Intravitreal AAV vector delivery induces integrin-dependent ocular inflammation, complement activation, and antiviral and DNA damage responses

Background: Intravitreal delivery of adeno-associated virus (AAV) vectors offers a promising, minimally invasive strategy for retinal gene therapy, but remains limited by dose-dependent intraocular inflammation. Corticosteroid therapy, the current standard for managing gene therapy-associated uveitis (GTAU), can be ineffective or contraindicated, highlighting the need for alternative immunomodulatory approaches and deeper understanding of AAV-induced inflammation. Methods: Using porcine and mice models, we characterized immune responses triggered by AAV2.7m8 vector. Results: DNA damage foci in transduced retinas. Finally, a mechanistic study of intravitreal AAV delivery in mice using integrin-blocking antibodies revealed a role for peripheral leukocytes in mediating ocular inflammation in this species. Conclusion: Our work identified new markers of ocular inflammation and potential targets to modulate GTAU.