Thèses sur le sujet « Maladie rétinienne »
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Gegnaw, Shumet T. « The connection between circadian clock impairment and retinal disease ». Electronic Thesis or Diss., Strasbourg, 2023. http://www.theses.fr/2023STRAJ120.
Texte intégralThis thesis investigated how circadian clock misregulation, which has not been clearly associated with retinal genetic disease so far, could contribute to degeneration and influence development and function in the retina. The rod-specific knockout of Bmal1 clock gene (rod-Bmal1KO) from the mouse line carrying the P23H mutation of rhodopsin exacerbated the retinal degeneration phenotypes, such as reduction in ERG response and rods loss, induced by the P23H mutation alone. These observations were corroborated by RNA-Seq analysis, where we found major changes in expression of genes related to phototransduction and metabolic processes, between the (rod-Bmal1KO/P23H) double mutant and P23H retinas. We showed that during development, Per1 and Per2 clock genes deficiency in mice significantly affects gene expression of phototransduction and cell cycle components. We found that adult mice deficient for Per1 and Per2 genes lack a daily modulation of light sensitivity, under scotopic and mesopic conditions. We also found an impaired daily modulation of light sensitivity in mice deficient for Bmal1 clock gene in rods. Additionally, we investigated how rod degeneration could impact on the global rhythmic capacity of the retina by measuring PER2::LUC bioluminescence rhythms in P23H mice. We showed that the retinal clock in P23H/+ heterozygous mice displays circadian rhythms with significantly increased robustness and amplitude. These effects likely involve activation of glial cells
Burin, des Roziers Cyril. « Nouveaux mécanismes génétiques expliquant les vitréorétinopathies héréditaires et génération d’un modèle murin de la maladie de Wagner par approche CRISPR/Cas9 ». Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCB162/document.
Texte intégralPas de résumé
Albinet, Jean-Luc. « Aspects étiologiques de la prolifération vitréo-rétinienne ». Bordeaux 2, 1990. http://www.theses.fr/1990BOR23101.
Texte intégralVrignaud, Laurent. « Approche multidisciplinaire des occlusions veineuses rétiniennes ». Bordeaux 2, 1994. http://www.theses.fr/1994BOR23002.
Texte intégralMokadem, Ahmad. « Aspects cliniques et thérapeutiques des vascularites rétiniennes ». Bordeaux 2, 1994. http://www.theses.fr/1994BOR23064.
Texte intégralMonnier-Petit, Lolita. « Development of rAAV-mediated gene addition therapies in canine models of severe inherited photoreceptor dystrophies ». Nantes, 2014. http://archive.bu.univ-nantes.fr/pollux/show.action?id=f80a662b-787d-4b2c-aa75-d384eba6c3ae.
Texte intégralLes dystrophies rétiniennes héréditaires sont des maladies cécitantes causées par des mutations dans des gènes exprimés par les photorécepteurs ou l'épithélium pigmentaire rétinien (EPR). Récemment, la thérapie génique d'addition a été utilisée avec succès chez des modèles animaux de rétinopathies héréditaires récessives. Ces études ont ouvert la voie à plusieurs essais cliniques pour des maladies de l'EPR, avec des résultats encourageants. L'étape suivante est de développer un traitement pour les pathologies qui touchent directement les photorécepteurs. Pour le développement de ces nouvelles thérapies, les preuves de concept chez des modèles gros animaux qui miment les symptômes des patients sont une étape importante. En effet, la distribution, la densité et la proportion des photorécepteurs chez les modèles gros animaux sont très proches de celles des primates. Ici, nous avons évalué l'efficacité de la thérapie génique d'addition chez deux modèles canins de formes sévères de dégénérescence des photorécepteurs: (i) le chien Pde6β-/-, un modèle de dystrophie bâtonnet-cone et (ii) le chien Rpgrip1-/-, un modèle de dystrophie cône-bâtonnet. A l'aide de vecteurs dérivés du virus adeno-associé, nous avons montré qu'il était possible de restaurer la fonction rétinienne, de préserver la structure des photorécepteurs et le comportement visuel des deux modèles canins, pendant au moins 24 mois après l'injection. Ces résultats sont prometteurs pour le traitement des patients atteints de dégénérescence des photorécepteurs
Martin, Ronan. « Phototoxicité rétinienne solaire et milieux professionnels exposés ». Bordeaux 2, 1994. http://www.theses.fr/1994BOR2M140.
Texte intégralMendez, Gomez Juan Luis. « Biomarqueurs rétiniens de la maladie d'Alzheimer et du vieillissement cérébral ». Thesis, Bordeaux, 2016. http://www.theses.fr/2016BORD0370/document.
