Mobilization and transduction of CD34(+) peripheral blood stem cells in patients with X-linked chronic granulomatous disease
| Autor: | Marion-Gabriele Ott, Hans Martin, Dieter Hoelzer, Oliver G. Ottmann, Manuel Grez, Heike Bialek, Heike Merget-Millitzer, Reinhard Seger, Johann Peter Hossle, Nicole Brüggenolte |
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| Rok vydání: | 2002 |
| Předmět: |
Adult
Male Adolescent Genetic enhancement Immunology CD34 Antigens CD34 Granulomatous Disease Chronic Colony-Forming Units Assay Chronic granulomatous disease Antigens CD Reference Values hemic and lymphatic diseases medicine Humans Leukapheresis Progenitor cell Membrane Glycoproteins business.industry NADPH Oxidases Hematology medicine.disease Flow Cytometry Hematopoietic Stem Cells Hematopoietic Stem Cell Mobilization Respiratory burst Transplantation Haematopoiesis NADPH Oxidase 2 Stem cell business Stem Cell Transplantation |
| Zdroj: | Journal of hematotherapystem cell research. 11(4) |
| ISSN: | 1525-8165 |
| Popis: | As a single-gene defect in phagocytes, the X-linked form of chronic granulomatous disease (X-CGD) is a disorder potentially amenable to gene therapy by transfer of a functional copy of the gp91(phox) gene into hematopoietic stem cells (HSC). Although antimicrobial agents and interferon-gamma (IFN-gamma) have significantly improved its prognosis, CGD is still associated with high morbidity and mortality. The disease can be cured by bone marrow transplantation (BMT); however, BMT in CGD has been associated with unacceptably high rates of morbidity, mortality, and graft failure, except in very selected cases in which an HLA-identical donor is available. Prerequisites for a clinical gene therapy of CGD are an efficient mobilization of peripheral blood stem cells (PBSC) as well as the preservation of their viability and hematopoietic potential following transduction and ex vivo culture. We show that (i) mobilization and collection of CD34(+) cells after a 4-week IFN-gamma-free period by G-CSF results in sufficient numbers of cells for transplantation; (ii) the quality of collected stem cells is not altered in comparison to cells obtained from healthy volunteers as assessed by long-term culture initiating cells (LTC-IC) and progenitor cell expansion; (iii) retroviral transfer of the gp91(phox) gene under defined, serum-free conditions leads to high and stable reconstitution of the respiratory burst activity in X-CGD neutrophils derived from transduced CD34(+) progenitor and LTC-IC. Withdrawal of IFN-gamma in CGD patients may improve mobilization of CD34(+) stem cells by G-CSF. The gene transfer conditions established here are applicable to a clinical approach for gene therapy of X-CGD. |
| Databáze: | OpenAIRE |
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