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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.
Afiliação
  • Whitehead M; John Van Geest Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK. michael1993whitehead@gmail.com.
  • Sage A; Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, UK.
  • Burgoyne T; UCL Institute of Ophthalmology, London, UK.
  • Osborne A; Paediatric Respiratory Medicine, Primary Ciliary Dyskinesia Centre, Guy's and St Thomas' NHS Foundation Trust, London, UK.
  • Yu-Wai-Man P; John Van Geest Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK.
  • Martin KR; John Van Geest Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK.
Gene Ther ; 30(9): 723-735, 2023 09.
Article em En | MEDLINE | ID: mdl-37386155
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Capsídeo / Parvovirinae Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Capsídeo / Parvovirinae Idioma: En Ano de publicação: 2023 Tipo de documento: Article