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Prepublished online as a Blood First Edition Paper on September 5, 2002; DOI 10.1182/blood-2002-07-2131.
Submitted July 18, 2002
Accepted August 22, 2002
Gene therapy of apolipoprotein E-deficient mice using a novel macrophage-specific retroviral vector
Peter J Gough* and Elaine W Raines
Department of Pathology, University of Washington, Seattle, WA, USA
* Corresponding author; email: pgough{at}u.washington.edu.
The use of retroviral gene transfer into haematopoietic stem cells for human gene therapy has been hampered by the absence of retroviral vectors that can generate long-lasting, lineage-specific gene expression. In this study we have developed self-inactivating retroviral vectors that incorporate gene regulatory elements from the macrophage-restricted, human CD68 gene. Through the transplantation of transduced murine haematopoietic stem cells (HSCs), we show that a vector incorporating a 342 bp fragment of 5' flanking sequence from the CD68 gene, in addition to the CD68 first intron, was able to direct macrophage-specific expression of an EGFP reporter gene in inflammatory cell exudates and lymphoid organs in vivo. Levels of EGFP expression generated by this vector were greater than a standard Moloney murine leukemia retroviral vector, and were stable for at least a year after transplantation of transduced HSCs. To evaluate the ability of this vector to generate therapeutically-useful levels of gene expression, we transplanted apolipoprotein E (ApoE) deficient mice with ApoE-deficient HSCs transduced with a virus encoding ApoE. Macrophages from these mice expressed levels of ApoE that were comparable to those from wild-type mice, and vector-driven expression of ApoE in macrophages was sufficient to reverse both hypercholesterolemia and atherosclerotic lesion development. The future application of this retroviral vector should provide a powerful tool to further elucidate macrophage function and for human gene therapy.
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