Self-Limiting AAV-Mediated FGF7 Expression Promoters Re-epithelialization and Accelerates Cutaneous Wound Healing

The skin serves as a vital barrier against external damage. Severe wounds, particularly chronic ones, compromise this barrier, which can result in infection, pain, disfigurement and life-threatening complications. However, there are limited pharmacological interventions that can substantially enhance wound healing. Gene therapy offers a promising strategy by enabling the sustained local expression of therapeutic factors. In this study, we demonstrate that the AAV-DJ vector efficiently delivers genes to dermal cells, where transgene expression exhibits a self-limiting profile characterized by robust expression during wound healing, followed by a rapid decline after cell proliferation and wound closure. Furthermore, we show that AAV-mediated delivery of the fibroblast growth factors Fgf1, Fgf2 and Fgf7 (KGF) significantly accelerates wound closure, with Fgf7 having the most pronounced effect. Mechanistically, dermally expressed FGF7 promotes keratinocyte proliferation and migration in a paracrine manner, thereby enhancing re-epithelialization. Furthermore, the downstream factor SFN (Stratifin, 14-3-3σ) was identified as a partial mediator of the pro-healing effects of FGF7. Taken together, these results demonstrate the efficacy and safety of AAV-mediated gene delivery in promoting wound healing and provide a foundation for extending gene therapy applications to other skin disorders.