A comparative study on intra-articular versus systemic gene electrotransfer in experimental arthritis.
BACKGROUND
Electric pulse mediated gene transfer has been applied successfully in vivo for increasing naked DNA administration in various tissues. To achieve non-viral gene transfer into arthritic joint tissue, we investigated the use of electrotransfer (ET). Because anti-inflammatory cytokine strategies have proven efficient in experimental models of arthritis, we compared the therapeutic efficiency of local versus systemic delivery of the interleukin-10 (IL-10) using in vivo ET.


METHODS
A plasmid vector expressing IL-10 was transferred into DBA/1 mouse knee joints by ET with 12 pulses of variable duration and voltage. The kinetics of transgene expression were analyzed by specific enzyme-linked immunosorbent assay (ELISA) in sera and knees. Optimal conditions were then used to deliver increasing amounts of IL-10 plasmid intra-articularly (i.a.) in the collagen-induced arthritis (CIA) mouse model. The therapeutic efficiency was compared with the potency of intra-muscular (i.m.) ET.


RESULTS
Following i.a. ET, local IL-10 secretion peaked on day 7 and dropped 2 weeks after. A second ET produced the same kinetics without enhancing gene transfer efficiency, while transgene was still detected in injected muscles 4 weeks after ET. Only the i.m. ET of 25 microg of IL-10 significantly inhibited all the clinical and biological features of arthritis. The i.a. ET only showed mild improvement of arthritis when 100 microg of IL-10 plasmid were electrotransfered weekly from day 18 following arthritis induction.


CONCLUSIONS
The present results suggest that gene transfer into arthritic joints by ET is an effective means to deliver anti-inflammatory cytokines. However, short duration of transgene expression impedes a significant effect for the treatment of arthritis, making i.m. ET more potent than i.a. ET for clinical benefit in CIA.
Khoury
M
M
Inserm, U 475, F-34000 Montpellier, France.
Bigey
P
P
Louis-Plence
P
P
Noel
D
D
Rhinn
H
H
Scherman
D
D
Jorgensen
C
C
Apparailly
F
F
D000818:Animals; D001169:Arthritis, Experimental / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D002358:Cartilage, Articular / Q000378:metabolism*; D002417:Cattle; D049109:Cell Proliferation; D003094:Collagen / Q000276:immunology / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D018274:Electroporation; D005240:Feasibility Studies; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D007700:Kinetics; D007719:Knee Joint / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D010957:Plasmids; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D013997:Time Factors; D019076:Transgenes
D016207:Cytokines; D003094:Collagen