title: Nrl knockdown by AAV-delivered CRISPR/Cas9 prevents retinal degeneration in mice.
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.
authors.affiliation: Ocular Gene Therapy Core, National Eye Institute, NIH, 6 Center Drive, Room 307, Bethesda, Maryland 20892, USA.
authors.forename: Wenhan
authors.identifier: 0000-0002-0125-4358
authors.initials: W
authors.lastname: Yu
authors.affiliation: Ocular Gene Therapy Core, National Eye Institute, NIH, 6 Center Drive, Room 307, Bethesda, Maryland 20892, USA.
authors.forename: Suddhasil
authors.initials: S
authors.lastname: Mookherjee
authors.affiliation: Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, NIH, 6 Center Drive, Room 307, Bethesda, Maryland 20892, USA.
authors.forename: Vijender
authors.initials: V
authors.lastname: Chaitankar
authors.affiliation: Ocular Gene Therapy Core, National Eye Institute, NIH, 6 Center Drive, Room 307, Bethesda, Maryland 20892, USA.
authors.forename: Suja
authors.initials: S
authors.lastname: Hiriyanna
authors.affiliation: Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, NIH, 6 Center Drive, Room 307, Bethesda, Maryland 20892, USA.
authors.forename: Jung-Woong
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, NIH, 6 Center Drive, Room 307, Bethesda, Maryland 20892, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Brooks
authors.affiliation: Ocular Gene Therapy Core, National Eye Institute, NIH, 6 Center Drive, Room 307, Bethesda, Maryland 20892, USA.
authors.forename: Yasaman
authors.initials: Y
authors.lastname: Ataeijannati
authors.affiliation: Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, NIH, 6 Center Drive, Room 307, Bethesda, Maryland 20892, USA.
authors.forename: Xun
authors.initials: X
authors.lastname: Sun
authors.affiliation: Genetic Engineering Core, National Eye Institute, NIH, 6 Center Drive, Room B102, Bethesda, Maryland 20892, USA.
authors.forename: Lijin
authors.initials: L
authors.lastname: Dong
authors.affiliation: Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, NIH, 6 Center Drive, Room 307, Bethesda, Maryland 20892, USA.
authors.forename: Tiansen
authors.identifier: 0000-0002-9537-2573
authors.initials: T
authors.lastname: Li
authors.affiliation: Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, NIH, 6 Center Drive, Room 307, Bethesda, Maryland 20892, USA.
authors.forename: Anand
authors.identifier: 0000-0002-1975-1141
authors.initials: A
authors.lastname: Swaroop
authors.affiliation: Ocular Gene Therapy Core, National Eye Institute, NIH, 6 Center Drive, Room 307, Bethesda, Maryland 20892, USA.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Wu
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics*; D064113:CRISPR-Cas Systems; D002470:Cell Survival / Q000235:genetics*; D000229:Dependovirus; D005136:Eye Proteins / Q000235:genetics*; D000072669:Gene Editing / Q000379:methods; D055785:Gene Knockdown Techniques; D051379:Mice; D017949:Retinal Cone Photoreceptor Cells / Q000166:cytology / Q000378:metabolism*; D012162:Retinal Degeneration / Q000235:genetics*; D017948:Retinal Rod Photoreceptor Cells / Q000166:cytology / Q000378:metabolism*; D012174:Retinitis Pigmentosa / Q000235:genetics
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D005136:Eye Proteins; C084884:Nrl protein, mouse