Influence of Pre-existing Anti-capsid Neutralizing and Binding Antibodies on AAV Vector Transduction

Abstract : Pre-existing immunity to adeno-associated virus (AAV) is highly prevalent in humans and can profoundly impact transduction efficiency. Despite the relevance to AAV-mediated gene transfer, relatively little is known about the fate of AAV vectors in the presence of neutralizing antibodies (NAbs). Similarly, the effect of binding antibodies (BAbs), with no detectable neutralizing activity, on AAV transduction is ill defined. Here, we delivered AAV8 vectors to mice carrying NAbs and demonstrated that AAV particles are taken up by both liver parenchymal and non-parenchymal cells; viral particles are then rapidly cleared, without resulting in transgene expression. In vitro, imaging of hepatocytes exposed to AAV vectors pre-incubated with either NAbs or BAbs revealed that virus is taken up by cells in both cases. Whereas no successful transduction was observed when AAV was pre-incubated with NAbs, an increased capsid internalization and transgene expression was observed in the presence of BAbs. Accordingly, AAV8 vectors administered to mice passively immunized with anti-AAV8 BAbs showed a more efficient liver transduction and a unique vector biodistribution profile compared to mice immunized with NAbs. These results highlight a virtually opposite effect of neutralizing and binding antibodies on AAV vectors transduction.
Type de document :
Article dans une revue
Molecular Therapy - Methods and Clinical Development, Nature Publishing Group, 2018, 9, pp.119-129. 〈10.1016/j.omtm.2018.02.003〉
Liste complète des métadonnées

Littérature citée [13 références]  Voir  Masquer  Télécharger

https://hal.sorbonne-universite.fr/hal-01830017
Contributeur : Gestionnaire Hal-Upmc <>
Soumis le : mercredi 4 juillet 2018 - 14:54:50
Dernière modification le : vendredi 31 août 2018 - 09:03:02

Fichier

1-s2.0-S2329050118300159-main....
Publication financée par une institution

Licence


Distributed under a Creative Commons Paternité 4.0 International License

Identifiants

Citation

Zachary Fitzpatrick, Christian Leborgne, Elena Barbon, Elisa Masat, Giuseppe Ronzitti, et al.. Influence of Pre-existing Anti-capsid Neutralizing and Binding Antibodies on AAV Vector Transduction. Molecular Therapy - Methods and Clinical Development, Nature Publishing Group, 2018, 9, pp.119-129. 〈10.1016/j.omtm.2018.02.003〉. 〈hal-01830017〉

Partager

Métriques

Consultations de la notice

326

Téléchargements de fichiers

8