Texte intégralThe eye and central nervous system (CNS) have a common embryological origin, and easily observable retinal structures may reflect brain damage. The primary objective of this thesis was to analyze the relationship between retinal disorders and clinical (cognitive decline, dementia) and para-clinical (brain imaging) brain aging manifestations. Two types of retinal "biomarkers" were analyzed: the retinal nerve fiber layer (RNFL) and vascular structures. The data used come from the population-based cohort 3-Cities Alienor. We have shown that subjects with reduced RNFL thickness (measured by spectral-domain optical coherence tomography, SD-OCT) showed a reduced episodic memory score (cognitive function that is principally affected in Alzheimer's disease, AD) after 2 years of follow-up; over this short period of time no association with dementia risk was found. A reduced RNFL thickness was also associated with altered MRI parameters in visual pathways and in limbic system regions, which are particularly vulnerable in AD. Finally we have shown that reduced vascular choroid layer thickness was associated with larger white matter hyperintensities volumes. Vascular and neurodegenerative disease processes are associated with brain aging. Thus, alterations in the CNS by AD and brain aging could be reflected in the retina. Other research is still needed before considering the retina as a potential biomarker of brain aging
Bordure, Christian. « Apport de l'hématologie à l'exploration des occlusions veineuses rétiniennes ». Bordeaux 2, 1993. http://www.theses.fr/1993BOR23117.
Texte intégralBouaita, Aïcha. « Essais de thérapie génique contre la dégénérescence rétinienne chez la souris Harlequin déficiente pour la protéine mitochondriale AIF ». Paris 6, 2012. http://www.theses.fr/2012PA066566.
Texte intégralKaram, Alice. « Retinal ciliopathies in Huntington's and SCA7 disorders ». Thesis, Strasbourg, 2013. http://www.theses.fr/2013STRAJ069/document.
Texte intégralPolyglutamine (polyQ) disorders are dominantly inherited neurodegenerative disorders caused by the expansion of CAG repeats translated into long polyQ tracts in the corresponding proteins. These diseases include Spinocerebellar ataxia 7(SCA7) and Huntington’s Disease (HD), caused by polyQ expansion ataxin-7 (ATXN7) and huntingtin (htt), respectively. SCA7 and HD mouse models develop similar retinopathies suggesting common pathomechanisms. In my thesis, I found that, in response to polyQ toxicity, SCA7 photoreceptors (PR) undergo several cell fates ranging from their deconstruction, to their migration and their death. Moreover, this cell death activates the proliferation of Müller glial cells and their differentiation into PR like cells. The pathomechanisms underlying HD and SCA7 are still unknown. Recently, I found that ATXN7 and htt are localized to the PR cilia and that the mutant proteins lead to a progressive loss of the wild-type proteins that correlates with defects in the PR cilia
Deladurantaye, Pascal. « Étude du potentiel du formatage temporel d'impulsions laser pour les thérapies rétiniennes sélectives ». Master's thesis, Université Laval, 2016. http://hdl.handle.net/20.500.11794/27310.
Texte intégralThe rationale of selective retina therapies (SRT) is to confine laser-induced damages to the retinal pigment epithelium (RPE) in order to produce therapeutic effects equivalent to those generated in classical photocoagulation, while sparing the photoreceptors. For this purpose, SRT use shorter irradiation times (~ 1µs) to reduce thermal conduction to the neural retina. At these time scales, a transition from thermal to photomechanical cellular damage mechanisms occurs. Indeed, intracellular microcavitation inside RPE cells was shown to be a dominant mechanism leading to cell death in SRT. Microcavitation is a phenomenon where transient vapor bubbles are generated around laser-heated cellular pigments. The control of the maximum size of these bubbles is of paramount importance in SRT to avoid photomechanical alterations of the photoreceptors, which would compromise the selectivity of the treatment. The goal of this study is to evaluate the potential of temporal laser pulse formatting as a mean of ensuring minimal heat conduction around cellular pigments while controlling the size of the bubbles at the same time. In order to conduct a first proof of concept, the focus was kept on the physical mechanisms involved for the case of isolated melanin pigments suspended in water, both experimentally and theoretically. The outcomes of preliminary experiments conducted with leporine RPE sheets ex vivo are also presented. The results of this study represent crucial initial steps in a program that will thereafter examine the biological response of retinal tissues to various pulse formats in order to determine irradiation conditions that will optimize the selectivity and the therapeutic window of SRT.
Tournon-Aubry, Isabelle Aubry. « Intérêt de l'hémodilution normovolémique par dextrans dans le traitement des occlusions veineuses rétiniennes (étude sur 38 cas) ». Montpellier 1, 1988. http://www.theses.fr/1988MON11202.
