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.

Immunoadsorption enables successful rAAV5-mediated repeated hepatic gene delivery in nonhuman primates

“…2,[13][14][15][16][17][18] However, those strategies have limitations because they show limited efficacy in the presence of high NABs titers, require the development of another product, or have safety issues. 19,20 Plasmapheresis and immunoadsorption (IA) are extracorporeal blood-purification techniques that have been developed to remove large-molecular-weight substances from the plasma. Importantly, these techniques are safe medical procedures performed worldwide both in adults and children.…”

Dual muscle-liver transduction imposes immune tolerance for muscle transgene engraftment despite preexisting immunity

“…Compared with classical tissue engraftment procedures involving the transfer of allogenic cells and MHC components, rAAV gene transfer raises specific concerns related to the immunogenicity of rAAV capsids and the processing and recognition of a newly expressed transgene by the host immune system. Preexisting anticapsid antibody responses observed for adenoassociated virus (AAV) serotypes, prevalent mostly in humans (5,6), can impair treatment effectiveness (7), which advocates for the use of other rAAV serotypes, engineered capsids (8), and immunosuppression procedures (9). Of equal importance, cytotoxic T cell (CTL) responses to the capsid were encountered in human liver clinical trials (10), representing an important concern that is currently handled with transient immunosuppression regimens (11).…”

Targeted delivery of acid alpha-glucosidase corrects skeletal muscle phenotypes in Pompe disease mice

“…Furthermore, neutralizing antibodies (nAbs) against the AAV capsids may not only exclude patients from treatment eligibility but may further prevent re-dosing AAV therapies, although immunomodulation and tolerization approaches are currently under study that may show a path forward to overcome nAbs against AAV capsids 39 . Another potential advantage of the AAV approach is that it may help overcome nAbs against the replacement enzyme.…”

“…Immunogenicity of the replacement enzyme still remains a major concern with targeted ERT, and immunogenicity may even be enhanced if the antibody directs the fusion protein to antigen presenting cells or due to creation of possible neoepitopes in the scFv or junctions of the fusion protein. Liver depot gene therapy has been shown to produce immune tolerization in mice, and promising evidence for the ability of liver depot gene therapy to reverse pre-existing anti-drug antibodies has been shown in mice 38,39 . Clinical trials to test whether this is true in humans have already begun.…”