AAV8 Can Induce Innate and Adaptive Immune Response in the Primate Eye

• Published in: Molecular therapy Vol. 25; no. 12; pp. 2648 - 2660
• Main Authors: Reichel, Felix F., Dauletbekov, Daniyar L., Klein, Reinhild, Peters, Tobias, Ochakovski, G. Alex, Seitz, Immanuel P., Wilhelm, Barbara, Ueffing, Marius, Biel, Martin, Wissinger, Bernd, Michalakis, Stylianos, Bartz-Schmidt, Karl Ulrich, Fischer, M. Dominik
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.12.2017; Elsevier Limited; American Society of Gene & Cell Therapy
• Subjects: AAV; Adaptive Immunity; Animals; Antigens; Apoptosis; Biomarkers; Capsid Proteins - immunology; Clinical trials; Color blindness; Cytokines; Dependovirus - genetics; Dependovirus - immunology; Eye - immunology; Female; Gene Expression; Gene therapy; Genetic Therapy; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; Genetic Vectors - immunology; Humans; Immune privilege; Immune response; Immunity, Humoral; Immunity, Innate; Inflammation; Kinases; Macaca fascicularis; Male; Original; Primates; Retina; Retina - immunology; Retina - metabolism; Signal Transduction; Surgery; Tumor necrosis factor-TNF; immune response; gene therapy; AAV
• ISSN: 1525-0016; 1525-0024; 1525-0024
• DOI: 10.1016/j.ymthe.2017.08.018

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). Reichel et al. (2017) provide analysis of immune response to clinical-grade AAV8 in primates, along with preliminary clinical data from a gene therapy trial. The high-dose group of animals demonstrated mononuclear infiltrates, upregulation of IFNγ-mediated cytokines, and activation of adaptive immune response cells four weeks after injection.