CRISPR–Cas9 Genome Editing in Female Infertility: Molecular Targets, Therapeutic Applications and Future Perspectives

Abstract

Female infertility is a heterogenous clinical condition rooted in the interplay of genetic, endocrine, anatomical, and environmental factors. Variants responsible for failure of ovarian development, folliculogenesis, meiotic progression and early embryogenesis can lead to reproductive failure, whereas the highly complex genetic architectures of polycystic ovary syndrome and endometriosis have been suggested through this. CRISPR–Cas9 provides a flexible platform to investigate the mechanisms underlying these mechanisms via targeted gene disruption, sequence modification and control of expression. It is also advised that a molecular alteration ca be does not imply it is possible to regain fertility. This narrative review, reviews the controlling genetic factors of female infertility, the operating principles of older and newer CRISPR systems, and experimental uses in reproductive biology. Confirmed cases confirm gene-function analyses in human preimplantation embryos and epigenetic reloading of FMR1 in fragile X syndrome derived neurons, but these findings do not indicate ovarian rescue or better pregnancy results. Progression to the clinic is limited by tissue-specific delivery, inefficient or unpredictable DNA repair, mosaicism, off-target activity, and deleterious on-target chromosomal abberations. Base and prime editing may reduce the requirement for double-strand breaks, but introduce their own efficacy, specificity and delivery challenges. Heritable alterations also bring new ethical questions about consent, intergenerational risk, equitable access, and regulation. The immediate role of CRISPR in reproductive medicine will therefore be for disease modelling and functional validation, as opposed to mainstream medicine. Any future therapeutic intervention must demonstrate solid reproductive efficacy, be all-inclusive of the genome, and an ethically sound level of regulation.