Texte intégralVacca, Ophélie. « Potentiel thérapeutique de la dystrophine-dp71 et barrières rétiniennes ». Thesis, Paris 6, 2014. http://www.theses.fr/2014PA066158/document.
Texte intégralFormation and maintenance of the blood-retinal barrier (BRB) is required for proper vision and breaching of this barrier contributes to the pathology in a wide variety of retinal conditions such as diabetic retinopathy (DR) or Central retinal vein occlusion (CRVO). Dystrophin Dp71 being a key membrane cytoskeletal protein, expressed mainly in Müller glial cells, its absence has been related to BRB permeability through delocalization and down-regulation of the AQP4 and Kir4.1 channels. Dp71-null mouse is thus an excellent model to approach the study of retinal pathologies showing blood-retinal barrier permeability. Our results collectively demonstrated that in Dp71 deficient mouse with compromised barriers, normal BRB permeability and retinal homeostasis can be restored through over-expression of Dp71 via adeno-associated virus. This study is the basis for development of new therapeutic strategies in dealing with diseases with BRB breakdown and macular edema such as DR or CRVO
Olivier, Guillaume. « Physiopathologie des dystrophies rétiniennes héréditaires associées aux variants pathogènes du gène IMPG1 ». Thesis, Montpellier, 2020. http://www.theses.fr/2020MONTT021.
Texte intégralInherited retinal disorders are a clinically and genetically heterogeneous group.They are progressive Mendelian genetic diseases that cause dysfunction then cell death, including photoreceptors and retinal pigment epithelium cells (RPE). Cells death is accompanied by intra-retinal pigment deposits generally located in the retinal periphery, thus constituting the majority subgroup of pigment retinitis (RP). More rarely, lesions of various appearance affecting the macula, central region of the retina, forming the subgroup of macular dystrophies (MD). These neurodegeneration gradually lead to more or less complete blindness, without therapeutic. Despite the identification of over 90 genes associated with RP, conventional genetic testing (Sanger, panel) fails to detect a molecular diagnosis in about one third of RP patients. The identification of new genes is of major interest for understanding the disease, for establishing phenotype / genotype correlations, for improving genetic counseling, and finally for defining therapeutic pathways.For this purpose, the genetic study of a large family with autosomal dominant RP without molecular diagnosis was carried out by exome sequencing. NGS approach made it possible to identify a pathogenic splicing variant in IMPG1, a gene never described in RP. IMPG1 had been previously associated with vitelliform macular dystrophy (VMD). A complementary genetic analysis on multicentric cohorts of patients with RP or DMV, allowed to identify six additional pathogenic variants (including five new variants), in 10 other families with dominant or recessive forms of RP or DMV.We followed our study performing in vivo functional study in medaka fish, then in mice by invalidating the orthologous gene of the human IMPG1. The fish study, the use of morpholino, showed that the Impg1 gene product plays an important role, in the early development and maintenance of the biological functions of the retina. The length of the outer segments of rod and cone photoreceptors were reduced by 20% and 90% respectively. However, the invalidation of Impg1 expression is transient in fish and very limited phenotype analyzes.Impg1-/- mice helped to perform more complete visual functional studies and to examine their evolution over a long period. Impg1-/- mice show an abnormal accumulation of autofluorescent deposits visible with fundoscope and optical coherence tomography (OCT) from 9 months of age. Electroretinogram (ERG) is reduced by about 20%. The electron microscopy of mice retinas makes it possible to highlight the precise localization of the anomalies, within interphotoreceptor matrix. The mouse animal model seems to reproduce DMV phenotype while the fish model shows similarities with RP.To summarize, this thesis work allows us to extend the clinical spectrum of disorders associated with mutations in IMPG1 gene. Two new diagnoses must therefore be added to VMD: autosomal dominant and recessive RP. The animal models developed allow a better understanding of the cellular mechanisms affected by invalidation of the IMPG1 gene. However, the mechanism explaining macular or peripheral involvement in humans, as well as the different modes of transmission and penetrance variations have not yet been elucidated
Ameqrane, Ilhame. « Dégénérescence rétinienne chez la souris rd10 Implication de SIRT 1 et PGC-1 alpha ? » Paris 5, 2011. http://www.theses.fr/2011PA05T041.
