Master's internship proposal (M1)

Team: Immunology of gene transfer
Supervisor: Gwladys GERNOUX
gwladys.gernoux@univ-nantes.fr
Tel: +33 2 28 08 04 60

New therapies targeting the genome such as gene transfer have shown remarkable potential to treat diseases still incurable by pharmacological conventional treatments. These innovative biotherapies were first demonstrated for monogenic rare diseases but the spectrum of their applications is now extended to correct much more challenging acquired diseases with higher prevalence such as Alzheimer’s disease, age-related macular degeneration, diabetes or heart failure.

Among the vectors used for gene transfer, recombinant Adeno-Associated-Virus (rAAV) are now considered efficient and successful viral vectors for the treatment of inherited disorders as demonstrated by recent FDA and EMA approvals for Luxturna®, Glybera® and Zolgensma®. However, when protocols were translated to patients, limits imposed by the host immune system emerged especially when the vector is delivered systemically. Indeed, pre-existing memory T cells against the AAV viral capsid can be reactivated after gene transfer and can lead to transduced cell clearance. Surprisingly, the activation/reactivation of anti-AAV T cells has not been observed in preclinical studies, although some large animal models are natural hosts for wild-type AAV. It is therefore essential to develop animal models mimicking this immune response to assess the impact of pre-existing human immune cells on the efficacy of gene transfer.

A rodent model has been developed in the lab in the past years. This model consists in an HLA-A2 transgenic humanized mouse model mimicking the inflammation induced by the AAV vector in the liver after adoptive transfer of human PBMCs with preexisting anti-capsid T cells.

The aim of this internship is to study the T cell fate and effect on the efficiency of gene transfer in vivo by analyzing the vector biodistribution, transgene expression as well as in situ and peripheral immune responses.