Interindividual variability in immune response to AAV ocular gene delivery across species impedes immunomonitoring

Adeno-associated viruses (AAVs) have been used in gene therapy, especially for inherited retinal diseases. Despite their effectiveness in gene transduction, immune responses to the AAV capsid and transgene products have been reported, which can compromise both the efficacy and the safety of AAV-mediated therapies. The eye is regarded as an immune-privileged organ where immune activity is constitutively suppressed. Here, we highlight that immunomonitoring in an ocular gene transfer reveals variable immune responses, whatever the species (human clinical trial, nonhuman primates, mice), the site of injection, the cassette, and the dose. We further explored factors contributing to this variability, investigating the potential correlation among immune parameters in a controlled experimental setting. In a syngeneic murine model after a subretinal injection of AAV, our results highlight an interindividual variability of immune parameters, emphasizing the importance of considering inherent variability among individuals when designing personalized therapies.