Texte intégralRetinopathies are characterized by a progressive degeneration of photoreceptors, leading to blindness. Until now, there are no treatments to prevent the loss of photoreceptors, that’s why it’s important to study the mechanisms involved in the degenerative processes. Rd10 mouse is a good model for retinopathy because the first steps of degeneration occur after the development of the different retinal layers. SIRT 1 is a desacetylase protein involved in DNA repair and in survival cell. PGC-1 alpha is a target of SIRT1, has particularly been studied for its roles in mitochondrial metabolism. PGC-1 alpha desacetylation by SIRT1 has been shown to reduce neuronal death in several neurodegenerative diseases. Retina is part of the central neuronal system, that’s why we studied the involvement of SIRT1 and POGC-1 alpha in a model in retinitis pigmentosa. First, we characterized SIRT1 and PGC-1 alpha expression in normal mouse retina. In rd10 retina, we observed an alteration of SIRT1 expression correlated with photoreceptor apoptosis. Then, we showed a decrease in PGC-1 alpha acetylation since early stages of degeneration, supposing that the activation of the protein increases during the degenerative process. PGC-1 alpha is known to be desacetylated only by SIRT1 which suggest that SIRT1/PGC-1 alpha axis could be important in the development of retinal degeneration. This study is the first to characterize SIRT1 and PGC-1 alpha in retina and to highlight their potential involvement during retinal degeneration
Rosell, Mélissa. « Synthèse et évaluation de lipophénols deutérés, un nouveau concept pour réduire les stress oxydant et carbonylé dans les maladies rétiniennes ». Thesis, Montpellier, 2017. http://www.theses.fr/2017MONTT188/document.
Texte intégralAge Related Macular Degeneration (AMD) and Genetic Stargardt’s disease share a common cytotoxic mechanism involving carbonyl and oxidative stress. Hence both stresses represent promising therapeutic targets. A lipophenol lead molecule has been previously highlighted. This molecule is composed by an alkylphloroglucinol moiety and a lipid part which is a polyunsaturated fatty acid, the docosahexaenoic acid (DHA, C22:6, ω3). In order to improve the antioxidant activity of this lipophenol, the total synthesis of two deuterated DHA on bis-allylic positions was performed. The cross-coupling between the deuterated DHA and the alkylphloroglucinol moiety led to the corresponding deuterated lipophenols. The impact of the deuterium to limit the cell toxicity and the lipid peroxidation was highlighted thanks to in vitro biological studies performed on retinal pigment epithelium cell line
Chiffre, Thomas. « Efficacité de la radiothérapie dans la dégénérescence maculaire exsudative liée à l'âge ». Bordeaux 2, 1999. http://www.theses.fr/1999BOR23042.
Texte intégralMakhoul, Maya. « Activation des cellules rétiniennes lors d'uvéites autoimmunes expérimentales : rôle des cytokines pro-inflammatoires et effet du transfert du gène SOCS1 ». Doctoral thesis, Universite Libre de Bruxelles, 2012. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209688.
Texte intégralNotre travail de thèse s’inscrit précisément dans ce contexte du rôle de l’activation des cellules rétiniennes et plus spécifiquement de celles de la barrière hémato rétinienne (BHR) dans le développement d’uvéite non infectieuses.
Lors de ce travail, nous avons tout d’abord caractérisé in vivo, dans deux modèles expérimentaux, l’expression de la molécule d’adhésion VCAM-1 (Vascular Adhesion Molecule) sur les cellules de la BHR. VCAM-1 est une molécule d’adhésion qui facilite l’extravasation des leucocytes du sang vers les tissus. Nous avons montré que VCAM-1 n’est pas exprimé dans l’œil sain mais est induit progressivement lors de la maladie et que l’intensité et l’extension de son expression étaient dépendantes de la sévérité de la maladie. Par ailleurs, nous avons montré que VCAM-1 pouvait être induit sur l’ensemble des cellules de la BHR.
Nous avons ensuite analysé in vitro, sur les cellules de l’EPR (Epithélium Pigmentaire Rétinien) qui forment la partie externe de la BHR, les effets antagonistes du TNFα sur l’induction des molécules de CMH de classe II par l’IFNγ. Durant le processus inflammatoire, l’EPR est la cible d’un ensemble de cytokines secrétées par les cellules inflammatoires. Il a été donc intéressant d’étudier les effets d’autres cytokines présentes lors de l’inflammation sur l’induction du CMHII par l’IFNγ au niveau de l’EPR. Nous avons démontré que le TNFα inhibe l’expression du CMH II induit par l’IFNγ sur les ARPE par régulation négative du CIITA (Class II Transactivator). Comme l’activation des lymphocytes T par les cellules de l’EPR dépend de leur niveau d’expression du CMH II, notre étude soutient l’idée que le TNFα possède des propriétés immunomodulatrices sur l’activation de ces cellules, et participe ainsi à la phase de résolution de l’inflammation.
Enfin, nous avons étudié les effets du blocage de l’activation des cellules rétiniennes par l’IFNγ en surexprimant le gène SOCS1 (Suppressor Of Cytokine Signaling) in vivo et in vitro.
