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- Title
Transgene optimization significantly improves SIN vector titers, gp91<sup>phox</sup> expression and reconstitution of superoxide production in X-CGD cells.
- Authors
Moreno-Carranza, B; Gentsch, M.; Stein, S.; Schambach, A.; Santilli, G.; Rudolf, E.; Ryser, M. F.; Haria, S.; Thrasher, A. J.; Baum, C.; Brenner, S.; Grez, M.
- Abstract
Gene therapy has proven to be of potential value for the correction of inherited hematopoietic disorders. However, the occurrence of severe side effects in some of the clinical trials has questioned the safety of this approach and has hampered the use of long terminal repeat-driven vectors for the treatment of a large number of patients. The development of self-inactivating (SIN) vectors with reduced genotoxicity provides an alternative to the currently used vectors. Our initial attempts to use SIN vectors for the correction of a myeloid disorder, chronic granulomatous disease, failed due to low vector titers and poor transgene expression. The optimization of the transgene cDNA (gp91phox) resulted in substantially increased titers and transgene expression. Most notably, transgene optimization significantly improved expression of a second cistron located downstream of gp91phox. Thus, optimization of the transgene sequence results in higher expression levels and increased therapeutic index allowing the use of low vector copy numbers per transduced cell and weaker internal promoters.Gene Therapy (2009) 16, 111–118; doi:10.1038/gt.2008.143; published online 11 September 2008
- Subjects
GENE therapy; HEMATOPOIETIC stem cells; GENETICS; GENE expression; TRANSGENE expression; SUPEROXIDE dismutase; SCIENTIFIC method
- Publication
Gene Therapy, 2009, Vol 16, Issue 1, p111
- ISSN
0969-7128
- Publication type
Article
- DOI
10.1038/gt.2008.143