Département d‘immunologie, Institut Cochin, Inserm U.567, CNRS UMR 8104, Laboratoire membre de l‘IFR 116, Université René Descartes, 27, rue du Faubourg‐Saint‐Jacques, 75014 Paris Laboratoire de virologie et pathogenèse moléculaires, CNRS UMR‐5537, Université Claude‐Bernard Lyon I, Faculté de médecine RTH Laennec, 7, Rue Guillaume‐Paradin, 69008 Lyon * Adresse actuelle : Laboratoire d‘immunologie biologique, CHU Henri‐Mondor, 51, av. du Maréchal‐de‐Lattre‐de‐Tassigny, 94010 Créteil Cedex
The initial concept of gene therapy was to correct a genetic disease by transferring the normal allele of the deficient gene to the most affected cells or tissues. This explains why patients with cystic fibrosis, a recessive autosomal monogenic disease which mainly affects the respiratory and digestive tracts, have been the first to be treated by gene therapy using an adenovirus vector. In fact, the first generation adenovirus vectors provoke a vigourous stimulation of innate immunity, followed by the induction of a specific cellular and humoral response. This response accounts for the vaccinal properties of adenovirus, and is considered as responsible for the rapid decrease of the transgene expression and the low efficiency of vector re‐administrations in animal models. In humans, the data from phase I trials are more difficult to interpret, but they seem to confirm the observations in the other models. The immunogenicity of adenovirus vectors have originally been associated with a residual, low level expression of certain viral genes. However, some recent observations suggest that the capsid of the input vector itself would play a crucial role in this process,
via its interaction with major actors of the immune response, macrophages and dendritic cells. Different strategies have been proposed to enhance the efficiency and specificity of delivery of therapeutic genes, using adenovirus vectors. The most promising ones consist in the modifications of the capsid to alter the natural tropism of the virus and redirect it to the desired cell targets. As a complement to this retargeting strategies, the modifications of immunogenic epitopes, and of the domains of interaction of the viral capsid with the cells of the immune system might contribute to improve the efficacy and the biosafety of the new generation adenovirus vectors in the near future.