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Juliette Varin, Miguel Miranda de Sousa Dias, Thomas Pugliese, Marion Neuillé, Nassima Bouzidi, Christelle Michiels, Melissa Desrosiers, José-Alain Sahel, Isabelle S Audo, Deniz Dalkara, Christina Zeitz; Development of two gene therapy approaches for Complete Congenital Stationary Night Blindness (cCSNB). Invest. Ophthalmol. Vis. Sci. 2018;59(9):4526.
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To date, no treatment is available for cCSNB when mutations in GRM6 or LRIT3 are involved. The aim of this work is to develop two gene therapy approaches to restore the wild-type phenotype in two mouse models of cCSNB using AAV.
Animal experiments were performed in compliance to the Statement for the Use of Animals in Ophtalmic and Vision Research. Two different gene-specific AAV vectors have been developed for each mouse model (AAV-Grm6 and AAV-Grm6-MBD or AAV-Lrit3-GFP and AAV-Lrit3), driven by a Grm6-promotor. These vectors have been injected intravitreally in KO mice (P300 or P30 or P15). Subsequently, the rescue has been followed by studying the visual function through ERG recordings (8 weeks, 16 weeks and 24 weeks post-injection) and optomotor tests but also gene expression and protein correct localization. Control injections with an AAV-GFP construct have also been performed.
For the Grm6 gene therapy approach, expression of the gene and correct localization of the protein and other partners of the cascade have been partially restored in one P300 mouse 5 months post-injection. ERG recordings and behavioral tests are currently ongoing for the newly injected ones. Concerning the Lrit3 project, GFP fluorescence was detectable 15 days post-injection confirming the efficient transgene delivery for the AAV-Lrit3-GFP construct. ERG recordings for animals injected with AAV-Lrit3 were performed and preliminary results revealed a partial rescue of the b-wave on 2 animals under scotopic conditions. Similarly, this rescue led to an improvement of the visual acuity in these two animals compared to untreated ones.
These preliminary results are encouraging for this ongoing study, even though more mice are needed. This project has a potential clinical value and will significantly contribute to treat patients with retinal disorders by a gene therapy based approach.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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