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Nat Commun. 2017 Mar 14;8:14716. doi: 10.1038/ncomms14716.

Nrl knockdown by AAV-delivered CRISPR/Cas9 prevents retinal degeneration in mice.

Author information

1
Ocular Gene Therapy Core, National Eye Institute, NIH, 6 Center Drive, Room 307, Bethesda, Maryland 20892, USA.
2
Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, NIH, 6 Center Drive, Room 307, Bethesda, Maryland 20892, USA.
3
Genetic Engineering Core, National Eye Institute, NIH, 6 Center Drive, Room B102, Bethesda, Maryland 20892, USA.

Abstract

In retinitis pigmentosa, loss of cone photoreceptors leads to blindness, and preservation of cone function is a major therapeutic goal. However, cone loss is thought to occur as a secondary event resulting from degeneration of rod photoreceptors. Here we report a genome editing approach in which adeno-associated virus (AAV)-mediated CRISPR/Cas9 delivery to postmitotic photoreceptors is used to target the Nrl gene, encoding for Neural retina-specific leucine zipper protein, a rod fate determinant during photoreceptor development. Following Nrl disruption, rods gain partial features of cones and present with improved survival in the presence of mutations in rod-specific genes, consequently preventing secondary cone degeneration. In three different mouse models of retinal degeneration, the treatment substantially improves rod survival and preserves cone function. Our data suggest that CRISPR/Cas9-mediated NRL disruption in rods may be a promising treatment option for patients with retinitis pigmentosa.

PMID:
28291770
PMCID:
PMC5355895
DOI:
10.1038/ncomms14716
[Indexed for MEDLINE]
Free PMC Article

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