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Abstract

Volume 23, Issue 6 (November 2021) 23, 590–599; 10.4103/aja.aja_97_20

Rescue of male infertility through correcting a genetic mutation causing meiotic arrest in spermatogonial stem cells

Ying-Hua Wang1, Meng Yan1, Xi Zhang2, Xin-Yu Liu1, Yi-Fu Ding1, Chong-Ping Lai1, Ming-Han Tong2, Jin-Song Li1,3,4

1 State Key Laboratory of Cell Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
2 State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China
3 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
4 School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China

Correspondence: Dr. MH Tong (minghan@sibcb.ac.cn) or Dr. JS Li (jsli@sibcb.ac.cn)

Date of Submission 08-Oct-2020 Date of Acceptance 02-Dec-2020 Date of Web Publication 02-Feb-2021

Abstract

Azoospermia patients who carry a monogenetic mutation that causes meiotic arrest may have their biological child through genetic correction in spermatogonial stem cells (SSCs). However, such therapy for infertility has not been experimentally investigated yet. In this study, a mouse model with an X-linked testis-expressed 11 (TEX11) mutation (Tex11PM/Y) identified in azoospermia patients exhibited meiotic arrest due to aberrant chromosome segregation. Tex11PM/Y SSCs could be isolated and expanded in vitro normally, and the mutation was corrected by clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated endonuclease 9 (Cas9), leading to the generation of repaired SSC lines. Whole-genome sequencing demonstrated that the mutation rate in repaired SSCs is comparable with that of autonomous mutation in untreated Tex11PM/Y SSCs, and no predicted off-target sites are modified. Repaired SSCs could restore spermatogenesis in infertile males and give rise to fertile offspring at a high efficiency. In summary, our study establishes a paradigm for the treatment of male azoospermia by combining in vitro expansion of SSCs and gene therapy.

Keywords: azoospermia; gene therapy; male infertility; meiotic arrest; spermatogonial stem cells; testis-expressed 11

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