biostudies-literatureXia KChinese Academy of SciencesGuangdong Special Support PlanNatural Science Foundation of Guangdong ProvinceNational Natural Science Foundation of ChinaSpecial Project for Research and Development in Key areas of Guangdong ProvinceNational Key Research and Development Program of China100792https://www.ebi.ac.uk/biostudies/studies/S-EPMC9729833biostudies-literatureUnknown3(11)Leydig cell failure (LCF) caused by gene mutation results in testosterone deficiency and infertility. Serum testosterone levels can be recovered via testosterone replacement; however, established therapies have shown limited success in restoring fertility. Here, we use a luteinizing hormone/choriogonadotrophin receptor (Lhcgr)-deficient mouse model of LCF to investigate the feasibility of gene therapy for restoring testosterone production and fertility. We screen several adeno-associated virus (AAV) serotypes and identify AAV8 as an efficient vector to drive exogenous Lhcgr expression in progenitor Leydig cells through interstitial injection. We observe considerable testosterone recovery and Leydig cell maturation after AAV8-Lhcgr treatment in pubertal Lhcgr^-/- mice. Of note, thCell reports. MedicineAAV-mediated gene therapy produces fertile offspring in the Lhcgr-deficient mouse model of Leydig cell failure.PMC97298332019B020235002819015142018YFA010720081730005819713142018YFA0801404XDA160207012022A1515010371817210038210166932130046821715642019BT02Y276Feng XKe QWang FDong LMa YYang BMao FFChen HZhang SYang CLai XDeng CXia KLi YLuo PLei ZHuang WOu WLiu CTu XXiang APfalseAAV-mediated gene therapy produces fertile offspring in the Lhcgr-deficient mouse model of Leydig cell failure.Leydig cell failure (LCF) caused by gene mutation results in testosterone deficiency and infertility. Serum testosterone levels can be recovered via testosterone replacement; however, established therapies have shown limited success in restoring fertility. Here, we use a luteinizing hormone/choriogonadotrophin receptor (Lhcgr)-deficient mouse model of LCF to investigate the feasibility of gene therapy for restoring testosterone production and fertility. We screen several adeno-associated virus (AAV) serotypes and identify AAV8 as an efficient vector to drive exogenous Lhcgr expression in progenitor Leydig cells through interstitial injection. We observe considerable testosterone recovery and Leydig cell maturation after AAV8-Lhcgr treatment in pubertal Lhcgr^-/- mice. Of note, th2022-01-01T00:00:00Z2022 Nov2026-07-14T15:56:37.078Z2024-12-04T03:11:33.517ZS-EPMC97298333627028510.1016/j.xcrm.2022.100792