Rescue of Male Infertility through Correcting a Genetic Mutation Causing Meiotic arrest in Spermatogonial Stem Cells [WGS]

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 X-linked TEXT11 mutation (Tex11PM/Y) identified in azoospermia patients exhibited meiotic arrest due to aberrant chromosome segregation. Text11PM/Y SSCs could be isolated and expanded in vitro normally and the mutation was corrected by CRISPR-Cas9, leading to generation of repaired SSC lines. Whole-genome sequencing demonstrated that mutation rate in repaired SSCs are comparable with autonomous mutation in untreated Text11PM/Y SSCs, and no predicted off-target sites are modified. Repaired SSCs could restore spermatogenesis in infertility 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. Whole genome sequencing (WGS) analysis of the corrected SSCs