene transcription for processes such as development and differentiation. However, recent studies have identified an alternative modification, 5-hydroxymethylcytosine (5hmC), which is formed by oxidation of 5mC by ten-eleven translocation (TET) enzymes. The overall levels of 5hmC in the mammalian genome are approximately 10% of 5mC levels, although higher levels have been detected in tissues of the central nervous system (CNS). The functions of 5hmC are not yet fully known, but evidence suggests that 5hmC may be both an intermediate product during the removal of 5mC by passive or active demethylation processes and also an epigenetic modification in its own right, regulating chromatin or transcriptional factors involved in processes such as neurodevelopment or environmental stress response. This review highlights our current understanding of the role that 5hmC plays in neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), fragile X-associated tremor/ataxia syndrome (FXTAS), Friedreich ataxia (FRDA), Huntington's disease (HD), and Parkinson's disease (PD).
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Affiliation(s)
- Sahar Al-Mahdawi
- Ataxia Research Group, Division of Biosciences, Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge, UK ; Synthetic Biology Theme, Institute of Environment, Health and Societies, Brunel University London Uxbridge, UK
| | - Sara Anjomani Virmouni
- Ataxia Research Group, Division of Biosciences, Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge, UK ; Synthetic Biology Theme, Institute of Environment, Health and Societies, Brunel University London Uxbridge, UK
| | - Mark A Pook
- Ataxia Research Group, Division of Biosciences, Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge, UK ; Synthetic Biology Theme, Institute of Environment, Health and Societies, Brunel University London Uxbridge, UK
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15
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Friedreich's Ataxia: A Neuronal Point of View on the Oxidative Stress Hypothesis. Antioxidants (Basel) 2014; 3:592-603. [PMID: 26785073 PMCID: PMC4665420 DOI: 10.3390/antiox3030592] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2014] [Revised: 05/06/2014] [Accepted: 05/16/2014] [Indexed: 12/02/2022] Open
Abstract
A prominent feature of Friedreich’s ataxia (FRDA) is the neurodegeneration of the central and peripheral nervous systems, but little information is available about the mechanisms leading to neuronal damage in this pathology. Currently, no treatments delay, prevent, or reverse the inexorable decline that occurs in this condition. Evidence of oxidative damage has been demonstrated in Friedreich’s ataxia, and this damage has been proposed as the origin of the disease. Nevertheless, the role of oxidative stress in FRDA remains debatable. The lack of direct evidence of reactive oxygen species overproduction in FRDA cells and tissues and the failure of exogenous antioxidants to rescue FRDA phenotypes questions the role of oxidative stress in this pathology. For example, the antioxidant “idebenone” ameliorates cardiomyopathy in FRDA patients, but this therapy does not improve neurodegeneration. To date, no known pharmacological treatment with antioxidant properties cures or delays FRDA neuropathology. This review reports and discusses the evidence of oxidative stress in FRDA and focuses on the existing knowledge of the apparent ineffectiveness of antioxidants for the treatment of neuronal damage.
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16
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Libri V, Yandim C, Athanasopoulos S, Loyse N, Natisvili T, Law PP, Chan PK, Mohammad T, Mauri M, Tam KT, Leiper J, Piper S, Ramesh A, Parkinson MH, Huson L, Giunti P, Festenstein R. Epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich's ataxia: an exploratory, open-label, dose-escalation study. Lancet 2014; 384:504-13. [PMID: 24794816 DOI: 10.1016/s0140-6736(14)60382-2] [Citation(s) in RCA: 109] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
BACKGROUND Friedreich's ataxia is a progressive degenerative disorder caused by deficiency of the frataxin protein. Expanded GAA repeats within intron 1 of the frataxin (FXN) gene lead to its heterochromatinisation and transcriptional silencing. Preclinical studies have shown that the histone deacetylase inhibitor nicotinamide (vitamin B3) can remodel the pathological heterochromatin and upregulate expression of FXN. We aimed to assess the epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich's ataxia. METHODS In this exploratory, open-label, dose-escalation study in the UK, male and female patients (aged 18 years or older) with Friedreich's ataxia were given single doses (phase 1) and repeated daily doses of 2-8 g oral nicotinamide for 5 days (phase 2) and 8 weeks (phase 3). Doses were gradually escalated during phases 1 and 2, with individual maximum tolerated doses used in phase 3. The primary outcome was the upregulation of frataxin expression. We also assessed the safety and tolerability of nicotinamide, used chromatin immunoprecipitation to investigate changes in chromatin structure at the FXN gene locus, and assessed the effect of nicotinamide treatment on clinical scales for ataxia. This study is registered with ClinicalTrials.gov, number NCT01589809. FINDINGS Nicotinamide was generally well tolerated; the main adverse event was nausea, which in most cases was mild, dose-related, and resolved spontaneously or after dose reduction, use of antinausea drugs, or both. Phase 1 showed a dose-response relation for proportional change in frataxin protein concentration from baseline to 8 h post-dose, which increased with increasing dose (p=0·0004). Bayesian analysis predicted that 3·8 g would result in a 1·5-times increase and 7·5 g in a doubling of frataxin protein concentration. Phases 2 and 3 showed that daily dosing at 3·5-6 g resulted in a sustained and significant (p<0·0001) upregulation of frataxin expression, which was accompanied by a reduction in heterochromatin modifications at the FXN locus. Clinical measures showed no significant changes. INTERPRETATION Nicotinamide was associated with a sustained improvement in frataxin concentrations towards those seen in asymptomatic carriers during 8 weeks of daily dosing. Further investigation of the long-term clinical benefits of nicotinamide and its ability to ameliorate frataxin deficiency in Friedreich's ataxia is warranted. FUNDING Ataxia UK, Ataxia Ireland, Association Suisse de l'Ataxie de Friedreich, Associazione Italiana per le Sindromi Atassiche, UK National Institute for Health Research, European Friedreich's Ataxia Consortium for Translational Studies, and Imperial Biomedical Research Centre.
