Adeno-associated-virus-mediated gene delivery to ovaries restores fertility in congenital infertile mice

Oocytes and granulosa cells closely interact with each other during follicular development, and a lack of appropriate signaling between them results in infertility. Attempts to manipulate oocyte microenvironment have been impeded by the impermeability of the blood-follicle barrier (BFB). To establish a strategy for manipulating oogenesis, we use adeno-associated viruses (AAVs), which have a unique ability of transcytosis. Microinjecting of AAVs into the ovarian stroma penetrates the BFB and achieves long-term gene expression. Introduction of an AAV carrying the mouse Kitl gene restores oogenesis in congenitally infertile Kitl(Sl-t)/Kitl(Sl-t) mutant mouse ovaries, which lack Kitl expression but contain only primordial follicles. Healthy offspring without AAV integration are born by natural mating. Therefore, AAV-mediated gene delivery not only provides a means for studying oocyte-granulosa interactions through the manipulation of the oocyte microenvironment but could also be a powerful method to treat female infertility resulting from somatic cell defects.