Progress for ocular adeno-associated virus (AAV) gene therapy has been hindered by AAV-induced inflammation, limiting dose escalation and long-term efficacy. Broadly, the extent of inflammatory responses alters with age and sex, yet these factors are poorly represented in pre-clinical development of ocular AAV gene therapies. Here, we combined clinical imaging, flow cytometry, and bulk sequencing of sorted microglia to interrogate the longitudinal inflammatory response following intravitreal delivery of AAV2 in young (3-month-old), middle aged (9-month-old), and old (18-month-old) Cx3cr1-creER:R26tdTomato+/- mice of both sexes. Young males and females exhibited a similar dynamic response, with peak inflammation evident at days 10-12 and signs of clinical resolution by day 28. However, the magnitude of the transcriptional response by microglia and adaptive T cell infiltrate differed between sexes. With age, increased and persistent inflammation were observed in both sexes, although old males maintained their microglia transcriptional AAV response signature. Contrarily, females demonstrated greater divergence in their inflammatory response across age, with enriched cellular stress and inflammatory gene expression in older mice and corresponding signs of retinal degeneration. These findings inform crucial sex and age differences for the therapeutic application of ocular gene therapy, highlighting the need to further understand these factors to overcome AAV immunogenicity.
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