Efficient intrathymic gene transfer following in situ administration of a rAAV serotype 8 vector in mice and nonhuman primates.
In: ISSN: 1525-0016, 2009
academicJournal
Zugriff:
International audience ; 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.
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Efficient intrathymic gene transfer following in situ administration of a rAAV serotype 8 vector in mice and nonhuman primates.
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Autor/in / Beteiligte Person: | Moreau, Aurélie ; Vicente, Rita ; Dubreil, Laurence ; Adjali, Oumeya ; Podevin, Guillaume ; Jacquet, Chantal ; Deschamps, Jack Yves ; Klatzmann, David ; Cherel, Yan ; Taylor, Naomi ; Moullier, Philippe ; Zimmermann, Valérie S ; Vecteurs viraux et transfert de gènes in vivo ; Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM) ; Institut de Génétique Moléculaire de Montpellier (IGMM) ; Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM) ; Department of Biochemistry ; University of Coimbra Portugal (UC) ; Développement et Pathologie du Tissu Musculaire (DPTM) ; Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes ; Service de chirurgie infantile ; Biologie et thérapeutique des pathologies immunitaires (BTPI) ; Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS) ; Department of Molecular Genetics and Microbiology Gainesville (UF|MGM) ; Department of Medicine Gainesville (UF|Medicine) ; University of Florida Gainesville (UF)-University of Florida Gainesville (UF) |
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Zeitschrift: | ISSN: 1525-0016, 2009 |
Veröffentlichung: | HAL CCSD ; Cell Press, 2009 |
Medientyp: | academicJournal |
DOI: | 10.1038/mt.2008.272 |
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