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Prepublished online as a Blood First Edition Paper on August 1, 2002; DOI 10.1182/blood-2001-12-0165. This Article Full Text Full Text (PDF) All Versions of this Article: 2001-12-0165v1 100/13/4381    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Roesler, J. Articles by Malech, H. L. Search for Related Content PubMed PubMed Citation Articles by Roesler, J. Articles by Malech, H. L. Related Collections Phagocytes Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 December 2002, Vol. 100, No. 13, pp. 4381-4390 GENE THERAPY Third-generation, self-inactivating gp91phox lentivector corrects the oxidase defect in NOD/SCID mouse-repopulating peripheral blood-mobilized CD34+ cells from patients with X-linked chronic granulomatous disease Joachim Roesler, Sebastian Brenner, Anatoly A. Bukovsky, Narda Whiting-Theobald, Thomas Dull, Michael Kelly, Curt I. Civin, and Harry L. Malech From the Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; Cell Genesys, Foster City, CA; and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD. HIV-1-derived lentivectors are promising for gene transfer into hematopoietic stem cells but require preclinical in vivo evaluation relevant to specific human diseases. Nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice accept human hematopoietic stem cell grafts, providing a unique opportunity for in vivo evaluation of therapies targeting human hematopoietic diseases. We demonstrate for the first time that hematopoietic stem cells from patients with X-linked chronic granulomatous disease (X-CGD) give rise to X-CGD-phenotype neutrophils in the NOD/SCID model that can be corrected using VSV-G-pseudotyped, 3rd-generation, self-inactivating (SIN) lentivector encoding gp91phox. We transduced X-CGD patient-mobilized CD34+ peripheral blood stem cells (CD34+PBSCs) with lentivector-gp91phox or amphotropic oncoretrovirus MFGS-gp91phox and evaluated correction ex vivo and in vivo in NOD/SCID mice. Only lentivector transduced CD34+PBSCs under ex vivo conditions nonpermissive for cell division, but both vectors performed best under conditions permissive for proliferation (multiple growth factors). Under the latter conditions, lentivector and MFGS achieved significant ex vivo correction of X-CGD CD34+PBSCs (18% and 54% of cells expressing gp91phox, associated with 53% and 163% of normal superoxide production, respectively). However, lentivector, but not MFGS, achieved significant correction of human X-CGD neutrophils arising in vivo in NOD/SCID mice that underwent transplantation (20% and 2.4%, respectively). Thus, 3rd-generation SIN lentivector-gp91phox performs well as assessed in human X-CGD neutrophils differentiating in vivo, and our studies suggest that the NOD/SCID model is generally applicable for in vivo study of therapies evaluated in human blood cells expressing a specific disease phenotype. © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Tesio, L. Gammaitoni, M. Gunetti, V. Leuci, Y. Pignochino, N. Jordaney, S. Capellero, C. Cammarata, L. Caione, G. Migliaretti, et al. Sustained Long-Term Engraftment and Transgene Expression of Peripheral Blood CD34+ Cells Transduced with Third-Generation Lentiviral Vectors Stem Cells, June 1, 2008; 26(6): 1620 - 1627. [Abstract] [Full Text] [PDF] S. Brenner, M. F. Ryser, N. L. Whiting-Theobald, M. Gentsch, G. F. Linton, and H. L. 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Brenner, N. L. Whiting-Theobald, G. F. Linton, K. L. Holmes, M. Anderson-Cohen, P. F. Kelly, E. F. Vanin, A. M. Pilon, D. M. Bodine, M. E. Horwitz, et al. Concentrated RD114-pseudotyped MFGS-gp91phox vector achieves high levels of functional correction of the chronic granulomatous disease oxidase defect in NOD/SCID/{beta}2-microglobulin-/- repopulating mobilized human peripheral blood CD34+ cells Blood, October 15, 2003; 102(8): 2789 - 2797. [Abstract] [Full Text] [PDF] F. Geronimi, E. Richard, I. Redonnet-Vernhet, I. Lamrissi-Garcia, M. Lalanne, C. Ged, F. Moreau-Gaudry, and H. de Verneuil Highly Efficient Lentiviral Gene Transfer in CD34+ and CD34+/38-/lin- Cells from Mobilized Peripheral Blood after Cytokine Prestimulation Stem Cells, July 1, 2003; 21(4): 472 - 480. [Abstract] [Full Text] [PDF]

	Copyright © 2002 by American Society of Hematology         Online ISSN: 1528-0020