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Genetically corrected stem Leydig cells (SLCs) transplantation may provide a new approach for treating HPH. Here, a novel nonsense\u2010point\u2010mutation mouse model (<jats:italic>Lhcgr<\/jats:italic><jats:sup>W495X<\/jats:sup>) is first generated based on a gene mutation relative to HPH patients. To verify the efficacy and feasibility of SLCs transplantation in treating HPH, wild\u2010type SLCs are transplanted into <jats:italic>Lhcgr<\/jats:italic><jats:sup>W495X<\/jats:sup> mice, in which SLCs obviously rescue HPH phenotypes. Through comparing several editing strategies, optimized PE2 protein (PEmax) system is identified as an efficient and precise approach to correct the pathogenic point mutation in <jats:italic>Lhcgr<\/jats:italic>. Furthermore, delivering intein\u2010split PEmax system via lentivirus successfully corrects the mutation in SLCs from <jats:italic>Lhcgr<\/jats:italic><jats:sup>W495X<\/jats:sup> mice <jats:italic>ex vivo<\/jats:italic>. Gene\u2010corrected SLCs from <jats:italic>Lhcgr<\/jats:italic><jats:sup>W495X<\/jats:sup> mice exert ability to differentiate into functional Leydig cells in vitro. Notably, the transplantation of gene\u2010corrected SLCs effectively regenerates Leydig cells, recovers testosterone production, restarts sexual development, rescues spermatogenesis, and produces fertile offspring in <jats:italic>Lhcgr<\/jats:italic><jats:sup>W495X<\/jats:sup> mice. Altogether, these results suggest that PE\u2010based gene editing in SLCs ex vivo is a promising strategy for HPH therapy and is potentially leveraged to address more hereditary diseases in reproductive system.<\/jats:p>","DOI":"10.1002\/advs.202300993","type":"journal-article","created":{"date-parts":[[2023,9,12]],"date-time":"2023-09-12T01:15:10Z","timestamp":1694481310000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Precise Correction of <i>Lhcgr<\/i> Mutation in Stem Leydig Cells by Prime Editing Rescues Hereditary Primary Hypogonadism in Mice"],"prefix":"10.1002","volume":"10","author":[{"given":"Kai","family":"Xia","sequence":"first","affiliation":[{"name":"Center for Stem Cell Biology and Tissue Engineering Key Laboratory for Stem Cells and Tissue Engineering Ministry of Education National\u2010Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine Zhongshan School of Medicine 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