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12 results on '"Marazova, Katia"'

1. Optogenetics.

Author

Duebel J, Marazova K, and Sahel JA

Subjects
Gene Transfer Techniques, Genetic Vectors, Humans, Optogenetics methods, Retinal Degeneration rehabilitation, Vision Disorders rehabilitation
Abstract

Purpose of Review: In this review, we will discuss the recent developments in optogenetics and their potential applications in ophthalmology to restore vision in retinal degenerative diseases., Recent Findings: In recent years, we have seen major advances in the field of optogenetics, providing us with novel opsins for potential applications in the retina. Microbial opsins with improved light sensitivity and red-shifted action spectra allow optogenetic stimulation at light levels well below the safety threshold in the human eye. In parallel, remarkable success in the development of highly efficient viral vectors for ocular gene therapy led to new strategies of using these novel optogenetic tools for vision restoration., Summary: These recent findings show that novel optogenetic tools and viral vectors for ocular gene delivery are now available providing many opportunities to develop potential optogenetic strategies for vision restoration.

Published
2015
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2. Clinical characteristics and current therapies for inherited retinal degenerations.

Author

Sahel JA, Marazova K, and Audo I

Subjects
Animals, Bardet-Biedl Syndrome genetics, Choroideremia genetics, Clinical Trials as Topic, Color Vision Defects genetics, Disease Models, Animal, Eye Diseases, Hereditary genetics, Genetic Diseases, X-Linked genetics, Genetic Heterogeneity, Genetic Therapy, Humans, Leber Congenital Amaurosis genetics, Macular Degeneration genetics, Myopia genetics, Night Blindness genetics, Optogenetics, Retinal Degeneration genetics, Retinal Degeneration pathology, Retinal Degeneration therapy
Abstract

Inherited retinal degenerations (IRDs) encompass a large group of clinically and genetically heterogeneous diseases that affect approximately 1 in 3000 people (>2 million people worldwide) (Bessant DA, Ali RR, Bhattacharya SS. 2001. Molecular genetics and prospects for therapy of the inherited retinal dystrophies. Curr Opin Genet Dev 11: 307-316.). IRDs may be inherited as Mendelian traits or through mitochondrial DNA, and may affect the entire retina (e.g., rod-cone dystrophy, also known as retinitis pigmentosa, cone dystrophy, cone-rod dystrophy, choroideremia, Usher syndrome, and Bardet-Bidel syndrome) or be restricted to the macula (e.g., Stargardt disease, Best disease, and Sorsby fundus dystrophy), ultimately leading to blindness. IRDs are a major cause of severe vision loss, with profound impact on patients and society. Although IRDs remain untreatable today, significant progress toward therapeutic strategies for IRDs has marked the past two decades. This progress has been based on better understanding of the pathophysiological pathways of these diseases and on technological advances., (Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.)

Published
2014
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4. The primate model for understanding and restoring vision.

Author

Picaud, Serge, Dalkara, Deniz, Marazova, Katia, Goureau, Olivier, Roska, Botond, and Sahel, José-Alain

Subjects
PRIMATES, RETINAL degeneration, VISION, RETINAL diseases, DEGENERATION (Pathology)
Abstract

Retinal degenerative diseases caused by photoreceptor cell death are major causes of irreversible vision loss. As only primates have a macula, the nonhuman primate (NHP) models have a crucial role not only in revealing biological mechanisms underlying high-acuity vision but also in the development of therapies. Successful translation of basic research findings into clinical trials and, moreover, approval of the first therapies for blinding inherited and agerelated retinal dystrophies has been reported in recent years. This article explores the value of the NHP models in understanding human vision and reviews their contribution to the development of innovative therapeutic strategies to save and restore vision. [ABSTRACT FROM AUTHOR]

Published
2019
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5. Functional rescue of cone photoreceptors in retinitis pigmentosa.

