UMMS Affiliation

Department of Ophthalmology

Publication Date


Document Type



Amino Acids, Peptides, and Proteins | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Enzymes and Coenzymes | Eye Diseases | Genetics and Genomics | Molecular and Cellular Neuroscience | Nucleic Acids, Nucleotides, and Nucleosides | Ophthalmology | Translational Medical Research


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.


genome editing, retina, neurons, mouse model, endonucleases

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Copyright 2018 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (

DOI of Published Version



Transl Res. 2019 Jan;203:57-72. doi: 10.1016/j.trsl.2018.08.006. Epub 2018 Aug 24. Link to article on publisher's site

Journal/Book/Conference Title

Translational research : the journal of laboratory and clinical medicine

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Link to Article in PubMed

PubMed ID


Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.