June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Perioperative prednisolone administration attenuates systemic immune activation following intravitreal injection of AAV2, but fails to enable repeated gene transfer to the inner retina
Author Affiliations & Notes
  • Michael Whitehead
    Institute of Ophthalmology, University College London, London, London, United Kingdom
  • Patrick Yu-Wai-Man
    Institute of Ophthalmology, University College London, London, London, United Kingdom
  • Footnotes
    Commercial Relationships   Michael Whitehead None; Patrick Yu-Wai-Man GenSight, Code C (Consultant/Contractor)
  • Footnotes
    Support  Addenbrookes Charitable Trust Grant G109216, National Eye Research Council Grant G104353
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 76 – A0049. doi:
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      Michael Whitehead, Patrick Yu-Wai-Man; Perioperative prednisolone administration attenuates systemic immune activation following intravitreal injection of AAV2, but fails to enable repeated gene transfer to the inner retina. Invest. Ophthalmol. Vis. Sci. 2022;63(7):76 – A0049.

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

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Abstract

Purpose : Injection of adeno-associated virus serotype 2 (AAV2) vectors into the vitreous is associated with the induction of innate and adaptive immune responses that may limit therapeutic efficacy and inhibit vector readministration. Prednisolone is a glucocorticosteroid immunosuppressant that is commonly administered alongside intravitreal (IVT) injection of AAV2 in patients to limit the onset, duration and severity of intraocular inflammation. Whether this strategy can be utilised to enable vector readministration via attenuation of humoral immune activation, however, is unclear.

Methods : Adult male C57BL6/J mice were treated with 0.75 mg/kg/day prednisolone or PBS via intraperitoneal injections throughout the study. At 3wk, bilateral IVT injections of 1E10 viral genomes (vg)/eye AAV2.CAG.GFP were performed. At 6wk, mice received a second set of bilateral IVT injections of 1E10 vg/eye AAV2.CMV.mCherry. Mice were sacrificed at 9wk and eyes were processed into cryosections for immunohistochemical analysis. Spleens were extracted and lymphocyte populations were assessed with flow cytometry. Serum samples were collected throughout the study to assess levels of neutralising antibodies (NAbs) and total antigen-binding antibodies (TAbs).

Results : Prednisolone treatment was associated with significant reductions in NAb and TAb synthesis, and attenuated CD4 & CD8 T-cell and activated B-cell infiltration into the retina. Mechanistically, this was correlated with the inhibition of splenic germinal centre reactions and B-cell class-switching, however, regulatory T-cell levels were not changed in immunosuppressed mice. Despite the significant reduction in humoral immune activation exhibited in prednisolone-treated mice, the immunosuppressant alone proved insufficient in enabling vector readministration to the inner retina.

Conclusions : The present study highlights a cellular and molecular basis for perioperative steroid immunosuppression in attenuating anti-AAV2 immune activation when delivered via IVT injection. However, further improvements to circumvent humoral immune responses are likely to be required to enable vector readministration.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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