Development of a synthetic promoter for macrophage gene therapy

Weijing He, Mei Qiang, Wuqiong Ma, Anthony J. Valente, Marlon P. Quinones, Wen Wang, Robert L. Reddick, Qifu Xiao, Seema S. Ahuja, Robert A. Clark, Gregory L. Freeman, Senlin Li

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Macrophages have the potential to deliver therapeutic genes to many target tissues. Macrophage-specific synthetic promoters (SPs) generated by random ligation of myeloid/macrophage cis elements had activity up to 100-fold that of a native macrophage promoter in macrophage cell lines, but were minimally active in nonmyeloid cells. Mouse bone marrow cells (BMCs) transduced ex vivo with lentivectors expressing green fluorescent protein (GFP) driven either by an SP (SP-GFP) or a cytomegalovirus (CMV) promoter (CMV-GFP) were used for syngeneic transplantation of lethally irradiated mice. Blood leukocytes showed stable GFP expression for up to 15 months after transplantation. SP-GFP expression was selective for CD11b9+ macrophages, whereas CMV-GFP expression was observed in erythrocytes, as well as in both CD11b+ and CD11b - leukocytes. Furthermore, SP-GFP expression was much stronger than CMV-GFP expression in CD11b+ macrophages. apoE-/- BMCs transduced with the lentiviral vector encoding human apoE were used to transplant apoE-/- mice. Macrophage expression of apoE from 10 to 26 weeks of age significantly reduced atherosclerotic lesions in recipient apoE-/- mice. Thus, the novel SPs, especially when combined with lentivectors, are useful for macrophage-specific delivery of therapeutic genes.

Original languageEnglish (US)
Pages (from-to)949-959
Number of pages11
JournalHuman Gene Therapy
Volume17
Issue number9
DOIs
StatePublished - Sep 1 2006

    Fingerprint

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

He, W., Qiang, M., Ma, W., Valente, A. J., Quinones, M. P., Wang, W., Reddick, R. L., Xiao, Q., Ahuja, S. S., Clark, R. A., Freeman, G. L., & Li, S. (2006). Development of a synthetic promoter for macrophage gene therapy. Human Gene Therapy, 17(9), 949-959. https://doi.org/10.1089/hum.2006.17.949