Nous avons surexprimé le gène SOCS1 au niveau rétinien et étudier l’effet de cette surexpression sur le développement de l’UAE. L’analyse des grading clinique n’a pas montré de différence significative entre les yeux injectés par l’AAV2-SOCS1 versus l’AAV2-EGFP contrôle. Afin de normaliser par rapport à la diversité inter-individuelle de la maladie, nous avons calculé pour chaque souris un ratio des grades cliniques de l’œil injecté sur l’œil non-injecté. L’analyse de la moyenne de ces ratios montre un effet à la limite de la significativité entre le groupe SOCS1 et le groupe EGFP en terme de grades cliniques. La différence devient par contre significative lorsque l’analyse de ces ratios est faite sur les grades histologiques. Nos expériences mènent donc plutôt à la conclusion que l’expression de SOCS1, médié par injection intravitréenne de l’AAV2 ne protège globalement pas les yeux du développement d’une UAE.
Cette absence d’effet peut avoir comme explication que l’injection intravitréenne conduit à une infection relativement limitée des cellules rétiniennes impliquées dans le développement de l’UAE. Il se pourrait également que le niveau d’expression de la protéine SOCS1 soit trop faible pour obtenir un effet protecteur ou que la surexpression de SOCS1 affecte uniquement l’activation des cellules de la rétine par l’IFNγ mais pas par d’autres cytokines telles le TNFα, l’IL-17, ou l’IL-22 qui jouent aussi un rôle important dans le développement d’UAE. C’est cette dernière hypothèse que nous avons choisi d’investiguer in vitro. Nos résultats montrent que la surexpression de ce même gène SOCS1 dans les cellules d’EPR a un effet inhibiteur sur leur activation par l’IFNγ mais pas par le TNFα.
Ce travail met tout d’abord en évidence l’importante expression, in vivo, de VCAM1 par les cellules de la BHR lors d’UAE et in vitro les effets antagonistes du TNFα et de l’IFNγ sur la régulation de l’expression de molécules du CMHII à la surface de l’EPR. Nos expériences démontrent que la surexpression du gène SOCS1 après injection intravitréenne du vecteur AAV-CAG-SOCS1 n’a que peu d’effet sur le développement de la maladie. Par ailleurs, la surexpression de ce même gène SOCS1 dans les cellules d’EPR a un effet inhibiteur sur leur activation par l’IFNγ mais pas par le TNFα et l’IL-17.
Doctorat en sciences biomédicales
info:eu-repo/semantics/nonPublished
Koch, Edouard. « Étude morphométrique des artérioles rétiniennes chez l’homme par imagerie a haute résolution Imagerie des artérioles rétiniennes par optique adaptative, faisabilité et reproductibilité Morphometric analysis of smallarteries inthehuman retinausingadaptive optics imaging : relationshipwith bloodpressure and focalvascularchanges ». Thesis, Sorbonne université, 2018. http://www.theses.fr/2018SORUS418.
Texte intégralSmall arteries (i.e. diameter less than 150μm), so-called resistive arteries, are essential for regulating the distribution of blood flow. These vessels are modified during many conditions, including arterial hypertension which causes a thickening of their wall. Until recently, direct observation of retinal vessels was not possible in humans. Following the discovery by our team of the possibility of visualizing the wall of the retinal vessels in humans using an imaging technology using adaptive optics (OA), we studied normal and pathological human retinal vascular morphometry. For this, original clinical protocols have been implemented, in collaboration with computer scientists, ophthalmologists and cardiologists. After contributing to the development of image segmentation software to extract quantitative data on retinal vascular morphometry, we conducted prospective, observational, cross-sectional and longitudinal clinical studies. This work enabled us to validate a methodology for measuring parameters related to the microvascular structure, and to study its variations during hypertension and during focal pathologies (arteriovenous nicking, focal arteriolar narrowing). We were able to demonstrate that the variability of the retinal artery wall-to-lumen ratio (WLR) was 43% correlated with the blood pressure measured in consultation and to a lesser extent at age. This remodeling is eutrophic (i.e. without increasing the amount of the parietal material). The observation of focal arterial narrowing revealed a decrease in the internal diameter without parietal thickening and in some cases a disappearance of the focal narrowing, which suggests that these arterial narrowing are due to localized vasoconstriction. Finally, we have demonstrated that venous abnormalities occur near the arteries without direct contact with them, suggesting the existence of an indirect effect of the proximity between artery and veins on venous morphology. In diabetics, the team of Xavier Girerd with our contribution has demonstrated the existence of hypertrophic remodeling (increase in the amount of parietal material with reduction of light and parietal thickening). In patients with acute cerebral infarction, we found no correlation between the WLR and the Fazekas score, reflecting the degree of leukoaraiosis; the WLR itself is not significantly modified relative to a control population. We also studied the dynamics of retinal vasomotricity. Through various vasoconstrictor stimuli (oxygen, cold) and vasodilators (intermittent light stimulation, hypotensive treatment), we have documented the corresponding changes in caliber of small arteries and veins. Intermittent light stimulation appears to be the most promising method because of its simplicity and acceptability. In conclusion, through this work, we explored new methods of in vivo study of human retinal circulation. A broad field of clinical studies is opening up in the field of phenotyping microcirculation. Future work may be directed towards a better prediction of the risk of organic lesion, towards the follow-up of the hypotensive treatment and towards the role of the modifications induced by the diabetes in the occurrence of the diabetic retinopathy
Delettre-Cribaillet, Cécile. « Génétique des dystrophies héréditaires de la rétine : identification du gène responsable de l'atrophie optique dominante OPA1 ». Montpellier 1, 2002. http://www.theses.fr/2002MON1T002.
