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

Amine Meliani,Olivier Christophe,Helena Costa Verdera,Marcelo Simon Sola,Séverine Charles ,Romain Hardet,Francesca Fallarino,Giuseppe Ronzitti,Solenne Marmier,Christopher J Roy ,Takashi Kishimoto ,Laetitia Van Wittenberghe,Fanny Collaud,Florence Boisgérault ,Giorgia Manni,Christian Leborgne,Alicia Michaud ,Petr O Ilyinskii ,Alban Vignaud,Federico Mingozzi

doi:10.1038/s41467-018-06621-3

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.

Highlights

Gene therapy mediated by recombinant adeno-associated virus (AAV) vectors is a promising treatment for systemic monogenic diseases
Animals treated with empty nanoparticles (SVP[empty]), and control naive animals infused with only 4 × 1012 vg kg−1 of an AAV8-hF.IX vector alone at day 21, developed high-titer anti-AAV IgG antibodies
Successful vector re-administration, measured by plasma levels of hF.IX transgene product, was achieved only in animals receiving SVP[Rapa] and in the control group of naive animals dosed at day 21 with AAV8-hF.IX vector only (Fig. 1d)

Summary

Introduction

Gene therapy mediated by recombinant adeno-associated virus (AAV) vectors is a promising treatment for systemic monogenic diseases. We demonstrate that synthetic vaccine particles encapsulating rapamycin (SVP[Rapa]), co-administered with AAV vectors, prevents the induction of anti-capsid humoral and cellmediated responses This allows successful vector re-administration in mice and nonhuman primates. For many metabolic and degenerative diseases, treatment is critically needed early in life[10,11], prior to the onset of irreversible tissue damage Because of their non-integrative nature, systemic gene therapy with AAV vectors in pediatric patients is expected to be limited by tissue proliferation associated with organ growth, which results in significant vector dilution over time[12,13,14]. We demonstrate that co-administration of SVP[Rapa] with AAV vectors induce safe and effective control of capsid immunogenicity in an antigen-selective manner This approach allows for productive repeated dosing of the same AAV serotype in mice and in nonhuman primates. SVP[Rapa]-mediated immunomodulation represents an attractive strategy to reduce AAV vector immunogenicity

Methods

Results

Conclusion