Efficient intrathymic gene transfer following in situ administration of a rAAV serotype 8 vector in mice and nonhuman primates

Moreau, A.; Vicente, R.; Dubreil, L.; Adjali, O.; Podevin, G.; Jacquet, C.; Deschamps, J. Y.; Klatzmann, D.; Cherel, Y.; Taylor, N.; Moullier, P.; Zimmermann, V. S.

Mol Ther

2009-03 / vol 17 / pages 472-9


The thymus is the primary site of T-cell development and plays a key role in the induction of self-tolerance. We previously showed that the intrathymic (i.t.) injection of a transgene-expressing lentiviral vector (LV) in mice can result in the correction of a T cell-specific genetic defect. Nevertheless, the efficiency of thymocyte transduction did not exceed 0.1-0.3% and we were unable to detect any thymus transduction in macaques. As such, we initiated studies to assess the capacity of recombinant adeno-associated virus (rAAV) vectors to transduce murine and primate thymic cells. In vivo administration of AAV serotype 2-derived single-stranded AAV (ssAAV) and self-complementary AAV (scAAV) vectors pseudotyped with capsid proteins of serotypes 1, 2, 4, 5, and 8 demonstrated that murine thymus transduction was significantly enhanced by scAAV2/8. Transgene expression was detected in 5% of thymocytes and, notably, transduced cells represented 1% of peripheral T lymphocytes. Moreover, i.t. administration of scAAV2/8 particles in macaques, by endoscopic-mediated guidance, resulted in significant gene transfer. Thus, in healthy animals, where thymic gene transfer does not provide a selective advantage, scAAV2/8 is a unique tool promoting the in situ transduction of thymocytes with the subsequent export of gene-modified lymphocytes to the periphery.

Read on PubMed

10.1038/mt.2008.272 mt2008272 [pii]

1525-0024 (Electronic) 1525-0016 (Linking)

IGMM team(s) involved in this publication

Humans; Animals; Mice; Phenotype; Cell Differentiation; Cell Line; Cell Movement; Kinetics; Dependovirus/classification/*genetics; Genetic Vectors/*administration & dosage/*genetics/pharmacology; Genome, Viral/genetics; Macaca fascicularis/*metabolism; Thymus Gland/cytology/*metabolism; Transgenes/*genetics

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