Schlegel, J. and Hoffmann, J. and Röll, D. and Müller, B. and Günther, S. and Zhang, W. and Janise, A. and Vössing, Christine and Fühler, B. and Neidhardt, John and Khanna , H. and Lorenz, B. and Stieger, K. (2019) Toward genome editing in X-linked RP: development of a mouse model with specific treatment relevant features. Translational research, 203. pp. 57-72. ISSN 1878-1810

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Abstract Genome editing represents a powerful tool to treat inherited disorders. Highly specific endonucleases induce a DNA double strand break near the mutant site, which is subsequently repaired by cellular DNA repair mechanisms that involve the presence of a wild type template DNA. In vivo applications of this strategy are still rare, in part due to the absence of appropriate animal models carrying human disease mutations and knowledge of the efficient targeting of endonucleases. Here we report the generation and characterization of a new mouse model for X-linked retinitis pigmentosa (XLRP) carrying a point mutation in the mutational hotspot exon ORF15 of the RPGR gene as well as a recognition site for the homing endonuclease I-SceI. Presence of the genomic modifications was verified at the RNA and protein levels. The mutant protein was observed at low levels. Optical coherence tomography studies revealed a slowly progressive retinal degeneration with photoreceptor loss starting at 9 months of age, paralleling the onset of functional deficits as seen in the electroretinogram. Early changes to the outer retinal bands can be used as biomarker during treatment applications. We further show for the first time efficient targeting using the I-SceI enzyme at the genomic locus in a proof of concept in photoreceptors following adeno-associated virus mediated gene transfer in vivo. Taken together, our studies not only provide a human-XLRP disease model but also act as a platform to design genome editing technology for retinal degenerative diseases using the currently available endonucleases.

Item Type: Article
Subjects: Technology, medicine, applied sciences > Medicine and health
Divisions: Faculty of Medicine and Health Sciences > Department of Human Medicine
Date Deposited: 12 Mar 2020 11:25
Last Modified: 12 Mar 2020 11:25
URN: urn:nbn:de:gbv:715-oops-44401
DOI: 10.1016/j.trsl.2018.08.006

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