Lentiviral-mediated gene delivery to synovium: Potent intra-articular expression with amplification by inflammation

Elvire Gouze, Robert Pawliuk, Jean Noel Gouze, Carmencita Pilapil, Christina Fleet, Glyn D. Palmer, Christopher H. Evans, Philippe Leboulch, Steven C. Ghivizzani

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

Clinical translation of gene-based therapies for arthritis could be accelerated by vectors capable of efficient intra-articular gene delivery and long-term transgene expression. Previously, we have shown that lentiviral vectors transduce rat synovium efficiently in vivo. Here, we evaluated the functional capacity of transgene expression provided by lentiviral-mediated gene delivery to the joint. To do this, we measured the ability of a lentiviral vector containing the cDNA for human interleukin-1 receptor antagonist (LV-hIL-1Ra) to suppress intra-articular responses to IL-1β. Groups of rats were injected in one knee with 5 × 107 infectious units of LV-IL-1Ra. After 24 h, a range of doses of fibroblasts (3 × 103, 104 , 3 × 104, or 105 cells) genetically modified to overexpress IL-1β was injected into both knees. Intra-articular delivery of LV-hIL-1Ra strongly prevented swelling in all treated knees, even in those receiving the greatest dose of IL-1β+ cells. Cellular infiltration, cartilage erosion, and invasiveness of inflamed synovium were effectively prevented in LV-hIL-1Ra-treated knees and were significantly inhibited in contralateral joints. Beneficial effects were also observed systemically in the lentivirus-treated animals. Interestingly, intra-articular expression of the IL-1Ra transgene was found to increase in relation to the number of IL-1β+ cells injected. Further experiments using GFP suggest this is due to the proliferation of cells, stably modified by the integrative lentivirus, in response to inflammatory stimulation.

Original languageEnglish (US)
Pages (from-to)460-466
Number of pages7
JournalMolecular Therapy
Volume7
Issue number4
DOIs
StatePublished - Apr 1 2003

Keywords

  • Arthritis
  • Gene therapy
  • IL-1Ra
  • Lentivirus
  • Synovium

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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  • Cite this

    Gouze, E., Pawliuk, R., Gouze, J. N., Pilapil, C., Fleet, C., Palmer, G. D., Evans, C. H., Leboulch, P., & Ghivizzani, S. C. (2003). Lentiviral-mediated gene delivery to synovium: Potent intra-articular expression with amplification by inflammation. Molecular Therapy, 7(4), 460-466. https://doi.org/10.1016/S1525-0016(03)00024-8