期刊
SCIENCE ADVANCES
卷 5, 期 4, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aav3335
关键词
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资金
- Major Program of the National Natural Science Foundation of China [81790644]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDA16020603, XDPB10, XDBS01060200]
- National Natural Science Foundation of China [31322024, 31625013, 91732302, 31601134, 31600826, 81527901, 61727811, 91748212]
- National Key Basic Research Program of China [2016YFA0400900]
- National Young Scientists 973 Program of China [2013CB967700]
- Shanghai Brain-Intelligence Project from STCSM [16JC1420501]
- Shanghai Municipal Science and Technology Major Project [2018SHZDZX05]
- Program of Shanghai Academic Research Leader [9XD1404300]
- Anhui Provincial Natural Science Foundation [1808085MH289, 1708085QC57]
- Open Large Infrastructure Research of the Chinese Academy of Sciences
Although Cas9-mediated genome editing has been widely used to engineer alleles in animal models of human inherited diseases, very few homology-directed repair (HDR)-based genetic editing systems have been established in postnatal mouse models for effective and lasting phenotypic rescue. Here, we developed an HDR-based Cas9/RecA system to precisely correct Pde6b mutation with increased HDR efficiency in postnatal rodless (rd1) mice, a retinitis pigmentosa (RP) mutant model characterized by photoreceptor degeneration and loss of vision. The Cas9/RecA system incorporated Cas9 endonuclease enzyme to generate double-strand breaks (DSBs) and bacterial recombinase A (RecA) to increase homologous recombination. Our data revealed that Cas9/RecA treatment significantly promoted the survival of both rod and cone photoreceptors, restored the expression of PDE6B in rod photoreceptors, and enhanced the visual functions of rd1 mice. Thus, this study provides a precise therapeutic strategy for RP and other genetic diseases.
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