Texte intégralLe, Meur Guylène. « Evaluation d'un vecteur associé à l'adénovirus recombinant de sérotype 4 (AAV4) pour le traitement par thérapie génique d'un modèle canin de l'amaurose congénitale de Leber : le chien Briard RPE65-/- ». Nantes, 2007. http://archive.bu.univ-nantes.fr/pollux/show.action?id=343358f5-2fee-48c5-abaf-f33b77afa7f5.
Texte intégralThe vectors derived from the adeno-associated virus (AAV) allow an effective and stable gene transfer in the retina. Possible future applications of this gene therapy in ophthalmology will be the treatment of acquired or hereditary retinal degenerations. Leber congenital amaurosis is an early form of hereditary retinal degeneration. The RPE65-/-briard dog is one of the canine models of this retinal degeneration. After having shown that serotypes 2, 4 and 5 of AAV vectors allowed a stable gene transfer in dog and primate retina, we evaluated an AAV4 vector, which specifically targets the retinal pigmented epithelium, for the treatment of the RPE65-/-briard dog. This rpe65 gene transfer using an AAV4 vector carrying human rpe65 DNA under the control of a specific RPE65 human promoter, allowed a stable restoration of the retinal function and vision in the RPE65-/-treated dogs
Cereso, Nicolas. « Preuve de concept de thérapie génique d’une dystrophie rétinienne en l’absence de modèle animal de la pathologie : cas de la Choroïdérémie ». Thesis, Montpellier 1, 2014. http://www.theses.fr/2014MON1T019/document.
Texte intégralInherited retinal dystrophies (IRDs) lead to a progressive vision loss. The first clinical trials using gene transfer to treat such diseases have been performed with positive results. Prior to clinical trials, preclinical studies are usually performed on animal models. However, for many IRDs, appropriate animal models do not exist, which compromises their progress towards a clinical trial. An example of an IRD that lacks an appropriate model is choroideremia, which represents 2% of IRD patients. It is characterized by night blindness in childhood, followed by progressive loss of the visual field resulting in blindness by 40–50 years of age. Its early diagnosis and slow evolution result in a large therapeutic window making choroideremia a good candidate for gene therapy. Genetically, the disease is caused by a mutation in the CHM gene located on the X chromosome and encoding the Rab Escort Protein 1 (REP1). This protein is involved in the prenylation of small GTPases, the Rab proteins. To palliate the lack of an animal model, we generated a human cellular model of choroideremia in order to evaluate the efficacy of a gene therapy approach in the tissue that is affected in vivo.Towards this aim, we reprogrammed REP1-deficient fibroblasts from a CHM-/y patient into induced pluripotent stem cells (iPScs), which we differentiated into retinal pigment epithelium (RPE). We characterized the iPSc-derived RPE that is a polarized monolayer with a classic morphology, expresses characteristic markers, is functional for fluid transport and phagocytosis, and mimics the biochemical phenotype of patients. In terms of gene therapy and to evaluate the most efficient viral vector, I assayed a panel of 5 adeno-associated virus (AAV) vector serotypes and showed that AAV2/5 is the most efficient at transduce the iPSc-derived RPE. I then transduced the iPSc-derived RPE of a choroideremia patient with an AAV2/5-CAG-CHM and demonstrated that this vector is able to restore a normal prenylation function to the cells.To conclude, I demonstrated the superiority of the transduction efficiency of AAV2/5 in the iPSc-derived RPE and highlight the potential of a diseased RPE model derived from iPS cells to provide a proof of concept of gene therapy in the absence of a suitable animal model
Mougenot-Lhériteau, Elsa. « Évaluation de vecteurs associés à l'adénovirus recombinant (AAVr) pour le traitement par thérapie génique de modèles canins de l'amaurose congénitale de Leber : le teckel RPGRIP1 déficient et le briard RPE65 déficient ». Nantes, 2010. https://archive.bu.univ-nantes.fr/pollux/show/show?id=7bc97fdd-81ff-4f9a-b108-c661ca097f92.
