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Antigen-selective modulation of AAV immunogenicity with tolerogenic rapamycin nanoparticles enables successful vector re-administration

Florence Boisgérault 1 Amine Meliani 2 Romain Hardet 3 Solenne Marmier 3 Fanny Collaud 4 Giuseppe Ronzitti 4 Christian Leborgne 4 Helena Costa Verdera 3 Marcelo Simon Sola Severine Charles 4 Alban Vignaud 5 Laetitia van Wittenberghe 6 Giorgia Manni Olivier Christophe 7 Francesca Fallarino 8 Christopher Roy Alicia Michaud Petr Ilyinskii Takashi Kei Kishimoto Federico Mingozzi 4
1 INTEGRARE - Approches génétiques intégrées et nouvelles thérapies pour les maladies rares
2 Centre de recherche en myologie
3 Centre de recherche en Myologie – U974 SU-INSERM
4 Généthon
5 Coeur, Muscle et Vaisseaux
6 I-STEM - Institut des cellules souches pour le traitement et l'étude des maladies monogéniques
7 Hémostase et biologie vasculaire
8 Exp. Medicine and Bioch. Sciences
Résumé : Gene therapy mediated by recombinant adeno-associated virus (AAV) vectors is a promising treatment for systemic monogenic diseases. However, vector immunogenicity represents a major limitation to gene transfer with AAV vectors, particularly for vector re-administration. Here, we demonstrate that synthetic vaccine particles encapsulating rapamycin (SVP[Rapa]), co-administered with AAV vectors, prevents the induction of anti-capsid humoral and cell-mediated responses. This allows successful vector re-administration in mice and nonhuman primates. SVP[Rapa] dosed with AAV vectors reduces B and T cell activation in an antigen-selective manner, inhibits CD8+ T cell infiltration in the liver, and efficiently blocks memory T cell responses. SVP[Rapa] immunomodulatory effects can be transferred from treated to naive mice by adoptive transfer of splenocytes, and is inhibited by depletion of CD25+ T cells, suggesting a role for regulatory T cells. Co-administration of SVP[Rapa] with AAV vector represents a powerful strategy to modulate vector immunogenicity and enable effective vector re-administration.
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https://hal-univ-evry.archives-ouvertes.fr/hal-02177709
Contributor : Florence Boisgérault Connect in order to contact the contributor
Submitted on : Tuesday, July 9, 2019 - 11:57:52 AM
Last modification on : Friday, January 7, 2022 - 9:58:02 AM

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UNIV-EVRY | CNRS | U974 | I-STEM | INTEGRARE | SORBONNE-UNIVERSITE | SU-MEDECINE | EPHE | PSL | SU-TI | GS-HEALTH-DRUG-SCIENCES

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Florence Boisgérault, Amine Meliani, Romain Hardet, Solenne Marmier, Fanny Collaud, et al.. Antigen-selective modulation of AAV immunogenicity with tolerogenic rapamycin nanoparticles enables successful vector re-administration. Nature Communications, Nature Publishing Group, 2018, 9 (1), pp.4098. ⟨10.1038/s41467-018-06621-3⟩. ⟨hal-02177709⟩

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