Nature Communication: No immunogenicity! Can the spring of AAV mediated gene therapy be far behind?


Introduction: Recombinant adeno-associated virus (AAV) vectors exhibit promising outcomes on gene therapy with its durable expression in the targeting tissues. Even so, in most cases, AAV immunogenicity still represents a major limitation for its clinical trials. Recently, a research team from Sorbonne Université and INSERM U974 (France) has employed an effective means to avoid AAV immunogenicity, which makes AAV safer and provide reference for its further clinical trial.

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This result entitled by “Antigen-selective modulation of AAV immunogenicity with tolerogenic rapamycin nanoparticles enables successful vector re-administration” was published online on Oct 5th in the journal of Nature Communications. In the study, the authors co-administrated a synthetic vaccine particle containing rapamycin (SVP[Rapa]) with AAV vectors. Rapamycin encapsulated particles has been reported to alleviate the immune response when co-dosing with protein therapeutics. This team tactfully applied this combination on AAV mediated gene targeting which reduced anti-capsid humoral and T/B cell-mediated immune response, allowing for successful vector re-administration in mice and nonhuman primates.

Furthermore, Meliani and colleagues explored the underlying mechanism of how rapamycin contained particles reduce AVV immunogenicity. They found depletion of CD25+ T cells could abolish this anti-immunogenicity effects, suggesting a critical role of regulatory T cells in this process.

As a whole, this study discovered an effective means to reduce AAV immunogenicity, which not only ensures the durable expression off AAV in the targeting organ but also allows for re-dosing, providing a powerful strategy to AAV mediated gene therapy.

1. Therapeutic in vivo gene transfer for genetic disease using AAV: progress and challenges.
2. Overcoming the host immune response to adeno-associated virus gene delivery vectors: the race between clearance, tolerance, neutralization, and escape.
3. Antigen-selective modulation of AAV immunogenicity with tolerogenic rapamycin nanoparticles enables successful vector re-administration.

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