Retinitis pigmentosa (RP) is an inherited retinal dystrophy causing progressive and irreversible loss of retinal photoreceptors. Here, we developed a genome-editing tool characterized by the versatility of prime editors (PEs) and unconstrained PAM requirement of a SpCas9 variant (SpRY), referred to as PESpRY. The diseased retinas of Pde6b-associated RP mouse model were transduced via a dual AAV system packaging PESpRY for the in vivo genome editing through a non-NGG PAM (GTG). The progressing cell loss was reversed once the mutation was corrected, leading to substantial rescue of photoreceptors and production of functional PDE6β. The treated mice exhibited significant responses in electroretinogram and displayed good performance in both passive and active avoidance tests. Moreover, they presented an apparent improvement in visual stimuli-driven optomotor responses and efficiently completed visually guided water-maze tasks. Together, our study provides convincing evidence for the prevention of vision loss caused by RP-associated gene mutations via unconstrained in vivo prime editing in the degenerating retinas.
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1 May 2023
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March 17 2023
Vision rescue via unconstrained in vivo prime editing in degenerating neural retinas
Huan Qin
,
Huan Qin
*
(Conceptualization, Formal analysis, Investigation)
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
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Wenliang Zhang
,
Wenliang Zhang
*
(Conceptualization, Formal analysis, Investigation)
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
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Shiyao Zhang
,
Shiyao Zhang
*
(Investigation)
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
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Yuan Feng
,
Yuan Feng
*
(Formal analysis)
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
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Weihui Xu
,
Weihui Xu
(Investigation)
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
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Jia Qi
,
Jia Qi
(Investigation)
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
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Qian Zhang
,
Qian Zhang
(Investigation)
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
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Chunxiu Xu
,
Chunxiu Xu
(Investigation)
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
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Shanshan Liu
,
Shanshan Liu
(Investigation)
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
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Jia Zhang
,
Jia Zhang
(Investigation)
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
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Yushuang Lei
,
Yushuang Lei
(Investigation)
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
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Wanqin Liu
,
Wanqin Liu
(Investigation)
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
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Shuyu Feng
,
Shuyu Feng
(Investigation)
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
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Jingjing Wang
,
Jingjing Wang
(Investigation)
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
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Xuefei Fu
,
Xuefei Fu
(Formal analysis)
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
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Zifen Xu
,
Zifen Xu
(Investigation)
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
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Ping Li
,
Ping Li
(Investigation)
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
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Kai Yao
(Conceptualization, Funding acquisition, Project administration, Supervision, Visualization, Writing - original draft)
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
Correspondence to Kai Yao: kyao21@outlook.com
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1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
Wenliang Zhang
Conceptualization, Formal analysis, Investigation
*
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
Weihui Xu
Investigation
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
Jia Qi
Investigation
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
Qian Zhang
Investigation
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
Chunxiu Xu
Investigation
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
Shanshan Liu
Investigation
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
Jia Zhang
Investigation
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
Yushuang Lei
Investigation
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
Wanqin Liu
Investigation
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
Shuyu Feng
Investigation
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
Jingjing Wang
Investigation
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
Xuefei Fu
Formal analysis
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
Zifen Xu
Investigation
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
Ping Li
Investigation
1
Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology
, Wuhan, China
Correspondence to Kai Yao: kyao21@outlook.com
*
H. Qin, W. Zhang, S. Zhang, and Y. Feng contributed equally to this paper.
Disclosures: The authors declare no competing interests exist.
Received:
May 04 2022
Revision Received:
December 23 2022
Accepted:
February 08 2023
Online ISSN: 1540-9538
Print ISSN: 0022-1007
Funding
Funder(s):
National Natural Science Foundation of China
- Award Id(s): No. 31970930,No. 32100936
Funder(s):
Hubei Natural Science Foundation
- Award Id(s): No. 2020CFA069,No. 2018CFB434
Funder(s):
Wuhan University of Science and Technology
- Award Id(s): No. 1180002
© 2023 Qin et al.
2023
Qin et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Exp Med (2023) 220 (5): e20220776.
Article history
Received:
May 04 2022
Revision Received:
December 23 2022
Accepted:
February 08 2023
Connected Content
Commentary
Eye on genome editing
Citation
Huan Qin, Wenliang Zhang, Shiyao Zhang, Yuan Feng, Weihui Xu, Jia Qi, Qian Zhang, Chunxiu Xu, Shanshan Liu, Jia Zhang, Yushuang Lei, Wanqin Liu, Shuyu Feng, Jingjing Wang, Xuefei Fu, Zifen Xu, Ping Li, Kai Yao; Vision rescue via unconstrained in vivo prime editing in degenerating neural retinas. J Exp Med 1 May 2023; 220 (5): e20220776. doi: https://doi.org/10.1084/jem.20220776
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