Author

Sahel, José-Alain, Léveillard, Thierry, Picaud, Serge, Dalkara, Deniz, Marazova, Katia, Safran, Avinoam, Paques, Michel, Duebel, Jens, Roska, Botond, and Mohand-Said, Saddek

Subjects
RETINITIS pigmentosa, PHOTORECEPTORS, RETINAL degeneration, GENE therapy, RETINA physiology, HUMAN information processing, OPHTHALMOLOGY
Published
2013
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6. Inherited Retinal Degenerations: Current Landscape and Knowledge Gaps

Author

Jacque L. Duncan, Amy M. Laster, John D. Ash, Stephen P. Daiger, John G. Flannery, Alessandro Iannaccone, Eric A. Pierce, Marco A. Zarbin, Jose A. Sahel, David G. Birch, Donald J. Zack, University of California [San Francisco] (UC San Francisco), University of California (UC), Harvard Medical School [Boston] (HMS), Foundation Fighting Blindness [Columbia, MD, USA] (2FB), University of Texas Health Science Center, The University of Texas Health Science Center at Houston (UTHealth), Retina Foundation of the Southwest [allas, TX, USA] (RFS), University of Florida [Gainesville] (UF), Duke University School of Medicine [Durham, NC, USA], University of California [Berkeley] (UC Berkeley), Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Johns Hopkins University School of Medicine [Baltimore], Rutgers University [Newark], Rutgers University System (Rutgers), Foundation Fighting Blindness Scientific Advisory Board, and Marazova, Katia

Subjects
0301 basic medicine, Retinal degeneration, genetic structures, Genetic enhancement, [SDV]Life Sciences [q-bio], Biomedical Engineering, [SDV.GEN] Life Sciences [q-bio]/Genetics, and the Foundation Fighting Blindness Scientific Advisory Board, Bioinformatics, 03 medical and health sciences, chemistry.chemical_compound, Opthalmology and Optometry, medicine, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Genetic heterogeneity, Mechanism (biology), Retinal, Macular degeneration, medicine.disease, eye diseases, [SDV] Life Sciences [q-bio], Ophthalmology, 030104 developmental biology, RPE65, chemistry, Perspective, Identification (biology), business
Abstract

Inherited retinal degenerations (IRDs) represent a diverse group of progressive, visually debilitating diseases that can lead to blindness in which mutations in genes that are critical to retinal function lead to progressive photoreceptor cell death and associated vision loss. IRDs are genetically heterogeneous, with over 260 disease genes identified to date.1 The development of treatments and cures to modify the rate of disease progression has been limited to date, with some success of neurotrophic factor therapy and gene therapies reported from clinical trials.2–11 The best example of treatment success is gene augmentation therapy for IRD caused by mutations in the RPE65 gene, which recently received US Food and Drug Administration (FDA) approval, which in fact represented the first FDA-approved gene therapy (GT) for any genetically inherited disease.4–9 Recent developments in the IRD field have advanced understanding of the mechanisms responsible for vision loss, creating new opportunities to intervene in the course of disease by developing new therapeutic approaches. In 2013, a Delphi-style gathering of IRD experts led to the identification, by consensus, of top priorities to advance therapeutic efforts for IRDs, including the need for systematic genotyping, improved standardization of visual function testing, development of more rigorous and widespread data collection protocols, and increased data sharing.12 This document summarizes more recent advances in the IRD field and outlines specific knowledge gaps. These knowledge gaps present opportunities for further investigation to enable development of therapies that may slow down or prevent vision loss, or restore vision, in affected patients. Atrophic age-related macular degeneration (AMD) is included among the target inherited retinal diseases of interest because first, understanding AMD may contribute to understanding of inherited macular diseases, and second, understanding of the genetics and mechanism of inherited macular degenerations may contribute to understanding of AMD.

Published
2018

7. Let there be light: gene and cell therapy for blindness

Author

José-Alain Sahel, Deniz Dalkara, Olivier Goureau, Katia Marazova, Marazova, Katia, Sorbonne Universités à Paris pour l'Enseignement et la Recherche - - SUPER2011 - ANR-11-IDEX-0004 - IDEX - VALID, Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), Département Ophtalomologie Pathologies Vitréo-Rétiniennes, Fondation Ophtalmologique Adolphe de Rothschild, This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), Pierre et Marie Curie University (UPMC), the Centre National de la Recherche Scientifique (CNRS), Foundation Fighting Blindness (FFB) [CD-CL-0808-0466-CHNO], ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Fondation Ophtalmologique Adolphe de Rothschild [Paris]

