Lentiviral-mediated gene delivery to synovium: potent intra-articular expression with amplification by inflammation.
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-1beta. Groups of rats were injected in one knee with 5 x 10(7) infectious units of LV-IL-1Ra. After 24 h, a range of doses of fibroblasts (3 x 10(3), 10(4), 3 x 10(4), or 10(5) cells) genetically modified to overexpress IL-1beta 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-1beta(+) 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-1beta(+) 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.
Center for Molecular Orthopaedics, Boston, Massachusetts 02115, USA.
Elvire
E
Gouze
Robert
R
Pawliuk
Jean-Noel
JN
Gouze
Carmencita
C
Pilapil
Christina
C
Fleet
Glyn D
GD
Palmer
Christopher H
CH
Evans
Philippe
P
Leboulch
Steven C
SC
Ghivizzani
D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D005822:Genetic Vectors / Q000008:administration & dosage; D006614:Hindlimb / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007270:Injections, Intra-Articular; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D007596:Joints / Q000378:metabolism / Q000473:pathology; D016086:Lentivirus / Q000235:genetics*; D008297:Male; D008856:Microscopy, Fluorescence; D051381:Rats; D017208:Rats, Wistar; D012795:Sialoglycoproteins / Q000235:genetics* / Q000378:metabolism; D013583:Synovial Membrane / Q000378:metabolism*
C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D012795:Sialoglycoproteins