• Le 20 septembre 2019

Intramuscular AAV‐based gene transfer to the non-human primate : Deciphering host immune responses

Recombinant adeno-associated virus (rAAV) provides a clinically relevant platform for efficient and sustained gene therapy. Intramuscular (IM) rAAV-mediated expression of transgenes in the skeletal muscle has a wide range of promising clinical applications and the first gene therapy drug to have obtained Marketing Authorization Application in Europe was an rAAV delivered through IM route (Glybera® for Lipoprotein Lipase deficient patients). Despite these promising achievements, IM-mediated rAAV gene expression was shown to often induce transgene product rejection in large animal models. Until recently, it was admitted that the loss of transgene expression is due to a full cytotoxic elimination of transduced cells by host CD8 lymphocytes.

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 our preliminary data suggest a transitory loss of transgene expression, followed by a re-expression few months later, suggesting a reversible silencing of the transgene expression. Curiously, despite the detection of muscular cell infiltrates composed of CD8 T cells and CD4 T cells, we were able to detect functional viral genomes (vg) until at least five years following gene transfer in injected muscle. This preliminary data suggest an immunomodulation of the host immune responses against transgene products following IM rAAV-mediated gene transfer.

By focusing on the extinction phase of transgene expression, this project aims to decipher the host immune response after injection of rAAV into the skeletal muscle using the translational model of the non-human primate. These include characterizing of the infiltrated cells, but also assess the peripheral immune responses 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. This work will help translate safe and successful rAAV gene therapy products in humans for the treatment of rare diseases in general, and muscle-specific products in particular.

Contact: malo.journou@univ-nantes.fr