• Le 20 septembre 2019

In vivo AAV-based gene transfer : study of immunomodulation during immune response against transgenic product.

Among vector systems that allow efficient in vivo gene transfer, recombinant adeno-associated virus vectors (rAAV) have become the viral vector of choice for gene therapy and are currently evaluated in multiple clinical trials such as for the treatment of hemophilia, retinal dystrophies, metabolic diseases, or muscular diseases. Regarding the immune response against different transgene products after AAV delivery, several studies have documented the induction of immune tolerance while other studies have shown conventional cytotoxic CD8+ T cell responses with a rapid loss of transgene expression against more immunogenic transgene products. Host immunity balanced against the transgene product seems to depend on multiple factors including its immunogenicity, vector dose, animal model used or target tissue.

Interestingly, we have recently shown in the non-human primate model (NHP) that anti-transgene immunity following AAV-mediated gene transfer can lead to a non-conventional immune response : indeed, we have observed chronic inflammation in target tissues (liver/muscle) associated with the presence of immunoregulatory immune cells resulting in the persistence of viral genomes and/or long-term expression of the transgene product. In terms of clinical relevance, the NHP model is a relevant animal model in immunology that mimics to some extent the patient immune system however this large animal model is limited by ethical considerations and cost. In order to further investigate the unconventional immune response, it is necessary to find an alternative model to the primate.

Thus, the objective of this project will be to verify if the unconventional response described in our primate model after gene transfer could be observed in a mouse model. It will be necessary to decipher host immunity against the transgene product in mice with a particular interest to the functionality of T and B cells using conventional methods (ELISA, ELISPOT, immunohistochemistry). We will also focus on the persistence or not of the transgene and its location in the target tissue as it may relate to the immune response observed. If the results obtained in NHP model cannot be transposed into a conventional mouse model, it may be necessary to develop a humanized mouse model to study host immunity in a model that better reflects what happens in humans.

Contact : virginie.pichard@univ-nantes.fr