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Affiliation(s)
- Vincenzo Libri
- Leonard Wolfson Experimental Neurology Centre, University College London, London, UK; National Institute for Health Research Wellcome Trust Imperial Clinical Research Facility, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, UK
| | - Cihangir Yandim
- Gene Control Mechanisms and Disease Group, Department of Medicine and MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, UK
| | - Stavros Athanasopoulos
- National Institute for Health Research Wellcome Trust Imperial Clinical Research Facility, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, UK
| | - Naomi Loyse
- National Institute for Health Research Wellcome Trust Imperial Clinical Research Facility, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, UK
| | - Theona Natisvili
- Gene Control Mechanisms and Disease Group, Department of Medicine and MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, UK
| | - Pui Pik Law
- Gene Control Mechanisms and Disease Group, Department of Medicine and MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, UK
| | - Ping Kei Chan
- Gene Control Mechanisms and Disease Group, Department of Medicine and MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, UK
| | - Tariq Mohammad
- National Institute for Health Research Wellcome Trust Imperial Clinical Research Facility, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, UK
| | - Marta Mauri
- Max Delbrück Centre for Molecular Medicine, Berlin, Germany
| | - Kin Tung Tam
- School of Biological Sciences, University of Hong Kong, Hong Kong, China
| | - James Leiper
- Nitric Oxide Signalling Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, UK
| | - Sophie Piper
- Nitric Oxide Signalling Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, UK
| | - Aravind Ramesh
- Intensive Care Department, Christchurch Hospital, Christchurch, New Zealand
| | - Michael H Parkinson
- Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK
| | - Les Huson
- National Institute for Health Research Wellcome Trust Imperial Clinical Research Facility, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London, UK
| | - Paola Giunti
- Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK
| | - Richard Festenstein
- Gene Control Mechanisms and Disease Group, Department of Medicine and MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, UK.
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17
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Weidemann F, Scholz F, Florescu C, Liu D, Hu K, Herrmann S, Ertl G, Störk S. [Heart involvement in Friedreich's ataxia]. Herz 2014; 40 Suppl 1:85-90. [PMID: 24848865 DOI: 10.1007/s00059-014-4097-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Revised: 02/28/2014] [Accepted: 03/14/2014] [Indexed: 12/13/2022]
Abstract
Friedreich's ataxia is a rare hereditary disease and although the gene defect has already been identified as a deficiency of the mitochondrial protein frataxin, the pathophysiology is still unknown. Although a multisystem disorder organ involvement is predominantly neurological. Besides the characteristic features of spinocerebellar ataxia the heart is frequently also affected. Cardiac involvement typically manifests as hypertrophic cardiomyopathy, which can progress to heart failure and death. So far most research has focused on the neurological aspects and cardiac involvement in Friedreich's ataxia has not been systematically investigated. Thus, a better understanding of the progression of the cardiomyopathy, cardiac complications and long-term cardiac outcome is warranted. Although no specific treatment is available general cardiac therapeutic options for cardiomyopathy should be considered. The current review focuses on clinical and diagnostic features of cardiomyopathy and discusses potential therapeutic developments for Friedreich's ataxia.
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Affiliation(s)
- F Weidemann
- Medizinische Klinik und Poliklinik I, Deutsches Zentrum für Herzinsuffizienz, Universität Würzburg, Oberdürrbacherstr. 6, 97080, Würzburg, Deutschland,
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Schulz JB, Pandolfo M. 150 years of Friedreich ataxia: from its discovery to therapy. J Neurochem 2013; 126 Suppl 1:1-3. [PMID: 24024236 DOI: 10.1111/jnc.12327] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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Corrigendum. J Neurochem 2013. [DOI: 10.1111/jnc.12377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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