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

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

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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors / genetics*
  • CRISPR-Cas Systems
  • Cell Survival / genetics*
  • Dependovirus
  • Eye Proteins / genetics*
  • Gene Editing / methods
  • Gene Knockdown Techniques
  • Mice
  • 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

Substances

  • Basic-Leucine Zipper Transcription Factors
  • Eye Proteins
  • Nrl protein, mouse