In vivo prime editing rescues photoreceptor degeneration in nonsense mutant retinitis pigmentosa
Abstract The next-generation gene editing tool, prime editing (PE), is adept at correcting point mutations precisely with high editing efficiency and rare off-target events and shows promising therapeutic value in treating hereditary diseases. Retinitis pigmentosa (RP) is the most common type of inh...
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| Format: | Article |
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Nature Portfolio
2025-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57628-6 |
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| author | Yidian Fu Xiaoyu He Liang Ma Xin D. Gao Pengpeng Liu Hanhan Shi Peiwei Chai Shengfang Ge Renbing Jia David R. Liu Xianqun Fan Zhi Yang |
| author_facet | Yidian Fu Xiaoyu He Liang Ma Xin D. Gao Pengpeng Liu Hanhan Shi Peiwei Chai Shengfang Ge Renbing Jia David R. Liu Xianqun Fan Zhi Yang |
| author_sort | Yidian Fu |
| collection | DOAJ |
| description | Abstract The next-generation gene editing tool, prime editing (PE), is adept at correcting point mutations precisely with high editing efficiency and rare off-target events and shows promising therapeutic value in treating hereditary diseases. Retinitis pigmentosa (RP) is the most common type of inherited retinal dystrophy and is characterized by progressive degeneration of retinal photoreceptors and, consequently, visual decline. To date, effective treatments for RP are lacking. Herein, a PE system is designed to target the PDE6B Y347X mutation in the rd1 mouse strain, a preclinical RP model. We screen and develop the PE system with epegRNA and RTΔRnH, which is delivered via dual-AAV in vivo with an editing efficiency of 26.47 ± 13.35%, with negligible off-target effects confirmed by AID-Seq and PE-tag. Treatment with the PE system in vivo greatly restores PDE6B protein expression and protects rod cells from degeneration. Mouse behavioural experiments also show that compared with no treatment, prime editing inhibits vision deterioration in littermate rd1 mice. This study provides a therapeutic opportunity for the use of PE to correct mutated RPs at the genomic level. |
| format | Article |
| id | doaj-art-48667b933eb84fb7b02f54561bb8ab3c |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-48667b933eb84fb7b02f54561bb8ab3c2025-08-20T02:56:16ZengNature PortfolioNature Communications2041-17232025-03-0116111610.1038/s41467-025-57628-6In vivo prime editing rescues photoreceptor degeneration in nonsense mutant retinitis pigmentosaYidian Fu0Xiaoyu He1Liang Ma2Xin D. Gao3Pengpeng Liu4Hanhan Shi5Peiwei Chai6Shengfang Ge7Renbing Jia8David R. Liu9Xianqun Fan10Zhi Yang11Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineMerkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MITInstitute of Advanced Biotechnology, Institute of Homeostatic Medicine, and School of Medicine, Southern University of Science and TechnologyDepartment of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineMerkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MITDepartment of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineAbstract The next-generation gene editing tool, prime editing (PE), is adept at correcting point mutations precisely with high editing efficiency and rare off-target events and shows promising therapeutic value in treating hereditary diseases. Retinitis pigmentosa (RP) is the most common type of inherited retinal dystrophy and is characterized by progressive degeneration of retinal photoreceptors and, consequently, visual decline. To date, effective treatments for RP are lacking. Herein, a PE system is designed to target the PDE6B Y347X mutation in the rd1 mouse strain, a preclinical RP model. We screen and develop the PE system with epegRNA and RTΔRnH, which is delivered via dual-AAV in vivo with an editing efficiency of 26.47 ± 13.35%, with negligible off-target effects confirmed by AID-Seq and PE-tag. Treatment with the PE system in vivo greatly restores PDE6B protein expression and protects rod cells from degeneration. Mouse behavioural experiments also show that compared with no treatment, prime editing inhibits vision deterioration in littermate rd1 mice. This study provides a therapeutic opportunity for the use of PE to correct mutated RPs at the genomic level.https://doi.org/10.1038/s41467-025-57628-6 |
| spellingShingle | Yidian Fu Xiaoyu He Liang Ma Xin D. Gao Pengpeng Liu Hanhan Shi Peiwei Chai Shengfang Ge Renbing Jia David R. Liu Xianqun Fan Zhi Yang In vivo prime editing rescues photoreceptor degeneration in nonsense mutant retinitis pigmentosa Nature Communications |
| title | In vivo prime editing rescues photoreceptor degeneration in nonsense mutant retinitis pigmentosa |
| title_full | In vivo prime editing rescues photoreceptor degeneration in nonsense mutant retinitis pigmentosa |
| title_fullStr | In vivo prime editing rescues photoreceptor degeneration in nonsense mutant retinitis pigmentosa |
| title_full_unstemmed | In vivo prime editing rescues photoreceptor degeneration in nonsense mutant retinitis pigmentosa |
| title_short | In vivo prime editing rescues photoreceptor degeneration in nonsense mutant retinitis pigmentosa |
| title_sort | in vivo prime editing rescues photoreceptor degeneration in nonsense mutant retinitis pigmentosa |
| url | https://doi.org/10.1038/s41467-025-57628-6 |
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