Subjects
0301 basic medicine, Retinal degeneration, cis-trans-Isomerases, genetic structures, Degenerative Disorder, Genetic enhancement, [SDV]Life Sciences [q-bio], Genetic Vectors, Leber Congenital Amaurosis, Cell- and Tissue-Based Therapy, Reviews, Stem cells, Bioinformatics, Blindness, Retina, AAV vectors, 03 medical and health sciences, Macular Degeneration, Degenerative disease, Retinitis pigmentosa, Genetics, medicine, Humans, Stargardt Disease, Molecular Biology, Clinical Trials as Topic, business.industry, Adenoviruses, Human, Lentivirus, Genetic Therapy, Gene Therapy, Macular degeneration, Dependovirus, medicine.disease, eye diseases, 3. Good health, Stargardt disease, Optogenetics, [SDV] Life Sciences [q-bio], 030104 developmental biology, Cis-trans-Isomerases, Molecular Medicine, CRISPR-Cas Systems, business, Retinitis Pigmentosa
Abstract

International audience; Retinal degenerative diseases are a leading cause of irreversible blindness. Retinal cell death is the main cause of vision loss in genetic disorders such as retinitis pigmentosa, Stargardt disease and Leber congenital amaurosis, as well as in complex age-related diseases such as age-related macular degeneration (AMD). For these blinding conditions, gene and cell therapy approaches offer therapeutic intervention at various disease stages. The present review outlines recent advances in therapies for retinal degenerative disease, focusing on the progress and challenges in the development and clinical translation of gene and cell therapies. A significant body of preclinical evidence and initial clinical results pave the way for further development of these cutting edge treatments for patients with retinal degenerative disorders.

Published
2016

8. Transcriptomic analysis of human retinal detachment reveals both inflammatory response and photoreceptor death

Author

José-Alain Sahel, Alain Gaudric, David Mercier, David G. Charteris, Raymond Ripp, Wolfgang Raffelsberger, Ramin Tadayoni, Jean-Denis Muller, F. Metge, Thierry Léveillard, Marie-Noëlle Delyfer, Georges Caputo, Jean-François Korobelnik, Olivier Poch, P.O. Barale, Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Equipe 14 - Inflammation dans la dégénérescence neuronale et le remodelage vasculaire (Inserm U968/CNRS UMR7210/UPMC UM80), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Unité Rétine, Uvéite et Neuro-Ophtalmologie, CHU Bordeaux [Bordeaux], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Information, Modèles, Apprentissage [Gif-sur-Yvette] (LIMA), Département Métrologie Instrumentation & Information (DM2I), Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département Ophtalmologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Vitreo-retinal Unit, Moorfields Eye Hospital, Fondation Ophtalmologique Adolphe de Rothschild [Paris], Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), The work was supported by the Institut National de la Santé et de la Recherche Médicale, CNRS, University of Strasbourg and the network Réseaux National de Génopôles (RNG 209)., Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Intégration des Systèmes et des Technologies (LIST), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Laboratoire d'Intégration des Systèmes et des Technologies (LIST), Fondation Ophtalmologique Adolphe de Rothschild, Université Paris-Saclay-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Laboratoire d'Intégration des Systèmes et des Technologies (LIST), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière, Centre Ophtalmologique des Quinze-Vingts, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Marazova, Katia

Subjects
Retinal degeneration, Pathology, Microarrays, Visual System, Gene regulatory network, degeneration, [SDV.GEN] Life Sciences [q-bio]/Genetics, SLCO4A1, immune response, Transcriptome, Mice, chemistry.chemical_compound, Molecular cell biology, 0302 clinical medicine, [STAT.AP] Statistics [stat]/Applications [stat.AP], retinal surgery, Neurobiology of Disease and Regeneration, Gene Regulatory Networks, histocompatibility, Mathematical Computing, 0303 health sciences, [STAT.AP]Statistics [stat]/Applications [stat.AP], Multidisciplinary, [STAT.ME] Statistics [stat]/Methodology [stat.ME], Cell Death, Reverse Transcriptase Polymerase Chain Reaction, Statistics, Retinal Degeneration, Neurodegeneration, neurodegeneration, Retinal detachment, Genomics, Middle Aged, Sensory Systems, 3. Good health, medicine.anatomical_structure, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Medicine, Retinal Disorders, medicine.symptom, Information Technology, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Research Article, Photoreceptor Cells, Vertebrate, Adult, medicine.medical_specialty, Science, DNA transcription, Down-Regulation, Inflammation, Biology, PKD2L1, transcriptome of human retinal tissues, pharmacological target, Databases, Young Adult, 03 medical and health sciences, Genomic Medicine, statistical analysis, medicine, Animals, Humans, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, therapeutic strategy, Aged, 030304 developmental biology, Clinical Genetics, Retina, [SDV.GEN]Life Sciences [q-bio]/Genetics, gene HLA-C, death of photoreceptor cells, photoreceptor damage, Immunity, Computational Biology, Reproducibility of Results, Retinal, medicine.disease, Computing Methods, Ophthalmology, Kinetics, chemistry, inflammation, Computer Science, 030221 ophthalmology & optometry, Clinical Immunology, Gene expression, Genome Expression Analysis, Pharmacogenomics, Neuroscience, Mathematics, Biomarkers
Abstract