Texte intégralLeber congenital amaurosis is an hereditary retinal dystrophy responsible for congenital blindness. The Dachshund dog RPGRIP1-/- and the Briard dog RPE65-/- are two canine models of this pathology. We have characterized the pathology in the dachshund dog RPGRIP1-/-. Then, we have developed a photoreceptor-specific AAV vector and we have evaluated the efficiency of this vector carrying either the human RPGRIP1 gene, or the canine RPGRIP1 gene. Replacement gene therapy with AAV vectors has already showed its efficacy in the Briard dog RPE65-/-. We have investigated the ability of the tetracycline-regulatable system to regulate retinal function in RPE65-/- Briard dogs
Jebara, Najate. « Organisation fonctionnelle de la perception des objets en vision centrale et en vision périphérique : sujets sains et pathologies ophtalmologiques ». Lille 2, 2009. http://www.theses.fr/2009LIL2S011.
Texte intégralPaquet-Durand, François. « Role of the Glycogen Synthase Kinase 3 for the Retinal Development and Homeostasis ». Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS060/document.
Texte intégralPost-translational modifications (PTMs) allow a higher degree of regulation for the control of gene expression by generating functional diversity at the proteome level. In the central nervous system, PTMs regulate stability or activity of transcription factors allowing a rapid response to external signals and a quick adaptation to a dynamic cellular microenvironment. In this context, I focused on the ubiquitously expressed and highly conserved Glycogen Synthase Kinases 3 (GSK3s). They are at the crossroad of multifunctional signalling pathways. During mammalian brain development, GSK3 kinases control the balance between proliferation and differentiation. Deregulation of GSK3 kinases activity has also a key role in neurodegenerative diseases by causing the accumulation/aggregations of proteins causing neuronal cell death. Drugs targeting GSK3s hold a lot of promises to treat such diseases. Whether these kinases are also important during retinal development and involved in retinal diseases remains an open question. Several studies suggest the importance of regulating GSK3 function in photoreceptor under pathological conditions. Therefore, the main objective of my PhD was to investigate the role of these kinases during photoreceptor development and homeostasis. To better understand the role of these two kinases during retinal development and to highlight potential differences with the developing brain, we also investigated their function in the control of the balance between proliferation and differentiation of retinal progenitors. To achieve my work, I used conditional knockout mice for Gsk3α and Gsk3β specifically deleted either in photoreceptor precursors or in retinal progenitors during early development. The lack of GSK3 kinases in photoreceptor precursors led to impaired photoreceptor maturation and function followed by their degeneration. Transcriptomic analysis (RNAseq) 6, 10 and 14 days postnatally prior degeneration revealed several genes downregulated belonging to biological processes involved in eye development and visual functions. Among them, the expression of the transcription factor Nrl that is required for rod photoreceptor development was decreased. Astonishingly, NRL expression was highly increased at protein level. By in vitro approaches, I demonstrated that GSK3-dependent phosphorylation regulates NRL protein stability. Despite such increase, a large number of NRL target genes were downregulated leading to impaired photoreceptor maturation and function. Surprisingly, a vast majority of these downregulated genes were also target genes for CRX, another transcription factor working in synergy with NRL. This work demonstrates that PTMs of NRL play a critical role in fine tuning the expression of a subset of genes involved photoreceptor development and homeostasis. Such findings could allow the development of innovative therapeutic strategies for retinal dystrophies. The functional characterisation of GSK3 in the course of retinal development by invalidating both Gsk3α and Gsk3β in retinal progenitors early during development revealed their requirement for controlling cell cycle exit and neuronal differentiation. Indeed, the complete lack of Gsk3α and Gsk3β led to microphtalmia in adults. Interestingly, the expression of only one Gsk3 allele was enough to rescue the phenotype. However, further analysis revealed a large number of displaced ganglion cells in the inner nuclear layer. The function of these cells remains to be determined, but their timing of production corresponds to other ganglion cells. Strikingly, these displaced ganglion cells project in distinct brain regions than normal ganglion cells. Therefore, our work could provide the first step toward determining the function of the displaced ganglion cells, which appear at low number in wildtype but whose function remains to be clarified
Salaun, Nicolas. « Effets des éblouissements colorés sur la fonction de sensibilité au contraste ». Bordeaux 2, 1999. http://www.theses.fr/1999BOR2M041.
Texte intégralOrhan, Le Gac De Lansalut Elise. « From gene identification and functional characterization to genome editing approaches for inherited retinal disorders ». Thesis, Paris 6, 2015. http://www.theses.fr/2015PA066218/document.
