Inflammation-inducible anti-TNF gene expression mediated by intra-articular injection of serotype 5 adeno-associated virus reduces arthritis.
BACKGROUND
The tumor necrosis factor (TNF)-alpha plays a central role in rheumatoid arthritis (RA) and current biotherapies targeting TNF-alpha have a major impact on RA treatment. The long-term safety concerns associated with the repetitive TNF blockade prompt optimization of therapeutic anti-TNF approaches. Since we recently demonstrated that intra-articular gene transfer using a recombinant adeno-associated virus serotype 5 (rAAV5) efficiently transduces arthritic joints, we evaluate its effect on collagen-induced arthritis (CIA) when encoding TNF antagonists.


METHODS
Recombinant AAV5 vectors encoding the human TNFRp55 extracellular domain fused to the Fc region of mice IgG1 (TR1) or a small molecular weight dimeric human TNFRp75 extracellular domain (TR2), under two different promoters, the CMV or a chimeric NF-kappaB-based promoter inducible by inflammation, were injected into mouse CIA joints.


RESULTS
Best protection against arthritis was obtained with the rAAV5 encoding the TR1, as reflected by delayed disease onset, decreased incidence and severity of joint damage. This effect was associated with a transient expression of the anti-TNF agent when expressed under a NF-kappaB-responsive promoter, only detectable during disease flare, while the antagonist expression was rapidly increased and stable when expressed from a CMV promoter. Importantly, using the intra-articular administration of the rAAV5-NF-kappaB-TR1 vector, we observed a striking correlation between local TR1 expression and inflammation.


CONCLUSIONS
These findings strongly support the feasibility of improving the safety of anti-TNF approaches for the treatment of arthritis by local rAAV5-mediated gene expression under an inflammation-responsive promoter, able to provide a limited, transient and therapeutically relevant expression of anti-TNF compounds.
Khoury
M
M
Inserm, U 844, F-34091 Montpellier, France.
Adriaansen
J
J
Vervoordeldonk
M J B M
MJ
Gould
D
D
Chernajovsky
Y
Y
Bigey
P
P
Bloquel
C
C
Scherman
D
D
Tak
P P
PP
Jorgensen
C
C
Apparailly
F
F
D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D019556:COS Cells; D002417:Cattle; D002522:Chlorocebus aethiops; D016207:Cytokines / Q000494:pharmacology; D000229:Dependovirus / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007249:Inflammation; D007270:Injections, Intra-Articular; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D015203:Reproducibility of Results; D019076:Transgenes; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha