June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Impact of subretinal AAV delivery on the transcriptomic inflammatory profile of the degenerating retina
Author Affiliations & Notes
  • Raghavi Sudharsan
    Clinical Sciences & Advanced Medicine, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, United States
  • Jennifer C Kwok
    Clinical Sciences & Advanced Medicine, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, United States
  • Gustavo D Aguirre
    Clinical Sciences & Advanced Medicine, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, United States
  • William A Beltran
    Clinical Sciences & Advanced Medicine, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, United States
  • Footnotes
    Commercial Relationships   Raghavi Sudharsan None; Jennifer Kwok None; Gustavo Aguirre None; William Beltran None
  • Footnotes
    Support  Foundation Fighting Blindness TRAP-VVIOI, Foundation Fighting Blindness Large Animal Model Translation and Research Center Grant, NIH grant EY006855
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 3023. doi:
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    • Get Citation

      Raghavi Sudharsan, Jennifer C Kwok, Gustavo D Aguirre, William A Beltran; Impact of subretinal AAV delivery on the transcriptomic inflammatory profile of the degenerating retina. Invest. Ophthalmol. Vis. Sci. 2023;64(8):3023.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Photoreceptor cell death in inherited retinopathies induces chronic inflammation. Additionally, AAV-mediated gene transfer also produces an inflammatory response in retinas. In this study, we investigated the specific contribution of AAV to innate and adaptive immune responses in the degenerating mutant retina.

Methods : Single cell transcriptomic profiling of neuroretinal cells isolated from a normal and a mutant PDE6B-RCD1 (advanced stage of degeneration, >75% photoreceptor loss) dog following subretinal AAV5-GFP injection was compared to that from untreated normal and mutant canine retinas. Various cell populations were identified using graph-based clustering tool from the Seurat package. Differential gene expression and pathway analysis (Ingenuity Pathway Analysis and GSEA) was performed on all cell clusters to identify biological pathways enriched under each of these 4 conditions.

Results : B- and T- cell populations were identified only in the AAV5-treated PDE6B-RCD1 retina. Various innate immune response and associated cytokine pathways (IL-6, IL-17, IL-33) were upregulated in the microglia and Müller glia of the normal and mutant AAV-treated retinas, with higher pathway activation scores for the latter. Integrin-dependent migration pathways as well as leukocyte migration pathways were uniquely upregulated in the microglia from the AAV-treated mutant retina.

Conclusions : Several signaling pathways involved in the innate immune response were uniquely upregulated in the mutant retina in response to subretinal AAV5 delivery. Additionally, an adaptive cellular immune response was activated only in the AAV- treated mutant retina. Further investigation into contribution of these pathways towards AAV-induced inflammation could lead to development of novel diagnostic tools and targeted ancillary treatments for retinal inflammation associated with AAV-mediated gene therapy.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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