TY - JOUR
T1 - Lentiviral-mediated gene delivery to synovium
T2 - Potent intra-articular expression with amplification by inflammation
AU - Gouze, Elvire
AU - Pawliuk, Robert
AU - Gouze, Jean Noel
AU - Pilapil, Carmencita
AU - Fleet, Christina
AU - Palmer, Glyn D.
AU - Evans, Christopher H.
AU - Leboulch, Philippe
AU - Ghivizzani, Steven C.
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2003/4/1
Y1 - 2003/4/1
N2 - 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.
AB - 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.
KW - Arthritis
KW - Gene therapy
KW - IL-1Ra
KW - Lentivirus
KW - Synovium
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U2 - 10.1016/S1525-0016(03)00024-8
DO - 10.1016/S1525-0016(03)00024-8
M3 - Article
C2 - 12727108
AN - SCOPUS:0037689517
SN - 1525-0016
VL - 7
SP - 460
EP - 466
JO - Molecular Therapy
JF - Molecular Therapy
IS - 4
ER -