Résumé :
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Despite the well-established safety and efficacy of rAAV vectors for in vivo gene transfer, there is still little information concerning the fate of vectors after systemic delivery. By using a proteomic approach, we screened for serum proteins interacting with different rAAV serotypes in various species. We report that proteins of the innate immunity system interact with many rAAV vectors in a species-specific manner. We showed that even in the absence of neutralizing antibodies, some human and dog proteins interact with AAV vectors and neutralize vector infectivity. One of these proteins was studied in more details. Interactions of this protein with rAAVs are species specific and do not depend on the degree of the protein homology: AAV serotypes captured by human and dog protein do not interact with their mouse homolog. Moreover, in the macaque, which is generally considered as one of the most relevant models for human preclinical trials, the homologue of human protein (98% of identity) does not interact with AAV. Interestingly, several AAV serotypes can escape capture by this protein and one of them, AAV9, has proved its efficiency in dogs under systemic delivery for whole body transduction. Altogether, the present chapter will describe new biomarkers in gene therapy, which are predictive of in vivo efficacy and safety as well as being critical factors impacting on regulatory toxicology studies design and interpretation.
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