Related Experiment Video
Updated: Mar 6, 2026
Adeno-Associated Virus-Mediated Delivery of CRISPR for Cardiac Gene Editing in Mice
Published on: August 2, 2018
Nrl knockdown by AAV-delivered CRISPR/Cas9 prevents retinal degeneration in mice
Wenhan Yu1, Suddhasil Mookherjee1, Vijender Chaitankar2
1Ocular Gene Therapy Core, National Eye Institute, NIH, 6 Center Drive, Room 307, Bethesda, Maryland 20892, USA.
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.
Insights
Gene editing using CRISPR/Cas9 successfully preserved cone photoreceptor function in mouse models of retinitis pigmentosa. This approach targets the NRL gene in rod cells, improving their survival and preventing secondary cone loss.
Area of Science:
- Ophthalmology
- Genetics
- Molecular Biology
Background:
- Retinitis pigmentosa causes blindness through cone photoreceptor loss, often secondary to rod degeneration.
- Preserving cone function is a critical therapeutic objective for retinitis pigmentosa.
Purpose of the Study:
- To investigate a genome editing strategy targeting the Neural retina-specific leucine zipper protein (Nrl) gene in rod photoreceptors.
- To determine if disrupting Nrl can prevent secondary cone degeneration and preserve vision in models of retinitis pigmentosa.
Main Methods:
- Adeno-associated virus (AAV)-mediated delivery of CRISPR/Cas9 to photoreceptors in mouse models.
- Targeting the Nrl gene, a key determinant of rod cell fate.
- Evaluating rod survival and cone function following Nrl disruption.
Main Results:
- Disruption of the Nrl gene led to rods acquiring partial cone features and enhanced survival.
- The treatment prevented secondary cone degeneration in the presence of rod-specific mutations.
- Significant improvement in rod survival and preservation of cone function was observed in three distinct mouse models.
Conclusions:
- CRISPR/Cas9-mediated Nrl disruption in rods shows potential for treating retinitis pigmentosa.
- This approach offers a promising strategy to prevent vision loss by enhancing rod survival and protecting cones.