International audience; BACKGROUND: Retinal detachment often leads to a severe and permanent loss of vision and its therapeutic management remains to this day exclusively surgical. We have used surgical specimens to perform a differential analysis of the transcriptome of human retinal tissues following detachment in order to identify new potential pharmacological targets that could be used in combination with surgery to further improve final outcome. METHODOLOGY/PRINCIPAL FINDINGS: Statistical analysis reveals major involvement of the immune response in the disease. Interestingly, using a novel approach relying on coordinated expression, the interindividual variation was monitored to unravel a second crucial aspect of the pathological process: the death of photoreceptor cells. Within the genes identified, the expression of the major histocompatibility complex I gene HLA-C enables diagnosis of the disease, while PKD2L1 and SLCO4A1 -which are both down-regulated- act synergistically to provide an estimate of the duration of the retinal detachment process. Our analysis thus reveals the two complementary cellular and molecular aspects linked to retinal detachment: an immune response and the degeneration of photoreceptor cells. We also reveal that the human specimens have a higher clinical value as compared to artificial models that point to IL6 and oxidative stress, not implicated in the surgical specimens studied here. CONCLUSIONS/SIGNIFICANCE: This systematic analysis confirmed the occurrence of both neurodegeneration and inflammation during retinal detachment, and further identifies precisely the modification of expression of the different genes implicated in these two phenomena. Our data henceforth give a new insight into the disease process and provide a rationale for therapeutic strategies aimed at limiting inflammation and photoreceptor damage associated with retinal detachment and, in turn, improving visual prognosis after retinal surgery.

Published
2011

9. The disruption of the rod-derived cone viability gene leads to photoreceptor dysfunction and susceptibility to oxidative stress

Author

Marie-Laure Niepon, Serge Picaud, Andranik Petrosian, Céline Jaillard, Thierry Léveillard, Emmanuelle Clérin, Olivier Poch, Irene Lee-Rivera, Wolfgang Raffelsberger, Bernd Kinzel, Therese Cronin, José-Alain Sahel, Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Novartis Pharma AG, Bunatian Institute of Biochemistry [Yerevan, Armenia] (BIB), Marazova, Katia, RETinal Training NETwork - INCOMING, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Bunatian Institute of Biochemistry, ANR Maladies rares, This work was supported by Inserm, the European commission (RETinal Training NETwork), ANR Maladies rares 2006 Grant and FFB USA., European Project, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, and Novartis Pharma AG [Basel, Switzerland]

Subjects
genetic structures, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Apoptosis, [SDV.GEN] Life Sciences [q-bio]/Genetics, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], chemistry.chemical_compound, Mice, 0302 clinical medicine, Thioredoxins, Retinal Rod Photoreceptor Cells, injury response, Genetics, Mice, Knockout, 0303 health sciences, Cell biology, medicine.anatomical_structure, Retinal Cone Photoreceptor Cells, Fibroblast Growth Factor 2, neuroprotection, Erg, microarray, Signal Transduction, Programmed cell death, Biology, Article, Retina, 03 medical and health sciences, Retinitis pigmentosa, medicine, Animals, Outer nuclear layer, Eye Proteins, Molecular Biology, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Gene Expression Profiling, Retinal, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, thioredoxin, medicine.disease, eye diseases, Oxidative Stress, chemistry, 030221 ophthalmology & optometry, retinal degeneration, Lipid Peroxidation, sense organs
Abstract

