UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Immunobiology of a rationally-designed AAV2 capsid following intravitreal delivery in mice

Whitehead, Michael; Sage, Andrew; Burgoyne, Tom; Osborne, Andrew; Yu-Wai-Man, Patrick; Martin, Keith R; (2023) Immunobiology of a rationally-designed AAV2 capsid following intravitreal delivery in mice. Gene Therapy 10.1038/s41434-023-00409-x. (In press). Green open access

[thumbnail of s41434-023-00409-x.pdf]
Preview
PDF
s41434-023-00409-x.pdf - Published Version

Download (7MB) | Preview

Abstract

Adeno-associated virus serotype 2 (AAV2) is a viral vector that can be used to deliver therapeutic genes to diseased cells in the retina. One strategy for altering AAV2 vectors involves the mutation of phosphodegron residues, which are thought to be phosphorylated/ubiquitinated in the cytosol, facilitating degradation of the vector and the inhibition of transduction. As such, mutation of phosphodegron residues have been correlated with increased transduction of target cells, however, an assessment of the immunobiology of wild-type and phosphodegron mutant AAV2 vectors following intravitreal (IVT) delivery to immunocompetent animals is lacking in the current literature. In this study, we show that IVT of a triple phosphodegron mutant AAV2 capsid is associated with higher levels of humoral immune activation, infiltration of CD4 and CD8 T-cells into the retina, generation of splenic germinal centre reactions, activation of conventional dendritic cell subsets, and elevated retinal gliosis compared to wild-type AAV2 capsids. However, we did not detect significant changes in electroretinography arising after vector administration. We also demonstrate that the triple AAV2 mutant capsid is less susceptible to neutralisation by soluble heparan sulphate and anti-AAV2 neutralising antibodies, highlighting a possible utility for the vector in terms of circumventing pre-existing humoral immunity. In summary, the present study highlights novel aspects of rationally-designed vector immunobiology, which may be relevant to their application in preclinical and clinical settings.

Type: Article
Title: Immunobiology of a rationally-designed AAV2 capsid following intravitreal delivery in mice
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41434-023-00409-x
Publisher version: https://doi.org/10.1038/s41434-023-00409-x
Language: English
Additional information: © 2023 Springer Nature Limited. This article is licensed under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10172885
Downloads since deposit
10Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item