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

Amine Meliani, Florence Boisgerault, Romain Hardet, Solenne Marmier, Fanny Collaud, Giuseppe Ronzitti, Christian Leborgne, Helena Costa Verdera, Marcelo Simon Sola, Severine Charles, Alban Vignaud, Laetitia van Wittenberghe, Giorgia Manni, Olivier Christophe, Francesca Fallarino, Christopher Roy, Alicia Michaud, Petr Ilyinskii, Takashi Kei Kishimoto and Federico Mingozzi ()
Additional contact information
Amine Meliani: Sorbonne Université and INSERM U974
Florence Boisgerault: EPHE
Romain Hardet: Sorbonne Université and INSERM U974
Solenne Marmier: Sorbonne Université and INSERM U974
Fanny Collaud: EPHE
Giuseppe Ronzitti: EPHE
Christian Leborgne: EPHE
Helena Costa Verdera: Sorbonne Université and INSERM U974
Marcelo Simon Sola: Sorbonne Université and INSERM U974
Severine Charles: EPHE
Alban Vignaud: EPHE
Laetitia van Wittenberghe: EPHE
Giorgia Manni: University of Perugia
Olivier Christophe: Université Paris-Sud
Francesca Fallarino: University of Perugia
Christopher Roy: Selecta Bioscience
Alicia Michaud: Selecta Bioscience
Petr Ilyinskii: Selecta Bioscience
Takashi Kei Kishimoto: Selecta Bioscience
Federico Mingozzi: Sorbonne Université and INSERM U974

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06621-3

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