Intra-articular electrotransfer of mouse soluble tumour necrosis factor receptor in a murine model of rheumatoid arthritis.
BACKGROUND
Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes inflammation and destruction of the joints. In the collagen-induced arthritis mouse model of RA, we developed a nonviral gene therapy method designed to block in situ the main cytokine tumour necrosis factor (TNF)-alpha


METHODS
Electrotransfer was used to deliver a plasmid encoding extracellular domain of mouse soluble TNF-alpha receptor type I fused to the Fc fragment of mouse immunoglobulin (Ig)G1 (pTNFR-Is) corresponding to a dimeric TNF-alpha soluble receptor fusion protein (mTNFR-Is/Ig).


RESULTS
Delivery of the plasmid into the knees at symptom onset improved the histological inflammation and destruction not only at the knees, but also at the ankles, indicating a local and a regional therapeutic effect. The plasmid was detected in synovial membrane and meniscus specimens from the injected joints. In the synovial membrane, 15 days post-injection, interleukin (IL)-17 and TNF-alpha mRNAs expression were increased, whereas IL-10 mRNA was unchanged. However, the empty plasmid exerted a pro-inflammatory effect 30 days post-injection.


CONCLUSIONS
These data indicate that local nonviral gene therapy against TNF-alpha is effective, although further work is needed to decrease plasmid induced inflammation.
Denys
Anne
A
EA4222, Li2P, University of Paris 13, Bobigny, France. a.denys@smbh.univ-paris13.fr
Thiolat
Allan
A
Descamps
Delphyne
D
Lemeiter
Delphine
D
Benihoud
Karim
K
Bessis
Nakacha
N
Boissier
Marie-Christophe
MC
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000628:therapy*; D018274:Electroporation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D023421:Models, Animal; D010957:Plasmids / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics* / Q000378:metabolism; D013583:Synovial Membrane / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D020381:Interleukin-17; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10