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Adeno\u2010associated virus serotype 8 (AAV8)\u2010mediated gene therapy shows potential in treating LCF in the Lhcgr\u2010deficient (<jats:italic>Lhcgr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>) mouse model. However, the gene\u2010treated mice still cannot naturally sire offspring, indicating the modestly restored testosterone and spermatogenesis in AAV8\u2010treated mice remain insufficient to support natural fertility. Recognizing this, we propose that enhancing gene delivery could yield superior results. Here, we screened a panel of AAV serotypes through in vivo transduction of mouse testes and identified AAVDJ as an impressively potent vector for testicular cells. Intratesticular injection of AAVDJ achieved markedly efficient transduction of Leydig cell progenitors, marking a considerable advance over conventional AAV8 vectors. AAVDJ\u2010Lhcgr gene therapy was well tolerated and resulted in significant recovery of testosterone production, substantial improvement in sexual development, and remarkable restoration of spermatogenesis in <jats:italic>Lhcgr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice. Notably, this therapy restored fertility in <jats:italic>Lhcgr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice through natural mating, enabling the birth of second\u2010generation. Additionally, this treatment led to remarkable improvements in adipose, muscle, and bone function in <jats:italic>Lhcgr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice. Collectively, our findings underscore AAVDJ\u2010mediated gene therapy as a promising strategy for LCF and suggest its broader potential in addressing various reproductive disorders.<\/jats:p>","DOI":"10.1111\/cpr.13680","type":"journal-article","created":{"date-parts":[[2024,5,31]],"date-time":"2024-05-31T06:40:02Z","timestamp":1717137602000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["<scp>AAV<\/scp>\u2010mediated gene therapy restores natural fertility and improves physical function in the <i>Lhcgr<\/i>\u2010deficient mouse model of <scp>Leydig<\/scp> cell failure"],"prefix":"10.1111","volume":"57","author":[{"given":"Suyuan","family":"Zhang","sequence":"first","affiliation":[{"name":"Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat\u2010sen University  Guangzhou Guangdong China"},{"name":"National\u2010Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat\u2010sen University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Yang","sequence":"additional","affiliation":[{"name":"Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat\u2010sen University  Guangzhou Guangdong China"},{"name":"National\u2010Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat\u2010sen University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoting","family":"Shen","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Center, The First Affiliated Hospital, Sun Yat\u2010sen University, The Key Laboratory for Reproductive Medicine of Guangdong Province  Guangzhou Guangdong 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Yat\u2010sen University  Guangzhou Guangdong China"},{"name":"National\u2010Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat\u2010sen University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Peng","sequence":"additional","affiliation":[{"name":"Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat\u2010sen University  Guangzhou Guangdong China"},{"name":"National\u2010Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat\u2010sen University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Luo","sequence":"additional","affiliation":[{"name":"Reproductive Medicine Center, The First Affiliated Hospital, Sun Yat\u2010sen University, The Key Laboratory for 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