Ocular gene therapy mediated by AAV vectors: an overview of immunosuppressive treatments and immunomonitoring of patients involved in clinical trials

Hereditary retinal diseases (RDs) are a group of diseases caused by monogenetic or multigenetic mutations in genes mostly expressed in the photoreceptors. RDs can eventually lead to severe vision impairment or blindness. Since the 1990s, ocular gene transfer mediated by adeno-associated virus (AAV)-derived vectors has been explored to treat hereditary ocular diseases via gene supplementation or gene editing, advancing gene therapy to the clinical trial stages and to one commercial product. By the end of 2024, 142 clinical trials had been initiated for different types of RDs. Immune responses remain a major concern in AAV-mediated gene therapy. Although the eye is considered as an immune-privileged organ, studies in animals and clinical evidence have demonstrated that ocular gene therapies mediated by AAV can trigger immune responses to the vector capsid and/or to the transgene genome and product. These immune responses may compromise the efficiency and safety of the therapy. In this review, we summarize clinical trials treating RDs with AAV and provide a comprehensive overview of reported immune responses, including local inflammation and systemic adaptive immune responses. Additionally, this review emphasizes that immunosuppression and immunomonitoring strategies are not yet standardized both for intraocular and systemic gene therapy clinical trials, and do not allow for accurate follow-up of side effects. It highlights the inter-individual variability among patients, reinforcing the need to evaluate multiple key immune parameters, including sensitive inflammation biomarkers, and to assess the impact of different immunosuppression regimens.