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Molecular signatures and Modulation of immunity to Adeno-Associated Virus vectors

Final Report Summary - MOMAAV (Molecular signatures and Modulation of immunity to Adeno-Associated Virus vectors)

The overall goal of the MoMAAV program is to better understand the nature of the interaction between adeno-associated virus (AAV) vectors and the immune system, and to devise new methods to modulate immunogenicity of these vectors. The work involves studies in humans in preclinical models.
The ERC funding allowed us to establish a gene therapy laboratory, hire key personnel, and acquired the acquire the necessary equipment to perform cutting edge immunology work applied to the field of gene therapy.
Human studies highlighted specific signatures of the interactions of the immune system with AAV vectors that were being exploited to identify and test strategies to modulate immune responses to AAV vectors, with the ultimate aim of translating the findings to human trials. These studies also identified subsets of immune cells involved in driving immune responses to AAV, which were previously not described, and their cytokine signature.
One example of this work is the identification of cytokines that are produced by dendritic cells upon exposure to the capsid, mainly IL-1beta and IL-6. Blockade of these cytokines results in significant dampening of capsid immunogenicity. Novel approaches to overcome humoral immunity to AAV are also being developed as part of the research conducted in the context of the MoMAAV project. These technologies include the use of rapamycin formulated in nanoparticles that, when administered at the time of vector infusion, allows to dose AAV vectors multiple times, to achieve full therapeutic efficacy or maintain transgene expression long-term. Further, other technologies were developed, which will allow to overcome pre-existing immunity to AAV, a major limitation to the use of the AAV vector gene transfer technology in humans.