International audience; Rod-derived cone viability factor (RdCVF) is a thioredoxin-like protein, which has therapeutic potential for rod-cone dystrophies such as retinitis pigmentosa (RP). Cone loss in rodent models of RP is effectively reduced by RdCVF treatment. In this study, we investigate the physiological role of RdCVF in the retina by analyzing the phenotype of the mouse lacking the RdCVF gene, Nxnl1. Although the mice do not show an obvious developmental defect, an age-related reduction of both cone and rod function and a delay in the dark-adaptation of the retina are recorded by electroretinogram (ERG). This functional change is accompanied by a 17% reduction in cone density and a 20% reduction in thickness of the outer nuclear layer. The transcriptome of the retina reveals early changes in the expression of genes involved in programmed cell death, stress-response and redox-signaling, which is followed by a generalized injury response with increased microglial activation, GFAP, FGF2 and lipid peroxidation levels. Furthermore, cones of the mice lacking Nxnl1 are more sensitive to oxidative stress with a reduction of 65% in the cone flicker ERG amplitude measured under hyperoxic conditions. We show here that the RdCVF gene, in addition to therapeutic properties, has an essential role in photoreceptor maintenance and resistance to retinal oxidative stress.

Published
2010

10. Genetic reactivation of cone photoreceptors restores visual responses in retinitis pigmentosa

Author

Erik Cabuy, Jens Duebel, Michel Paques, José-Alain Sahel, Valérie Forster, Martin Biel, Botond Roska, Peter Humphries, Didier Trono, Mathias Fradot, D. Balya, Serge Picaud, Karl Deisseroth, Sandra Siegert, Mathias W. Seeliger, Saddek Mohand-Said, Volker Busskamp, Anna C. Groner, Tim J. Viney, 'Frontiers in Genetics' program, Ecole Polytechnique Fédérale de Lausanne (EPFL)-National Center of Competence in Research, Neural Circuit Laboratories, Friedrich Miescher Institute for Biomedical Research, Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Diagnostics Research Group, Eberhard-Karls University, Center for Integrated Protein Science (CIPSM), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Ludwig-Maximilians-Universität München (LMU)-Helmholtz Zentrum München = German Research Center for Environmental Health, Smurfit Institute of Genetics, Trinity College Dublin, Fondation Ophtalmologique Adolphe de Rothschild [Paris], Department of Bioengineering, Department of Psychiatry and Behavioral Sciences, Stanford University, Friedrich Miescher Institute, US Office of Naval Research Naval International Cooperative Opportunities in Science and Technology Program grant, Foundation Fighting Blindness (USA), Swiss National Science Foundation, National Centers of Competence in Research Frontiers in Genetics, ANR-07-TECS-0014,MEDINAS,Matrices d'Electrodes en Diamant pour l'Interfaçage Neuronal Appliqué à la Suppléance fonctionnelle (MEDINAS)(2007), European Project, Fondation Ophtalmologique Adolphe de Rothschild, Marazova, Katia, Technologies pour la santé - Matrices d'Electrodes en Diamant pour l'Interfaçage Neuronal Appliqué à la Suppléance fonctionnelle (MEDINAS) - - MEDINAS2007 - ANR-07-TECS-0014 - TECSAN - VALID, Marie Curie Excellence Grant, EU HEALTH-F2- 223156, RETICIRC - INCOMING, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Ludwig Maximilian University of Munich [Germany] (LMU München)-Helmholtz-Zentrum München (HZM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-Ludwig Maximilian University of Munich [Germany] (LMU München)

Subjects
Retinal degeneration, Retinal Ganglion Cells, MESH: Evoked Potentials, Visual, genetic structures, Light, Serotypes, Expression, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Dependovirus, MESH: Mice, Knockout, Tissue Culture Techniques, chemistry.chemical_compound, Mice, 0302 clinical medicine, MESH: Genetic Vectors, MESH: Animals, Selectivity, Promoter Regions, Genetic, Halorhodopsin, Mice, Knockout, 0303 health sciences, Multidisciplinary, Halobacteriaceae, Visually guided, MESH: Retina, Retinal Degeneration, Anatomy, Dependovirus, 3. Good health, medicine.anatomical_structure, Retinal Cone Photoreceptor Cells, Halorhodopsins, Retinitis Pigmentosa, Visual phototransduction, MESH: Halorhodopsins, Movement, Genetic Vectors, Biology, Transfection, Retina, 03 medical and health sciences, MESH: Halobacteriaceae, Retinitis pigmentosa, MESH: Promoter Regions, Genetic, medicine, Animals, Humans, Visual Pathways, MESH: Tissue Culture Techniques, MESH: Vision, Ocular, MESH: Mice, Vision, Ocular, 030304 developmental biology, MESH: Visual Pathways, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Blindness, MESH: Transfection, Ganglion-Cells, Retinal, MESH: Retinal Ganglion Cells, Genetic Therapy, medicine.disease, MESH: Light, eye diseases, Disease Models, Animal, MESH: Retinal Cone Photoreceptor Cells, chemistry, Direction, MESH: Retinitis Pigmentosa, Evoked Potentials, Visual, sense organs, MESH: Disease Models, Animal, MESH: Gene Therapy, Neuroscience, 030217 neurology & neurosurgery, Model
Abstract

