AAV9 Gene Therapy for Ovarian Dysfunction and Reproductive Aging: Molecular Mechanisms, Therapeutic Targets, and Translational Perspectives.

Female infertility is a growing concern in developed countries as delayed childbearing and ovarian dysfunction become more common. Ovarian decline is characterized by follicular depletion, granulosa cell dysfunction, aneuploidy, spindle assembly defects, mitochondrial damage, DNA damage, telomere shortening, stromal remodeling, and cellular senescence. Current approaches (hormonal therapy, assisted reproductive technologies, platelet-rich plasma, stem cells, extracellular vesicles, and mitochondrial-targeted treatments) offer partial benefit but do not directly correct the molecular drivers of ovarian dysfunction. Gene therapy via viral vectors offers a more direct strategy. Adeno-associated virus serotype 9 (AAV9) is attractive for its broad tropism, long-term transgene expression, favorable safety profile, and evidence of ovarian somatic cell transduction, particularly in granulosa and interstitial cells. It remains experimental, however, and requires rigorous evaluation of biodistribution, immune response, off-target effects, germline safety, embryo development, offspring health, and tumorigenic risk. This review summarizes the mechanisms of ovarian dysfunction, current therapeutic limitations, AAV9's advantages, delivery routes, candidate genes, and translational safety concerns.