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

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 ade...

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Veröffentlicht in:Nature communications Jg. 8; H. 1; S. 14716 - 15
Hauptverfasser: Yu, Wenhan, Mookherjee, Suddhasil, Chaitankar, Vijender, Hiriyanna, Suja, Kim, Jung-Woong, Brooks, Matthew, Ataeijannati, Yasaman, Sun, Xun, Dong, Lijin, Li, Tiansen, Swaroop, Anand, Wu, Zhijian
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 14.03.2017
Nature Publishing Group
Nature Portfolio
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Animals
Basic-Leucine Zipper Transcription Factors - genetics
Cell Survival - genetics
CRISPR
CRISPR-Cas Systems
Dependovirus
Disease
Eye Proteins - genetics
Gene Editing - methods
Gene Knockdown Techniques
Genes
Genetic engineering
Genomes
Humanities and Social Sciences
Kinases
Mice
multidisciplinary
Mutation
Neurosciences
Photoreception
Photoreceptors
Retina
Retinal Cone Photoreceptor Cells - cytology
Retinal Cone Photoreceptor Cells - metabolism
Retinal Degeneration - genetics
Retinal Rod Photoreceptor Cells - cytology
Retinal Rod Photoreceptor Cells - metabolism
Retinitis Pigmentosa - genetics
RNA polymerase
Science
Science (multidisciplinary)
Visual acuity
United States > US
Maryland
ISSN:2041-1723, 2041-1723
Online-Zugang:Volltext
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Zusammenfassung: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. Retinitis pigmentosa is mainly caused by mutations that initially affect survival of rod photoreceptors, leading to secondary loss of cones. Here the authors use gene editing to prevent rod degeneration, leading to survival of cones and improved vision in mice.
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ISSN:2041-1723
2041-1723
DOI:10.1038/ncomms14716