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  • Title: Improved amphotropic retrovirus-mediated gene transfer into hematopoietic stem cells.
    Author: Bodine DM, Dunbar CE, Girard LJ, Seidel NE, Cline AP, Donahue RE, Orlic D.
    Journal: Ann N Y Acad Sci; 1998 Jun 30; 850():139-50. PubMed ID: 9668536.
    Abstract:
    The efficiency of amphotropic retrovirus-mediated gene transfer into human Hematopoietic Stem Cells (HSC) is less than 1%. This has impeded gene therapy for hematopoietic diseases. In this study we demonstrate that populations of mouse and human HSC contain low to undetectable levels of the amphotropic virus receptor mRNA (ampho R mRNA), and are resistant to transduction with amphotropic retroviral vectors. In a subpopulation of mouse HSC expressing 7-fold higher levels of ampho R mRNA, transduction with amphotropic retrovirus vectors was 30-fold higher. We conclude that retrovirus transduction of HSC correlates with ampho R mRNA levels. Our results predict that alternative sources of HSC or retroviruses will be required for human gene therapy of hematopoietic diseases. One alternative source of stem cells is from individuals treated with cytokines. We have previously shown that mice treated with G-CSF and SCF have an immediate increase in peripheral blood HSC immediately after treatment, followed by a 10-fold increase in bone marrow HSC 14 days after treatment. In this report we show that when rhesus monkey bone marrow cells collected 14 days after G-CSF and SCF treatment were transduced with amphotropic retroviruses, gene transfer levels were approximately 10%, which was easily detected by Southern blot analysis. We conclude that the increased gene transfer may be the result of increased expression of the amphotropic retrovirus receptor, increased numbers of cycling HSC or both.
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