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Efficient intrathymic gene transfer following in situ administration of a rAAV serotype 8 vector in mice and nonhuman primates.
- Source :
-
Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2009 Mar; Vol. 17 (3), pp. 472-9. Date of Electronic Publication: 2008 Dec 16. - Publication Year :
- 2009
-
Abstract
- 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.
- Subjects :
- Animals
Cell Differentiation
Cell Line
Cell Movement
Dependovirus classification
Genetic Vectors pharmacology
Genome, Viral genetics
Humans
Kinetics
Mice
Phenotype
Thymus Gland cytology
Dependovirus genetics
Genetic Vectors administration & dosage
Genetic Vectors genetics
Macaca fascicularis metabolism
Thymus Gland metabolism
Transgenes genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1525-0024
- Volume :
- 17
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Molecular therapy : the journal of the American Society of Gene Therapy
- Publication Type :
- Academic Journal
- Accession number :
- 19088703
- Full Text :
- https://doi.org/10.1038/mt.2008.272