Lentiviral vectors targeting WASp expression to hematopoietic cells, efficiently transduce and correct cells from WAS patients

S. Charrier, L. Dupré, S. Scaramuzza, L. Jeanson-Leh, M. P. Blundell, O. Danos, F. Cattaneo, A. Aiuti, R. Eckenberg, A. J. Thrasher, M. Grazia Roncarolo, A. Galy

Research output: Contribution to journalArticle

Abstract

Gene therapy has been proposed as a potential treatment for Wiskott-Aldrich syndrome (WAS), a severe primary immune deficiency characterized by multiple hematopoietic-specific cellular defects. In order to develop an optimal lentiviral gene transfer cassette for this application, we compared the performance of several internal promoters in a variety of cell lineages from human WAS patients. Vectors using endogenous promoters derived from short (0.5kb) or long (1.6kb) 5′ flanking sequences of the WAS gene, expressed the transgene in T, B, dendritic cells as well as CD34+ progenitor cells, but functioned poorly in non-hematopoietic cells. Defects of T-cell proliferation and interleukin-2 production, and the cytoskeletal anomalies in WAS dendritic cells were also corrected. The levels of reconstitution were comparable to those obtained following transduction with similar lentiviral vectors incorporating constitutive PGK-1, EF1-alpha promoters or the spleen focus forming virus gammaretroviral LTR. Thus, native regulatory sequences target the expression of the therapeutic WAS transgene to the hematopoietic system, as is naturally the case for WAS, and are effective for correction of multiple cellular defects. These vectors may have significant advantages for clinical application in terms of natural gene regulation, and reduction in the potential for adverse mutagenic events.

Original languageEnglish
Pages (from-to)415-428
Number of pages14
JournalGene Therapy
Volume14
Issue number5
DOIs
Publication statusPublished - Mar 2007

    Fingerprint

ASJC Scopus subject areas

  • Genetics

Cite this

Charrier, S., Dupré, L., Scaramuzza, S., Jeanson-Leh, L., Blundell, M. P., Danos, O., Cattaneo, F., Aiuti, A., Eckenberg, R., Thrasher, A. J., Roncarolo, M. G., & Galy, A. (2007). Lentiviral vectors targeting WASp expression to hematopoietic cells, efficiently transduce and correct cells from WAS patients. Gene Therapy, 14(5), 415-428. https://doi.org/10.1038/sj.gt.3302863