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 Blood, 15 November 2005, Vol. 106, No. 10, pp. 3386-3395.
Prepublished online as a Blood First Edition Paper on August 2, 2005; DOI 10.1182/blood-2004-12-4736.

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GENE THERAPY

Novel lentiviral vectors displaying "early-acting cytokines" selectively promote survival and transduction of NOD/SCID repopulating human hematopoietic stem cells

Els Verhoeyen, Maciej Wiznerowicz, Delphine Olivier, Brigitte Izac, Didier Trono, Anne Dubart-Kupperschmitt, and François-Loïc Cosset

From INSERM, U412, Lyon, France; Ecole Normale Supérieure de Lyon, Lyon, France; IFR128 BioSciences Lyon-Gerland, Lyon, France; Department of Microbiology and Molecular Medicine, Faculty of Medicine, University of Geneva, Switzerland; Institut Cochin, Hematology Department, Paris, France; CNRS, UMR 8104, Paris, France; and Univeristé Paris Descartes, Faculté De Médecine René Descartes, UMR-S 8104, Paris, France.

A major limitation of current lentiviral vectors (LVs) is their inability to govern efficient gene transfer into quiescent cells, such as human CD34+ cells, that reside in the G0 phase of the cell cycle and that are highly enriched in hematopoietic stem cells. This hampers their application for gene therapy of hematopoietic cells. Here, we designed novel LVs that overcome this restriction by displaying "early-acting cytokines" on their surface. Display of thrombopoietin, stem cell factor, or both cytokines on the LV surface allowed efficient gene delivery into quiescent cord blood CD34+ cells. Moreover, these surface-engineered LVs preferentially transduced and promoted survival of resting CD34+ cells rather than cycling cells. Finally, and most importantly, these novel LVs allowed superior gene transfer in the most immature CD34+ cells as compared to conventional LVs, even when the latter vectors were used to transduce cells in the presence of recombinant cytokines. This was demonstrated by their capacity to promote selective transduction of CD34+ cell in in vitro derived long-term culture-initiating cell (LTC-IC) colonies and of long-term NOD/SCID repopulating cells (SRCs) in vivo.


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