AAV‐mediated gene therapy restores natural fertility and improves physical function in the Lhcgr‐deficient mouse model of Leydig cell failure

Author:

Zhang Suyuan12,Yang Bin12,Shen Xiaoting3,Chen Hong45,Wang Fulin6,Tan Zhipeng12,Ou Wangsheng7,Yang Cuifeng6,Liu Congyuan12,Peng Hao12,Luo Peng36,Peng Limei12,Lei Zhenmin8,Yan Sunxing9,Wang Tao12,Ke Qiong12,Deng Chunhua6,Xiang Andy Peng12ORCID,Xia Kai12ORCID

Affiliation:

1. Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat‐sen University Guangzhou Guangdong China

2. National‐Local Joint Engineering Research Center for Stem Cells and Regenerative Medicine, Zhongshan School of Medicine, Sun Yat‐sen University Guangzhou Guangdong China

3. Reproductive Medicine Center, The First Affiliated Hospital, Sun Yat‐sen University, The Key Laboratory for Reproductive Medicine of Guangdong Province Guangzhou Guangdong China

4. Center for Stem Cells Translational Medicine, Shenzhen Qianhai Shekou Free Trade Zone Hospital Shenzhen Guangdong China

5. Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences Shenzhen Guangdong China

6. Department of Urology and Andrology The First Affiliated Hospital, Sun Yat‐sen University Guangzhou Guangdong China

7. State Key Laboratory of Ophthalmology, Zhong Shan Ophthalmic Center, Sun Yat‐sen University Guangzhou Guangdong China

8. Department of OB/GYN and Women's Health University of Louisville School of Medicine Louisville Kentucky USA

9. Guangzhou Cellgenes Biotechnology Co., Ltd. Guangzhou Guangdong China

Abstract

AbstractLeydig cell failure (LCF) caused by gene mutations leads to testosterone deficiency, infertility and reduced physical function. Adeno‐associated virus serotype 8 (AAV8)‐mediated gene therapy shows potential in treating LCF in the Lhcgr‐deficient (Lhcgr−/−) mouse model. However, the gene‐treated mice still cannot naturally sire offspring, indicating the modestly restored testosterone and spermatogenesis in AAV8‐treated 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‐Lhcgr gene therapy was well tolerated and resulted in significant recovery of testosterone production, substantial improvement in sexual development, and remarkable restoration of spermatogenesis in Lhcgr−/− mice. Notably, this therapy restored fertility in Lhcgr−/− mice through natural mating, enabling the birth of second‐generation. Additionally, this treatment led to remarkable improvements in adipose, muscle, and bone function in Lhcgr−/− mice. Collectively, our findings underscore AAVDJ‐mediated gene therapy as a promising strategy for LCF and suggest its broader potential in addressing various reproductive disorders.

Funder

Basic and Applied Basic Research Foundation of Guangdong Province

National Key Research and Development Program of China

Natural Science Foundation of Guangdong Province

National Natural Science Foundation of China

Special Project for Research and Development in Key areas of Guangdong Province

Publisher

Wiley

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