Ocular gene therapy has evolved rapidly into the clinical realm due to promising pre-clinical proof-of-concept studies, recognition of the high unmet medical need of blinding disorders, and the excellent safety profile of the most commonly used vector system, the adeno-associated virus (AAV). With several trials exposing subjects to AAV, investigators independently report about cases with clinically evident inflammation in treated eyes despite the concept of ocular immune privilege. Here, we provide a detailed analysis of innate and adaptive immune response to clinical-grade AAV8 in non-human primates and compare this to preliminary clinical data from a retinal gene therapy trial for CNGA3-based achromatopsia (ClinicalTrials.gov: 02610582).

These data illustrate that subretinal application of rAAV8 leads to a more favorable biodistribution profile compared to intravitreal injections. Extraocular biodistribution is limited after subretinal delivery, while intravitreal injection leads to both greater and more persistent systemic exposure, evident in blood and lymphatic tissues. With the knowledge on the dynamics of shedding in a setting mimicking clinical application, guidelines can be developed to refine clinical trial protocols to reduce the risk for trial subjects and their environment.

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