1. AAV-mediated gene therapy produces fertile offspring in the Lhcgr-deficient mouse model of Leydig cell failure
- Author
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Xia, Kai, Wang, Fulin, Lai, Xingqiang, Dong, Lin, Luo, Peng, Zhang, Suyuan, Yang, Cuifeng, Chen, Hong, Ma, Yuanchen, Huang, Weijun, Ou, Wangsheng, Li, Yuyan, Feng, Xin, Yang, Bin, Liu, Congyuan, Lei, Zhenmin, Tu, Xiang’an, Ke, Qiong, Mao, Frank Fuxiang, Deng, Chunhua, and Xiang, Andy Peng
- Abstract
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 Lhcgrexpression 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, this gene therapy partially recovers sexual development, substantially restores spermatogenesis, and effectively produces fertile offspring. Furthermore, these favorable effects can be reproduced in adult Lhcgr−/−mice. Our proof-of-concept experiments in the mouse model demonstrate that AAV-mediated gene therapy may represent a promising therapeutic approach for patients with LCF.
- Published
- 2022
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