Texte intégralThe first steps in vision occur in the retina when rod and cone photoreceptors transform light into a biochemical signal, which gets processed by bipolar cells, ganglion cells and finally by the brain. Our group investigates genetic causes and mechanisms involved in inherited stationary and progressive retinal diseases as congenital stationary night blindness (CSNB), and rod-cone dystrophy (RCD), also called retinitis pigmentosa. This thesis gives several insights on the retinal physiology. On one hand, we identified GPR179, a new gene mutated in complete CSNB, studied the localization and the physiopathology of missense and splice-site mutations. We also delivered a new knock-out mouse model which we functionally characterized, and studied GPR179 partners to provide a better understanding of the first visual synapse between photoreceptors and ON-bipolar cells. On the other hand, we genotypically and phenotypically characterized one of the most popular RCD model, the P23H rat model. There is currently no treatment for RCD and different therapeutic strategies are under investigation. We wanted to deliver the basis for a genome editing approach for RHO mutations, acting as a dominant negative effect, which cannot be addressed by current gene replacement strategies. We opened the field by performing in vitro, ex vivo and in vivo genome editing experiments using meganucleases, TALEN (Transcription Activator-Like Effector Nuclease) and finally CRISPR/Cas9 system (clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9) and revealed how challenging the setting of genome editing strategies was
Chao, de la Barca Juan Manuel. « Approche métabolomique des maladies dégénératives de la rétine et du nerf optique. : neuropathie optique héréditaire de Leber, athropie optique dominante et préconditionnement rétinien induit par la lumière The metabolomic signature of Leber's hereditary optic neuropathy reveals endoplasmic reticulum stress Metabolic signature of remote ischemic preconditioning involving a cocktail of amino acids and biogenic amines ». Thesis, Angers, 2016. http://www.theses.fr/2016ANGE0069.
Texte intégralWe have conducted a mass spectrometry targeted metabolomics approach, enabling us to quantify 188 metabolites including lipids and more polar molecules. Three condition related to the retina and the optic nerve have been studied: Leber hereditary optic neuropathy (LHON), dominant optic atrophy (DOA) due to OPA1 haploinsufficiency and retina light-induced preconditioning (RLIP). The main results we obtained are: LHON project: Concentrations of the whole pool of amino acid and some sphingomyelins (SM) were diminished whereas those of ten phosphatidylcholines (PC)were increased in fibroblasts carrying a LHON mutation. Fibroblasts from LHON-affected patients showed pharmacologically reversible endoplasmic reticulum stress. DOA project: Variations in the concentration of some lipids, glutamate and polar neuroprotective metabolites suggested pre-symptomatic alterations of the myelin sheath along with axonal metabolic dysfunction of the optic nerve in Opa1 +/-mice. A sexual dimorphism was also observed in the metabolome of the optic nerve. RLIP project: Preconditioning light seemed to elicit acute proteolysis and decreased NO production in the retina. Light stress was also related with lipid remodeling in the retina. A sexual dimorphism was also observed in the retina of control rats. Taken as a whole, our results show that the metabolomics approach is adapted and relevant for the study of the physiopathology of ocular diseases
Belhouachi, Nabila. « Sélection antigénique dans les lymphomes du système nerveux central ». Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCC216.
Texte intégralPrimary vitroretinal lymphoma (PVRL) is a high-grade lymphoma considered as a subtype of primary central nervous system lymphoma (PCNSL). Unusual localization is a feature of these rare entities. The vast majority of cases are diffuse large B cell lymphoma (DLBCL), mostly of activated B-cell (ABC). To investigate whether PVRLs display a specific IG repertoire contributing to explain their unusual localization, we analysed in detail the IG heavy and light chain sequences from PVRL and PCNSL cases, and we compared their repertoire to that of a publicly available IG heavy chain sequences dataset from systemic ABC-type DLBCLs. Our study was carried out on the largest PVRL series reported to date and showed that PVRL displayed a strikingly biased repertoire as the IGHV4-34 gene was used in 63.6% of cases. The frequency was significantly higher in PVRL compared to PCNSL and DLBCL. This gene has been repeatedly found to be preferentially used in various B-cell malignancies, but never to such an extent. Half of PVRL cases expressing the IGHV3-7 gene had stereotyped VH CDR3 features (subset). Altogether our data showed that PVRLs display a very biased IG repertoire strongly suggesting that antigen selection plays a major role in their development. Thus, PVRL display a highly restricted IG repertoire indicative of antigen selection, and distinct from that of PCNSL. Antigen(s) identification may provide promising perspectives in physiopathology concepts and therapeutic approaches