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

Nat Commun. 2018 Oct 5;9(1):4098. doi: 10.1038/s41467-018-06621-3.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dependovirus / immunology*
  • Drug Evaluation, Preclinical
  • Genetic Therapy*
  • Genetic Vectors / immunology*
  • Immunity, Cellular / drug effects
  • Immunity, Humoral / drug effects
  • Immunosuppressive Agents / administration & dosage*
  • Macaca fascicularis
  • Male
  • Mice, Inbred C57BL
  • Nanoparticles
  • Sirolimus / administration & dosage*
  • T-Lymphocytes / drug effects


  • Immunosuppressive Agents
  • Sirolimus