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AAV-Mediated Expression of Human VEGF, TNF-α, and IL-6 Induces Retinal Pathology in Mice

Authors
  • Weigelt, Carina M.1
  • Fuchs, Holger1
  • Schönberger, Tanja2
  • Stierstorfer, Birgit2
  • Strobel, Benjamin2
  • Lamla, Thorsten2
  • Ciossek, Thomas3
  • Bakker, Remko A.1
  • Redemann, Norbert H.1
  • 1 & Co. KG, Biberach an der Riß, Germany
  • 2 Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany
  • 3 Research Beyond Borders, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany
Type
Published Article
Journal
Translational Vision Science & Technology
Publisher
Association for Research in Vision and Ophthalmology (ARVO)
Publication Date
Sep 14, 2021
Volume
10
Issue
11
Identifiers
DOI: 10.1167/tvst.10.11.15
PMID: 34520511
PMCID: PMC8444492
Source
PubMed Central
Keywords
Disciplines
  • Article
License
Unknown

Abstract

Purpose Retinopathies display complex pathologies, including vasculopathies, inflammation, and fibrosis, leading ultimately to visual impairment. However, animal models accurately reflecting these pathologies are lacking. In this study, we evaluate the suitability 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 transgenes within 1 to 6 weeks. Akin to the role of VEGF-A in wet age-related macular degeneration, expression of VEGF-A led to several vasculopathies in mice, including neovascularization and vascular leakage. In contrast, the expression of the proinflammatory cytokines TNF-α or IL-6 induced retinal inflammation, as indicated by microglial activation. Furthermore, the expression of TNF-α, but not of IL-6, induced immune cell infiltration 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 mechanisms causing retinopathies and is easily adaptable to other genes and preclinical species supporting drug discovery for retinal diseases.

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