June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Extreme inter-individual variability of subretinal AAV-induced immune responses
Author Affiliations & Notes
  • Duohao REN
    Inserm UMR_S951, Univ Evry, University Paris-Saclay, Genethon, Evry, Île-de-France, France
    Inserm UMR_S968, Institut de la vision, Paris, Île-de-France, France
  • Audrey PINEIRO
    Inserm UMR_S951, Univ Evry, University Paris-Saclay, Genethon, Evry, Île-de-France, France
  • Gaelle CHAUVEAU
    Inserm UMR_S951, Univ Evry, University Paris-Saclay, Genethon, Evry, Île-de-France, France
    Inserm UMR_S968, Institut de la vision, Paris, Île-de-France, France
  • Julie VENDOMELE
    Inserm UMR_S951, Univ Evry, University Paris-Saclay, Genethon, Evry, Île-de-France, France
  • Divya AIL
    Inserm UMR_S968, Institut de la vision, Paris, Île-de-France, France
  • Deniz Dalkara
    Inserm UMR_S968, Institut de la vision, Paris, Île-de-France, France
  • Giuseppe RONZITTI
    Inserm UMR_S951, Univ Evry, University Paris-Saclay, Genethon, Evry, Île-de-France, France
  • Anne GALY
    Inserm UMR_S951, Univ Evry, University Paris-Saclay, Genethon, Evry, Île-de-France, France
  • Sylvain FISSON
    Inserm UMR_S951, Univ Evry, University Paris-Saclay, Genethon, Evry, Île-de-France, France
    Inserm UMR_S968, Institut de la vision, Paris, Île-de-France, France
  • Footnotes
    Commercial Relationships   Duohao REN None; Audrey PINEIRO None; Gaelle CHAUVEAU None; Julie VENDOMELE None; Divya AIL None; Deniz Dalkara None; Giuseppe RONZITTI None; Anne GALY None; Sylvain FISSON None
  • Footnotes
    Support  Chinese Scholarship Council (CSC) grant
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 2458. doi:
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      Duohao REN, Audrey PINEIRO, Gaelle CHAUVEAU, Julie VENDOMELE, Divya AIL, Deniz Dalkara, Giuseppe RONZITTI, Anne GALY, Sylvain FISSON; Extreme inter-individual variability of subretinal AAV-induced immune responses. Invest. Ophthalmol. Vis. Sci. 2023;64(8):2458.

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

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Abstract

Purpose : Ocular gene therapies that use adeno-associated viruses (AAV) to deliver genes have been successfully applied in some inherited retinal diseases. However, it has been reported that inflammation occurs in some patients. At present, immunomonitoring and finding pertinent biomarkers are crucial challenges for clinical application. Heterogeneity in the strength of the immune response between patients is traditionally thought to be the consequence of genetic background diversity and previous exposure to different pathogens. In a syngeneic murine model, we have previously reported that a single subretinal injection of AAV8 induces a systematic anti-transgene T-cell response, with variable levels of intensity. Here, we analysed complementary innate and adaptive immune components to have a better understanding of the immune consequences subsequent to a subretinal AAV injection and the degree of individual diversity in a standardized context

Methods : Transgene cassette encoding the HY male antigen, immunodominant in female H-2b background, was packaged into AAV8 under the ubiquitous PGK promoter. Several experiments were done with a single subretinal injection of high dose AAV8-HY in immunocompetent adult female C57BL/6 (H-2b) mice. At day 21, RT-droplet digital PCR (ddPCR), ELISpot, in vivo cytotoxicity and ELISA were performed to evaluate the transgene expression, antigen presenting cell markers, T-cell responses and antibody production. Principle component analysis, correlations, and diversity index have been calculated based on the data from each readout

Results : Surprisingly, we found a very strong variability of the immune response between mice, despite a steady local and systemic immune reactivity following the subretinal injection of AAV8-HY. Indeed, none of the mice display the same immune response profile albeit the identical genetic background, injected product, housing conditions, and the surgery being performed by the same individual

Conclusions : We provide experimental evidence on the extreme inter-individual variability of immune responses following subretinal AAV injections on syngeneic mice and in a highly standardized context. This suggests that in patients subjected to ocular gene therapy, in addition to variable genetic backgrounds and different immune history, immunomonitoring should take into account that no individual immunological parameter can predict the evolution of the immune response behavior

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

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