Let There Be Light Retinitis pigmentosa, a disease that can result from a wide variety of genetic defects, causes degeneration of photoreceptor cells in the retina and leads to blindness. In the course of the disease, it is generally the rod photoreceptor cells that degenerate first. Cone photoreceptor cells may persist, but in a damaged and nonfunctional state. Busskamp et al. (p. 413 , published online 24 June; see the cover; see the Perspective by Cepko ) have now applied a gene therapy approach to mouse models of retinitis pigmentosa. Inducing expression of a bacterial light-activated ion pump, halorho dopsin, in the damaged cone cells improved visual responses in the diseased mouse retinas. Thus, it may be possible to rescue cone photoreceptors therapeutically, even after they have already been damaged.

Published
2010

11. Rod-Derived Cone Viability Factor for Treating Blinding Diseases: From Clinic to Redox Signaling

Author

Thierry Léveillard, José-Alain Sahel, Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service du professeur Sahel, Centre hospitalier national d'ophtalmologie des 15-20, Institute of Ophthalmology, University College of London [London] (UCL), Fondation Ophtalmologique Adolphe de Rothschild, Inserm, UPMC, Retina France, Fédération de aveugles de France, Foundation Fighting Blindness, Novartis, Fovea Pharma, European Project, Marazova, Katia, EVI-GENORET (FP6) - INCOMING, and Fondation Ophtalmologique Adolphe de Rothschild [Paris]

Subjects
Retinal degeneration, Retinal Disorder, genetic structures, Cell Survival, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Blindness, medicine.disease_cause, Retinal Cone Photoreceptor Cells, Neuroprotection, Article, Translational Research, Biomedical, Mice, 03 medical and health sciences, Thioredoxins, 0302 clinical medicine, Retinal Diseases, Retinal Rod Photoreceptor Cells, medicine, Animals, Humans, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, Retina, Retinal Degeneration, General Medicine, medicine.disease, Cell biology, Oxidative Stress, medicine.anatomical_structure, 030221 ophthalmology & optometry, sense organs, Signal transduction, Oxidation-Reduction, Oxidative stress, Signal Transduction
Abstract

International audience; The identification of one mechanism that causes vision loss in inherited degenerative retinal disorders revealed a new signaling molecule that represents a potential therapy for these currently untreatable diseases. This protein, called rod-derived cone viability factor (RdCVF), maintains the function and consequently the viability of cone photoreceptor cells in the retina; mice that lack this factor exhibit a progressive loss of photoreceptor cells. The gene encoding RdCVF also encodes, by differential splicing, a second product that has characteristics of a thioredoxin-like enzyme and protects both photoreceptor cells and, more specifically, its interacting protein partner, the tau protein, against oxidative damage. This signaling pathway potentially links environmental insults to an endogenous neuroprotective response.

Published
2010

12. Spectrum of Rhodopsin Mutations in French Autosomal Dominant Rod–Cone Dystrophy Patients

Author

Gaël Manes, Shomi S. Bhattacharya, Veselina Moskova-Doumanova, Christian P. Hamel, José-Alain Sahel, Saddek Mohand-Said, Isabelle Audo, Xavier Zanlonghi, Marie-Elise Lancelot, Olivier Poch, Anne Friedrich, Aline Antonio, Christina Zeitz, Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Molecular Genetics, Institute of Ophthalmology, Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Exploration Fonctionnelle de la Vision, Clinique Sourdille, Centre de référence des affections sensorielles d'origine génétique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac, The project was financially supported by Foundation Fighting Blindness (I.A.), Foundation Voir et Entendre and BQR, Université Pierre et Marie Curie6 (C.Z), PHRC national adRP (C H)., Marazova, Katia, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)

