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

Abstract : 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.
Document type :
Journal articles
Complete list of metadatas

https://hal-univ-evry.archives-ouvertes.fr/hal-02177709
Contributor : Florence Boisgérault <>
Submitted on : Tuesday, July 9, 2019 - 11:57:52 AM
Last modification on : Thursday, July 11, 2019 - 1:20:24 AM

Links full text

Identifiers

Citation

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⟩

Share

Metrics

Record views

18