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Intravitreal AAV delivery induces integrin-dependent ocular inflammation and activation of complement, antiviral and DNA damage responses

ABSTRACT: Intravitreal (IVT) AAV administration is a promising, non-invasive strategy for retinal transduction. However, IVT AAV delivery is often associated with dose-limiting inflammation, and corticosteroid treatment used to manage ocular uveitis is contra-indicated in some patients. Therefore, novel immunomodulatory strategies are needed, requiring further understanding of AAV-triggered immunity mechanisms. Here we characterized immune responses to AAV2.7m8 in mice and pigs. IVT AAV delivery in mice revealed a key role for peripheral leukocytes in mediating ocular inflammation, while the response in pigs was predominantly driven by microglia activation and monocyte infiltration. Analysis of ocular humors identified MCP-1 and IP-10 as common AAV-induced inflammation markers in both species, with subsequent identification of MIP-1α, IL-6, and complement factor C3a as additional markers in pigs. We also detected DNA damage foci in treated retinas, including in regions exhibiting low or absent transgene expression, but with significant presence of vector genomes. Finally, snRNAseq detected significant transduction of retinal ganglion cells, identified astrocytes and microglia as the main sources of MCP-1 and IP-10, and revealed marked induction of interferon and pro-inflammatory signaling across all retinal cell populations. Thus, our work identified new markers of ocular inflammation and potential targets to modulate AAV-induced uveitis.

ORGANISM(S): Sus scrofa

PROVIDER: GSE308982 | GEO | 2026/04/07

REPOSITORIES: GEO

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Project description:Recombinant adeno-associated virus (AAV) is the leading platform for gene therapy in ocular disease. Progress for gene therapy has been hindered by AAV-induced inflammation, which limits dose escalation and long-term efficacy. Characterisation of the ocular immune response to AAV in mice has been restricted to young animals and demonstrate activation of microglia, antigen presentation and a dominant T cell lymphocyte infiltration. The extent of the inflammatory response alters with age and sex and these factors have not been fully represented in the pre-clinical development of ocular AAV gene therapies. Here, we intravitreally inject a null AAV2 vector in young (3-month), middle aged (9-month) and old (18-month) Cx3cr1-creER:R26tdTomato+/- mice of both sexes. Applying clinical imaging, flow cytometric analyses and bulk-sequencing of sorted resident microglia we interrogate the impact of sex and age on the longitudinal response of both microglia and infiltrating cellular response to AAV. Young animals have a dynamic response, with a peak in inflammation at D10-12 and signs of clinical resolution by D28. Despite similar kinetics in the inflammatory response between young male and females, sex differences are observed in the magnitude of the transcriptional response by microglia and the adaptive component of the infiltrating response. With age, the inflammation increases and persists after AAV2 injection. Based on the microglia transcriptional response to AAV, males maintain similar signature across age, although enhanced with increasing age. Contrary, females have greater divergence in their inflammatory response across age. Of particular note, old females have enriched cellular stress and inflammatory microglia gene signatures, with corresponding retinal degeneration. These findings inform crucial sex and age differences for therapeutic application of ocular gene therapy. Our dataset highlight the need to further define these differences to appropriately tackle AAV immunogenicity for all populations.

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Intravitreal AAV delivery induces integrin-dependent ocular inflammation and activation of complement, antiviral and DNA damage responses

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