AAV-mediated expression of human VEGF, TNF-α, and IL-6 induces retinal pathology in mice

Abstract

Purpose: Retinopathies display complex pathologies, including vasculopathies, inflam-mation, and fibrosis, leading ultimately to visual impairment. However, animal models accurately reflecting these pathologies are lacking. In this study, we evaluate the suitabil-ity of using Adeno-associated virus (AAV)-mediated long-term expression of cytokines to establish retinal pathology in the murine retina. Methods: We administered recombinant, Müller-glia targeted AAV-ShH10 into the mouse vitreous to induce retinal expression of either human vascular endothelial growth factor (VEGF)-A165, tumor necrosis factor alpha (TNF-α), or interleukin-6 (IL-6) and evaluated consequent effects by optical coherence tomography, fluorescein angiography, and histology. Results: Intravitreal injection of AAVs resulted in rapid and stable expression of the trans-genes within 1 to 6 weeks. Akin to the role of VEGF-A in wet age-related macular degen-eration, expression of VEGF-A led to several vasculopathies in mice, including neovas-cularization and vascular leakage. In contrast, the expression of the proinflammatory cytokines TNF-α or IL-6 induced retinal inflammation, as indicated by microglial activa-tion. Furthermore, the expression of TNF-α, but not of IL-6, induced immune cell infiltra-tion into the vitreous as well as vasculitis, and subsequently induced the development of fibrosis and epiretinal membranes. Conclusions: In summary, the long-term expression of human VEGF-A165, TNF-α, or IL-6 in the mouse eye induced specific pathologies within 6 weeks that mimic different aspects of human retinopathies. Translational Relevance: AAV-mediated expression of human genes in mice is an attractive approach to provide valuable insights into the underlying molecular mecha-nisms causing retinopathies and is easily adaptable to other genes and preclinical species supporting drug discovery for retinal diseases.