Intra-articular electrotransfer of plasmid encoding soluble TNF receptor variants in normal and arthritic mice.
BACKGROUND
Anti-inflammatory gene therapy is promising in inflammatory diseases such as rheumatoid arthritis (RA). We have previously demonstrated that intra-muscular (i.m.) electrotransfer (ET) of plasmids encoding three different human tumor necrosis factor-alpha-soluble receptor I variants (hTNFR-Is) exert protective effects in an experimental RA model. However, such a systemic approach could be responsible for side effects. The present study aimed at performing an intra-articular (i.a.) gene therapy by electrotransfer using the hTNFR-Is plasmids.


RESULTS
We evaluated targeting of mice joints by CCD optical imaging after i.a. ET of a luciferase-encoding plasmid and we showed that ET led to strongly increased transgene expression in a plasmid dose-dependent manner. Moreover, articular and seric hTNFR-Is was detectable for 2 weeks. As expected, systemic hTNFR-Is rates were lower after i.a. ET than after i.m. ET. A longer protein secretion could be achieved with several i.a. ETs. Also, we observed that hTNFR-Is expression within arthritic joints was slightly higher than in normal joints.


CONCLUSIONS
In collagen-induced arthritis (CIA), a mouse model for RA, we demonstrated that hTNFR-Is/mIgG1-encoding plasmid i.a. ET decreased joint destruction in the ankles. In conclusion, our results suggest that local TNFR-Is gene therapy may play a role in decreasing joint destruction in CIA.
Bloquel
C
C
Inserm, Eri-18, F-93017 Bobigny, France.
Denys
A
A
Boissier
M C
MC
Apparailly
F
F
Bigey
P
P
Scherman
D
D
Bessis
N
N
D000818:Animals; D000842:Ankle; D001169:Arthritis, Experimental / Q000628:therapy*; D016503:Drug Delivery Systems / Q000379:methods*; D018274:Electroporation; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007249:Inflammation / Q000628:therapy*; D007596:Joints; D051379:Mice; D010957:Plasmids / Q000008:administration & dosage*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000008:administration & dosage* / Q000235:genetics
D047888:Receptors, Tumor Necrosis Factor, Type I