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In Vivo CRISPR/Cas9-Mediated Genome Editing Mitigates Photoreceptor Degeneration in a Mouse Model of X-Linked Retinitis Pigmentosa

PURPOSE: Retinitis pigmentosa GTPase regulator (RPGR)-related X-linked retinitis pigmentosa is associated with one of the most severe phenotypes among inherited retinal disease. The aim of this study was to investigate Clustered Regularly Interspaced Short Palindromic Repeat/Cas9-mediated gene editi...

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Autores principales: Hu, Shuang, Du, Juan, Chen, Ningning, Jia, Ruixuan, Zhang, Jinlu, Liu, Xiaozhen, Yang, Liping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Association for Research in Vision and Ophthalmology 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401909/
https://www.ncbi.nlm.nih.gov/pubmed/32330228
http://dx.doi.org/10.1167/iovs.61.4.31
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author Hu, Shuang
Du, Juan
Chen, Ningning
Jia, Ruixuan
Zhang, Jinlu
Liu, Xiaozhen
Yang, Liping
author_facet Hu, Shuang
Du, Juan
Chen, Ningning
Jia, Ruixuan
Zhang, Jinlu
Liu, Xiaozhen
Yang, Liping
author_sort Hu, Shuang
collection PubMed
description PURPOSE: Retinitis pigmentosa GTPase regulator (RPGR)-related X-linked retinitis pigmentosa is associated with one of the most severe phenotypes among inherited retinal disease. The aim of this study was to investigate Clustered Regularly Interspaced Short Palindromic Repeat/Cas9-mediated gene editing therapy in a mouse model of Rpgr. METHODS: The Rpgr(−/y)Cas9(+/WT) male mice were used for this study. At 6 months of age, they received a single subretinal injection of adeno-associated virus vectors carrying sgRNA and donor template separately, and therapeutic effect was examined after 1, 6, and 12 months. RESULTS: Rpgr knockout mouse showed slow but progressive age-related retinal degeneration, which emulates the disease occurring in humans. Significant photoreceptor preservation was observed in the treated part of the retina, in sharp contrast to the untreated part of the retina in the same eye after 6 and 12 months. It was surprising that precise modification at the target locus as demonstrated by genomic DNA sequencing in the post-mitotic photoreceptor was observed. Moreover, the therapeutic effect lasts for up to 12 months and no off-target effects were shown. CONCLUSIONS: Our study strongly demonstrates that gene editing therapy is a promising therapeutic strategy to treat inherited retinal degeneration.
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spelling pubmed-74019092020-08-18 In Vivo CRISPR/Cas9-Mediated Genome Editing Mitigates Photoreceptor Degeneration in a Mouse Model of X-Linked Retinitis Pigmentosa Hu, Shuang Du, Juan Chen, Ningning Jia, Ruixuan Zhang, Jinlu Liu, Xiaozhen Yang, Liping Invest Ophthalmol Vis Sci Genetics PURPOSE: Retinitis pigmentosa GTPase regulator (RPGR)-related X-linked retinitis pigmentosa is associated with one of the most severe phenotypes among inherited retinal disease. The aim of this study was to investigate Clustered Regularly Interspaced Short Palindromic Repeat/Cas9-mediated gene editing therapy in a mouse model of Rpgr. METHODS: The Rpgr(−/y)Cas9(+/WT) male mice were used for this study. At 6 months of age, they received a single subretinal injection of adeno-associated virus vectors carrying sgRNA and donor template separately, and therapeutic effect was examined after 1, 6, and 12 months. RESULTS: Rpgr knockout mouse showed slow but progressive age-related retinal degeneration, which emulates the disease occurring in humans. Significant photoreceptor preservation was observed in the treated part of the retina, in sharp contrast to the untreated part of the retina in the same eye after 6 and 12 months. It was surprising that precise modification at the target locus as demonstrated by genomic DNA sequencing in the post-mitotic photoreceptor was observed. Moreover, the therapeutic effect lasts for up to 12 months and no off-target effects were shown. CONCLUSIONS: Our study strongly demonstrates that gene editing therapy is a promising therapeutic strategy to treat inherited retinal degeneration. The Association for Research in Vision and Ophthalmology 2020-04-24 /pmc/articles/PMC7401909/ /pubmed/32330228 http://dx.doi.org/10.1167/iovs.61.4.31 Text en Copyright 2020 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
spellingShingle Genetics
Hu, Shuang
Du, Juan
Chen, Ningning
Jia, Ruixuan
Zhang, Jinlu
Liu, Xiaozhen
Yang, Liping
In Vivo CRISPR/Cas9-Mediated Genome Editing Mitigates Photoreceptor Degeneration in a Mouse Model of X-Linked Retinitis Pigmentosa
title In Vivo CRISPR/Cas9-Mediated Genome Editing Mitigates Photoreceptor Degeneration in a Mouse Model of X-Linked Retinitis Pigmentosa
title_full In Vivo CRISPR/Cas9-Mediated Genome Editing Mitigates Photoreceptor Degeneration in a Mouse Model of X-Linked Retinitis Pigmentosa
title_fullStr In Vivo CRISPR/Cas9-Mediated Genome Editing Mitigates Photoreceptor Degeneration in a Mouse Model of X-Linked Retinitis Pigmentosa
title_full_unstemmed In Vivo CRISPR/Cas9-Mediated Genome Editing Mitigates Photoreceptor Degeneration in a Mouse Model of X-Linked Retinitis Pigmentosa
title_short In Vivo CRISPR/Cas9-Mediated Genome Editing Mitigates Photoreceptor Degeneration in a Mouse Model of X-Linked Retinitis Pigmentosa
title_sort in vivo crispr/cas9-mediated genome editing mitigates photoreceptor degeneration in a mouse model of x-linked retinitis pigmentosa
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401909/
https://www.ncbi.nlm.nih.gov/pubmed/32330228
http://dx.doi.org/10.1167/iovs.61.4.31
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