Subjects
Male, Retinal degeneration, genetic structures, DNA Mutational Analysis, Visual Acuity, [SDV.GEN] Life Sciences [q-bio]/Genetics, Gene mutation, medicine.disease_cause, Polymerase Chain Reaction, 0302 clinical medicine, Prevalence, Fluorescein Angiography, Child, Genes, Dominant, Genetics, 0303 health sciences, Mutation, biology, Middle Aged, Pedigree, 3. Good health, Phenotype, Rhodopsin, Female, France, Retinitis Pigmentosa, Tomography, Optical Coherence, Photoreceptor Cells, Vertebrate, Adult, Adolescent, Genotype, White People, Article, Young Adult, 03 medical and health sciences, Retinitis pigmentosa, Electroretinography, medicine, Rod-cone dystrophy, Humans, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Genetic heterogeneity, Point mutation, medicine.disease, eye diseases, 030221 ophthalmology & optometry, biology.protein, sense organs
Abstract

Rod-cone dystrophies, also called retinitis pigmentosa (RP), are a clinically and genetically heterogeneous group of inherited retinal disorders primarily affecting rods with secondary cone degeneration 1. RP patients initially often complain of night blindness. This is attributed to the primarily affected rods and clinical sign of the impaired rod function. Later on, when the secondary cone dysfunctions manifests, progressive visual field constriction, abnormal color vision and loss of central vision can be observed – signs of decreasing cone function. As the disease progresses and retinal dysfunction decreases, visual impairment increases: in some cases the disease may eventually result in very severe visual impairment or even blindness. RP is the most common inherited form of severe retinal degeneration, with a frequency of about 1 in 4000 births and more than 1 million affected individuals over the world. The mode of inheritance can be X-linked (5–15%) autosomal dominant (30–40%) or autosomal recessive (50–60%) The remaining patients represent isolated cases of which the inheritance trait can not be established 1. To date, 20 autosomal dominant RP (adRP) genes have been reported (http://www.sph.uth.tmc.edu/Retnet/). One of the major genes underlying this disorder is rhodopsin (RHO) coding for the light absorbing molecule that initiates the signal transmission cascade in rod photoreceptors. According to the literature, RHO mutation prevalence ranges from 0 to 50% cases of adRP in cohorts from various geographical origins, with higher numbers reported in the United States 2–18. The genetic and phenotypic heterogeneity is not only found in RP in general but also specifically reflected in adRP with RHO mutations: Over 120 mutations have been identified in different sites of the gene including specific hot spots (http://www.sph.uth.tmc.edu/Retnet/, http://www.hgmd.cf.ac.uk/ac/all.php, http://www.retina-international.org/sci-news/rhomut.htm) 19. Certain mutations in RHO lead to diffuse rod-cone dysfunction whereas other cases are implicated in a more restricted disease that may predominate in the inferior part of the retina such as in sector RP 20. Phenotypic classifications have been proposed to reflect this variability. In particular, Cideciyan and co-workers have distinguished two classes of disease expression with allele-specificity 21: class A mutants show severely generalized abnormal rod function early in life with a constant rate of cone disease progression across the retina with time. Class B mutants show more restricted disease and absent or lateonset night blindness. Other classifications have been proposed based on the underlying pathogenic mechanism involved in adRP due to RHO mutations. Mendes and co-workers classified the different types of mutations in 6 groups. Class I refers exclusively to rhodopsin mutations that fold correctly but are not transported to the outer segment. Class II, refers to mutations that misfold, are retained in the endopasmic reticulum (ER) and cannot easily reconstitute with 11-cis-retinal. Class III refers to mutations that affect endocytosis. Class IV mutations do not affect folding per se but might affect rhodopsin stability and posttranslational modification. Similarly, Class V mutations have no obvious folding defect but show an increased activation rate for transducin. Mutants that appear to fold correctly but lead to the constitutive activation of opsin in the absence of the chromophore and in the dark constitute Class VI. Other mutations with unclear biochemical or cellular defect, or uninvestigated defect were not classified 19. Our comprehensive study presented herein aim to investigate in detail a French adRP cohort coming from 2 different clinical centers, namely Quinze-Vingts hospital in Paris and the Centre Hospitalier Regional in Montpellier located in the south of France. We will present the prevalence of rhodopsin mutations in this cohort and show precise phenotype-genotype correlations. Novel mutations will be analyzed on its predicted pathogenic mechanism as well as frequently mutated sites will be presented as putative candidates for therapeutic approaches.

Published
2010

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