Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy.

Retinal gene therapy using adeno-associated viral (AAV) vectors has been a groundbreaking step-change in the treatment of inherited retinal diseases (IRDs) and could also be used to treat more common retinal diseases such as age-related macular degeneration and diabetic retinopathy. The delivery and expression of therapeutic transgenes in the eye is limited by innate and adaptive immune responses against components of the vector product, which has been termed gene therapy-associated uveitis (GTAU). This is clinically important as intraocular inflammation could lead to irreversible loss of retinal cells, deterioration of visual function and reduced durability of treatment effect associated with a costly one-off treatment. For retinal gene therapy to achieve an improved efficacy and safety profile for treating additional IRDs and more common diseases, the risk of GTAU must be minimised. We have collated insights from pre-clinical research, clinical trials, and the real-world implementation of AAV-mediated retinal gene therapy to help understand the risk factors for GTAU. We draw attention to an emerging framework, which includes patient demographics, vector construct, vector dose, route of administration, and choice of immunosuppression regime. Importantly, we consider efforts to date and potential future strategies to mitigate the adverse immune response across each of these domains. We advocate for more targeted immunomodulatory approaches to the prevention and treatment of GTAU based on better understanding of the underlying immune response.