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, darkness, for 1, 3, 7 and 12 months old Wfs1 WT

, Wfs1 E864K (in red) mice. Results for flashes at 5 ms, 0.5 Hz and 15.9 cd·s/m 2 are shown as mean ± SEM for both eyes

, for ON-bipolar and Müller cells, were recorded after 5 min long adaptation to bright light, as a response to flashes at 5 ms, 1 Hz and 159 cd·s/m 2. Results are shown as mean ± SEM for both eyes of 1, 3, 7 and 12 months old Wfs1 WT, Figure 49. Photopic ERG. A-wave (A), for cones, and b-wave (B)

A. Iv, Optic Neuropathy Optic neuropathy (OPN) has either an acquired or hereditary background (Table 10), 2014.

. Berger, what leads to other symptoms than loss of vision, such as demyelination in CNS, thus multiple sclerosis-like disease; as well as ataxia, myopathy, ocular muscle paralysis, sensorineural hearing loss etc. Leber hereditary optic neuropathy (LHON, OMIM #535000, prevalence 1/30 000) is one of mitochondrial OPNs. LHON is a unilateral disorder, Hence, it may be autoimmune or caused by gene mutations, inflammation, ischemia, trauma or toxicity (Touitou and LeHoang, 1991.

C. Dz-wai-man, visual acuity loss beginning with blurriness, OD atrophy (Figure 70), RGC dysfunction, pre-symptomatic swelling and subsequent thinning of the retinal nerve fiber layer (RNFL). Particularly, parallel RNFL-exclusive peripallary retinal that none of the ON parts is able to regenerate. Even more, in response to axonal atrophy or trauma, glial cells form scars that block the regeneration in a chemical and physical manner, 25% of cases the onset is bilateral. Males are affected four to five times more often than females, with aggravation in case of smoking, but a chance for spontaneous recovery, 1991.

. Hu, OA is its first neurological symptom, starting in adolescence and ending with blindness within 8 years. Unfortunately, a suitable WS mouse model comprising ophthalmologic symptoms has not yet been found, therefore the search for its treatment is delayed. In this thesis, I studied visual impairment in two WS mouse models along with a success of a gene therapy (GT) approach with the human WFS1 gene. Firstly, 3 and 6 months old Wfs1 exon8del mice were examined for the visual acuity (VA) and contrast sensitivity via changes in the optomotor reflex (OMR), the neural retinal function via electroretinogram (ERG), as well as the eye physiology via fundoscopy and optical coherence tomography (OCT). Also, the proportion of retinal ganglion cells (RGC) and the axonal loss at the age of 7 months were determined with anti-Brn3a immuno-labeling of retinal sections and electron microscopy of optic nerve (ON) sections, respectively. There was a progressive loss of VA and contrast sensitivity in Wfs1 exon8del-/-mice, starting already at 1 month of age. It was accompanied by optic disc pallor, retinal thinning as well as axonal damage. However, there was no RGC loss and the endoplasmic reticulum (ER) stress in the retina was at a normal level. It suggested a presence of another cause for the reported degeneration in KO mice; in opposition to what was proposed in the literature. I brief, KO mice exhibit significant WS ophthalmic phenotype. Secondly, in search for another model, visual functions of Wfs1 E864K mouse line were investigated. This line was originally a model of Wolfram-like Syndrome, characterized by dominant mutations in WFS1 leading to congenital progressive hearing impairment, diabetes mellitus and OA. Only homozygous mutants, however, showed expected visual impairment. Already at 1 month of age, Wfs1 E864K mice had drastic loss of RGC function, albeit keeping the cell number at a normal level. This was accompanied by retinal thinning and a severe ON damage, as shown with OCT and fundoscopy, respectively. In contrast, the RGC function in Wfs1 E864K/+ mice dropped slightly only at the age of 7 and 12 months, showing that the pathology of the E864K mutation-driven disease in mice is different than in humans. Therefore, Wfs1 E864K mice, with their strong ophthalmic phenotype, could potentially serve as a model of the classical WS. Finally, to investigate future treatment options, 1 month old Wfs1 exon8del+/+ (WT) and Wfs1 exon8del-/-(KO) mice underwent a uni-and bilateral intravitreal gene therapy (GT) with AAV-2/2-CMV-WFS1. Exams at 3 and 6 months of age showed improved VA, as well as optic pallor and axonal damage rescue in KO mice. Also, no adverse effects related to either GT or sham injections were noted, However, regeneration could be achieved if aspects of axonal survival, re-myelination, functional synapse formation, low ER stress and Ca 2+ balance were managed, 2009.

, / 1000 000) est une maladie neurodégénérative, qui se présente avec un début juvénile, intégrant le diabète insipide, diabète sucré, l'atrophie optique (AO), et la surdité. AO est généralement son premier symptôme neurologique, commençant à l'âge de 11 ans et se terminant par la cécité 8 ans plus tard. Malheureusement, un modèle murin du SW approprié aux symptômes ophtalmologiques n'a pas encore été trouvé, donc la recherche de la thérapie pour sauver la vision en est à ces débuts. Dans cette thèse j'ai étudié l'atteinte visuelle de deux modèles de souris mutantes pour le SW et succès d

, De plus, la proportion des cellules ganglionnaire de la rétine (CGRs) et la perte axonale dans le nerf optique (NO) à 7 mois ont été examinés avec marquage anti-Brn3a et microscopie électronique, respectivement. Il y avait une perte progressive de l'AV et la SC chez les souris KO à partir du 1 mois. Elle était accompagnée d'une pâleur du disque optique (DO), d'amincissement de la rétine ainsi que des lésions axonales. Par contre, il n'avait pas de perte des CGRs ni stress du réticulum endoplasmique dans la rétine, Premièrement, les souris Wfs1 exon8del sont été examinées à 3 et 6 mois pour l'acuité visuelle (AV) et la sensibilité aux contrastes (SC) via changements dans le reflexe optomoteur (ROM), la fonction rétinienne neurale par électrorétinogramme (ERG)

À. Deuxièmement and S. W. La-recherche-d&apos;un-autre-modèle-du, Déjà à 1 mois, les souris Wfs1 E864K avait une perte drastique de la fonction des CGRs, mais en gardant le nombre de cellules à un niveau normal. Ceci a été accompagné par un amincissement de la rétine et d'un sévère dommage du NO, comme montré par le TCO et la fondoscopie, respectivement. En conséquence, les souris Wfs1 E864K , avec leur fort phénotype ophtalmique, les fonctions visuelles de la lignée Wfs1 E864K de la souris ont été étudiées

. Enfin, les souris de la lignée Wfs1 exon8del à 1 mois ont subi une TG intravitréenne avec AAV-2/2-CMV-WFS1. Les examens à 3 et 6 mois ont montré une amélioration de l'AV, ainsi que le sauvetage de la pâleur du DO et réduction des lésions axonales chez les souris KO. En outre, aucun effet indésirable lié à des injections TG n'ont été noté. Suivant cette idée, les souris Wfs1 E864K ont également été soumis à la TG intravitréenne

, Wfs1 E864K comme une alternative, en particulier pour enquêter sur la fonction de Wfs1 dans l'oeil. Enfin, la GT intravitréenne avec WFS1 a un potentiel pour sauver partiellement le phénotype ophtalmique