Background: Severe terato-asthenozoospermia is frequently driven by pathogenic variants in flagellar and acrosomal genes (e.g., DNAH1, CFAP43/44, DPY19L2, CATSPER) and is associated with high sperm DNA fragmentation and embryo-level abnormalities, including aneuploidy.

Objective: To outline a translational framework in which CRISPR-Cas9 correction of validated paternal mutations—preferably in autologous spermatogonial stem cells (SSCs)—could mitigate abnormal embryogenesis and improve IVF/ICSI outcomes, while remaining compliant with current ethical and legal constraints.

Approach: We summarize evidence that ex vivo editing of SSCs can restore spermatogenesis and yield healthy offspring in preclinical models, supporting feasibility for disorders caused by single-gene defects that underlie severe sperm morphology and motility phenotypes. Key feasibility readouts include on-target efficacy, off-target/mosaicism profiling, restoration of normal sperm ultrastructure/motility, and downstream embryo quality (blastulation and euploidy rates) after assisted reproduction.

Anticipated Impact: If safety and efficacy thresholds are met, paternal gene correction could reduce embryo arrest and aneuploidy in couples with genetically mediated male-factor infertility, complementing existing selection and testing strategies. Emerging clinical data linking sperm DNA fragmentation to higher embryo aneuploidy underscores the potential utility of upstream, mutation-level interventions.

Ethics/Regulation: Clinical heritable human genome editing remains prohibited; South Africa’s National Health Research Ethics Council has clarified that neither the National Health Act nor the 2024 ethics guidelines legalise HHGE for therapy, and subsequent guidance has moved to further temper permissive interpretations. Internationally, the ISSCR classifies implantation of gene-edited embryos as currently unsafe or ethically unresolved. Any near-term application should focus on preclinical work and tightly regulated, non-implantation research pathways.

Conclusion: CRISPR-Cas9–enabled correction of paternal mutations—particularly via SSC-based strategies—represents a plausible future avenue to decrease abnormal embryo formation in severe sperm morphology and motility disorders. Rigorous preclinical validation, robust genomic safety assessment, and adherence to evolving national and international governance are essential precursors to any clinical translation.

J.E. Moloi is a Fertility Specialist and Gynaecology Endoscopist at the Joburg Fertility Centre (JFC), a prominent clinic in Johannesburg, South Africa.