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Pathophysiology and Gene Therapy of the Optic Neuropathy in Wolfram Syndrome Jolanta Jagodzinska

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Pathophysiology and Gene Therapy of the Optic Neuropathy in Wolfram Syndrome Jolanta Jagodzinska Pathophysiology and gene therapy of the optic neuropathy in Wolfram Syndrome Jolanta Jagodzinska To cite this version: Jolanta Jagodzinska. Pathophysiology and gene therapy of the optic neuropathy in Wolfram Syndrome. Human health and pathology. Université Montpellier, 2016. English. NNT : 2016MONTT057. tel-02000983 HAL Id: tel-02000983 https://tel.archives-ouvertes.fr/tel-02000983 Submitted on 1 Feb 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. ! Délivré par l’Université de Montpellier Préparée au sein de l’école doctorale Sciences Chimiques et Biologiques pour la Santé et de l’unité de recherche INSERM U1051 Institut des Neurosciences de Montpellier Spécialité : Neurosciences Présentée par Jolanta JAGODZINSKA Pathophysiology and gene therapy of the optic neuropathy in Wolfram Syndrome Soutenue le 22/12/2016 devant le jury composé de Timothy BARRETT, Pr, University of Birmingham Président Sulev KOKS, Pr, University of Tartu Rapporteur Marisol CORRAL-DEBRINSKI, DR2 CNRS, UPMC Paris 06 Examinateur Benjamin DELPRAT, CR1 INSERM, INM, Montpellier Examinateur Agathe ROUBERTIE, PH, CHRU Montpellier Examinateur Cécile DELETTRE-CRIBAILLET, CR1 INSERM, INM, Montpellier Directeur de thèse Christian HAMEL, Pr, PU-PH, CHRU Montpellier Co-directeur de thèse ACKNOWLEDGEMENTS I would like to express deep gratitude to my research supervisor, Dr Cécile Delettre-Cribaillet for her constant advice, trust, motivation, kindness and patience. Big thanks for the knowledge you passed on me and for the possibility to work with you! I would like to show my appreciation to Prof. Christian Hamel for creating constructive environ- ment, his inquiring approach, and countless possibilities for scientific progress. Especially, thank you for the invaluable advice and mentorship! I am immensely grateful to all the members of our research group for their help and consultation, especially Dr Marie Péquignot, Dr Emmanuelle Sarzi, Camille Mégy, and Mélanie Quiles. Also, I thank all the PhD students, employees and interns from INM, for the moral support and creating great atmosphere. It was a pleasure working with you! I would like to thank the animal facility staff for housing, Dr Volker Becker for his assistance with ImageJ macros, as well as CRIC and RHEM platform staff for the invaluable advice on TEM and his- tology; especially Dr Chantal Cazevieille. I am also tremendously grateful to Prof. Sulev Koks and Dr Benjamin Delprat for providing the animals used in my experiments. I would like to thank the following organizations for their generosity, which made my research pos- sible: L’Association Syndrome de Wolfram, La Retina France, AFM Telethon, La Fondation Maladie Rares, La Fondation Recherche Médicale, Inserm Transfer, and Labex EpiGenMed. I truly appreciate the input of Prof. Tim Barrett and Prof. Sulev Koks, the reviewers of this thesis, as well as Dr Marisol Corral-Debrinski, Dr Benjamin Delprat, and Dr Agathe Roubertie, the examiners. Thank you for your time and feedback! And last but not least, my dear family and fiancée, thank you for bearing with me during the PhD! 1 To my family and friends 2 Table of Contents 1. ABBREVIATIONS ........................................................................................................................................... 6 2. ABSTRACT ..................................................................................................................................................... 9 3. SUMMARY IN FRENCH ............................................................................................................................... 11 4. INTRODUCTION .......................................................................................................................................... 21 4.1. Wolfram Syndrome ............................................................................................................................. 21 4.1.1. Clinical features: diabetes ......................................................................................................... 22 4.1.2. Clinical features: optic atrophy ................................................................................................. 23 4.1.3. Other clinical features .............................................................................................................. 24 4.1.4. Treatment for Wolfram Syndrome ........................................................................................... 25 4.1.5. Final conclusions ....................................................................................................................... 26 4.2. Wolfram Syndrome-related genetic disorders .................................................................................... 27 4.3. Gene associated with Wolfram Syndrome: WFS1............................................................................... 28 4.3.1. Structure ................................................................................................................................... 28 4.3.2. Subcellular localization of the protein ...................................................................................... 30 4.3.3. Expression pattern: human ....................................................................................................... 30 4.3.4. Expression pattern: mouse ....................................................................................................... 31 4.3.5. WFS1 in stress response ........................................................................................................... 34 4.3.6. WFS1 in cell death and protein degradation ............................................................................ 38 4.3.7. WFS1 in calcium homeostasis ................................................................................................... 39 4.3.8. WFS1 in anabolism, proliferation and cell cycle ....................................................................... 40 4.3.9. WFS1 in protein biosynthesis and secretion ............................................................................. 41 4.3.10. WFS1 in development ............................................................................................................... 43 4.3.11. Final conclusions ....................................................................................................................... 43 4.4. Gene associated with Wolfram Syndrome: WFS2............................................................................... 44 4.5. Wolfram Syndrome mouse models ..................................................................................................... 45 4.6. Gene therapy for retinal ganglion cell disease .................................................................................... 47 4.6.1. Ocular gene therapy ................................................................................................................. 47 4.6.2. Non-viral vectors ....................................................................................................................... 49 4.6.3. Viral vectors .............................................................................................................................. 52 4.6.4. AAV in optic neuropathy ........................................................................................................... 53 3 4.6.5. AdV and LV in optic neuropathy ............................................................................................... 57 4.6.6. Final remarks ............................................................................................................................ 58 5. AIM OF THE STUDY .................................................................................................................................... 59 6. MATERIALS AND METHODS ....................................................................................................................... 60 6.1. Mice ..................................................................................................................................................... 60 6.1.1. Genotyping ............................................................................................................................... 61 6.2. Intraocular Pressure ............................................................................................................................ 62 6.3. Blood Glucose ...................................................................................................................................... 62 6.4. Visual acuity and contrast sensitivity .................................................................................................. 63 6.5. Electrophysiology ................................................................................................................................ 65 6.6. Eye fundus ..........................................................................................................................................
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