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Blood, 15 July 2004, Vol. 104, No. 2, pp. 364-373. Prepublished online as a Blood First Edition Paper on April 1, 2004; DOI 10.1182/blood-2003-07-2363. This Article Full Text (PDF) All Versions of this Article: 2003-07-2363v1 104/2/364    most recent Alert me when this article is cited Alert me if a correction is posted 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 Davis, B. Articles by Dropulic, B. Search for Related Content PubMed PubMed Citation Articles by Davis, B. Articles by Dropulic, B. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 16, 2003 Accepted March 19, 2004 ABC transporter inhibitor substrates enhance lentivirus vector transduction into primitive hematopoietic progenitor cells Brian Davis, Laurent Humeau, Vladimir Slepushkin, Gwendolyn Binder, Lauren Korshalla, Yajin Ni, E. Oluwakemi Ogunjimi, Lan-Fei Chang, Xiaobin Lu, and Boro Dropulic* VIRxSYS Corporation, Gaithersburg, Maryland, USA VIRxSYS Corporation, Gaithersburg, Maryland, USA; Sydney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA * Corresponding author; email: boro{at}virxsys.com. High gene transfer efficiencies have been difficult to achieve in hematopoietic progenitor cells (HPCs), but are important to therapeutic success of HPC gene therapy. Efficient gene transfer is especially challenging using column purified vector for clinical application, as opposed to centrifuged vector commonly used for research. We investigated novel approaches to increase transduction using a clinically applicable protocol and quantities of column purified lentiviral vector. Recognizing the association of ABC transporters with HPC biology, we investigated the effect of transporter inhibitors on transduction. We found the ABC transporter inhibitor verapamil improved transduction efficiency 2 to 6-fold into CD34+ liquid culture isolated from mobilized peripheral blood, bone marrow, and cord blood. Verapamil also improved transduction in human SRC transduction 3 to 4-fold, resulting in 80% to 90% transduction levels in primary and secondarily transplanted mice without alterations in multi-lineage reconstitution. Additional ABC transporter substrate inhibitors like quinidine, diltiazem, and ritonavir also enhanced transduction 2-3 fold, although ABC transporter inhibitors that are not substrates did not. Enhanced transduction was not observed in mature hematopoietic cells, neurospheres, mesenchymal stem cells, or hepatocytes. Enhancement of transduction in HPCs was observed with VSV-G pseudotyped lentiviral vector, but not with vector pseudotyped with RD114. Thus, we present a new approach for efficient delivery to primitive HPCs by VSV-G pseudotyped lentiviral vectors. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Tripp, P. Banerjee, M. Sieburg, V. Planelles, F. Li, and G. Feuer Induction of Cell Cycle Arrest by Human T-Cell Lymphotropic Virus Type 1 Tax in Hematopoietic Progenitor (CD34+) Cells: Modulation of p21cip1/waf1 and p27kip1 Expression J. Virol., November 15, 2005; 79(22): 14069 - 14078. [Abstract] [Full Text] [PDF]

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