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

Wenhan Yu, Suddhasil Mookherjee, Vijender Chaitankar, Suja Hiriyanna, Jung-Woong Kim, Matthew Brooks, Yasaman Ataeijannati, Xun Sun, Lijin Dong, Tiansen Li, Anand Swaroop and Zhijian Wu ()
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Wenhan Yu: Ocular Gene Therapy Core, National Eye Institute, NIH
Suddhasil Mookherjee: Ocular Gene Therapy Core, National Eye Institute, NIH
Vijender Chaitankar: Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, NIH
Suja Hiriyanna: Ocular Gene Therapy Core, National Eye Institute, NIH
Jung-Woong Kim: Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, NIH
Matthew Brooks: Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, NIH
Yasaman Ataeijannati: Ocular Gene Therapy Core, National Eye Institute, NIH
Xun Sun: Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, NIH
Lijin Dong: Genetic Engineering Core, National Eye Institute, NIH
Tiansen Li: Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, NIH
Anand Swaroop: Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, NIH
Zhijian Wu: Ocular Gene Therapy Core, National Eye Institute, NIH

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14716

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