期刊
CELL REPORTS
卷 40, 期 2, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2022.111061
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类别
资金
- National Natural Science Foundation of China [31522025, 31571080, 81873703, 31861163003]
- China Ministry of Science and Technology [2021ZD0203304]
- Tsinghua-Peking Center for Life Sciences
- Open Collaborative Research Program of Chinese Institute for Brain Research [2020-NKX-XM-04]
This study discovers that nonhomologous end-joining mediated editing can compensate gene mutations and restore lost mechanotransduction function, which is of great significance for treating human nonsyndromic deafness.
Although frameshift mutations lead to 22% of inherited Mendelian disorders in humans, there is no efficient in vivo gene therapy strategy available to date, particularly in nondividing cells. Here, we show that nonhomologous end-joining (NHEJ)-mediated nonrandom editing profiles compensate the frameshift mutation in the Pcdh15 gene and restore the lost mechanotransduction function in postmitotic hair cells of Pcdh15(av-3J) mice, an animal model of human nonsyndromic deafness DFNB23. Identified by an ex vivo evaluation system in cultured cochlear explants, the selected guide RNA restores reading frame in approximately 50% of indel products and recovers mechanotransduction in more than 70% of targeted hair cells. In vivo treatment shows that half of the animals gain improvements in auditory responses, and balance function is restored in themajority of injected mutant mice. These results demonstrate that NHEJ-mediated reading-frame restoration is a simple and efficient strategy in postmitotic systems.
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