Pre-existing retinal inflammation exacerbates gene therapy-associated uveitis in more rapidly progressive retinal degeneration

Inherited retinal diseases (IRDs) are often associated with signs of low-grade intraocular inflammation. With gene therapy-associated uveitis (GTAU) being recognized as a critical determinant of the efficacy of retinal gene therapies for IRDs, it is unclear whether such background inflammation might compound any immune response to viral vectors. We explored the immunological state of the retinas of Rpgr −/y mice as a model of slow-progressive retinitis pigmentosa (RP) and Rho P23H mice as a model of rapid-progressive RP utilizing multicolor flow cytometry. We subsequently assessed the cellular immune response to subretinal adeno-associated virus (AAV) gene therapy in these mouse models versus age-matched wild-type controls. Rho P23H mice exhibit increased immune cells within the retina, suggesting a degree of blood-retinal barrier breakdown, while Rpgr −/y retina remained immunologically quiescent. Subretinal gene augmentation therapy with clinically relevant AAV vectors resulted in a Th1 cell-mediated immune response in both models, but significantly greater immune cell infiltration was seen in Rho P23H retinas while the response in Rpgr −/y mirrored that of wild-type controls. Our findings indicate that background immunological changes in rapid retinal degeneration could compound the immune response to gene therapy, thus leading to clinically significant GTAU. Rapid retinal degeneration in mice heightens immune activity in the eye, worsening inflammation triggered by gene therapy. Milder disease shows little added immune response. These findings suggest that existing retinal inflammation may amplify immune reactions to viral gene delivery, potentially increasing the risk of treatment-related uveitis in retinal disease patients.