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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Wenhan Yu & Suddhasil Mookherjee & Vijender Chaitankar & Suja Hiriyanna & Jung-Woong Kim & Matthew Brooks & Yasaman Ataeijannati & Xun Sun & Lijin Dong & Tiansen Li & Anand Swaroop & Zhijian Wu, 2017. "Nrl knockdown by AAV-delivered CRISPR/Cas9 prevents retinal degeneration in mice," Nature Communications, Nature, vol. 8(1), pages 1-15, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14716
    DOI: 10.1038/ncomms14716
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