Intraarticular Gene Transfer of TNFR:Fc Suppresses Experimental Arthritis with Reduced Systemic Distribution of the Gene Product

Abstract

Tumor necrosis factor alpha (TNFalpha) plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA). Blockage of TNFalpha actions by systemic administration of TNF antagonists has recently been shown to ameliorate joint symptoms in RA patients. In the present study, a streptococcal cell wall (SCW)-induced rat arthritis model was used to evaluate the effect of different gene transfer routes of a TNF antagonist on the development and severity of arthritis. Successful delivery of a plasmid DNA encoding a rat TNF receptor-immunoglobulin Fc (TNFR:Fc) fusion gene prompted the subsequent administration of a recombinant adeno-associated virus (rAAV) vector encoding the antagonist, either locally (intraarticular) or systemically (intramuscular). The TNFR:Fc gene, delivered by either route, resulted in profound suppression of the arthritis as reflected in decreased inflammatory cell infiltration, pannus formation, cartilage and bone destruction, and mRNA expression of joint proinflammatory cytokines. Increased bioactive serum TNFR levels were detected as a result of rAAV-ratTNFR:Fc administration, concomitant with a decrease in circulating TNFalpha. Administration of the rAAV-ratTNFR:Fc vector to one joint also suppressed arthritis in the contralateral joint. Importantly, intraarticular administration resulted in significantly lower systemic distribution of the gene product. Hence, the use of rAAV as the delivery vector for TNFR:Fc effectively suppressed SCW-induced arthritis and may provide an approach for local delivery of antiarthritic therapy.

An inflammation-inducible adenoviral expression system for local treatment of the arthritic joint

“…The 'contralateral effect', that is the administration of the expression vector in one joint to suppress arthritis in distal or contralateral joints, has been reported by many laboratories. [47][48][49][50][51][52] This study, which shows activation of the IL-1/IL-6 enhancer-promoter in the contralateral joints by signals derived from the arthritic joint, suggests that there is crosstalk between joints. Treatment of one joint may interfere with this crosstalk and by this suppresses arthritis in the other contralateral joint.…”

Gene Therapy Challenges in Arthritis

“…The contralateral effect doesn't depend on : 1. the strategy using ex vivo or in vivo (Kim et al, 2002;Kim et al, 2005;Whalen et al, 1999) 2. the vector injected in vivo because it was observed using viral vector, adenovirus, adeno-associated virus and non viral vector (Chan et al, 2002;Ghivizzani et al, 1998;, 3. the model of arthritis because it is observed in CIA, AIA and Streptococcal Cell wall (SCW)-induced arthritis (Chan et al, 2002;Kim et al, 2005;Lechman et al, 2003), 4. species as observed in rabbits , in rats , in mice and also in human clinical trials (Chan et al, 2002;Ghivizzani et al, 1998;Wehling et al, 2009). The reason of the contralateral effect with in vivo gene transfer is not well known.…”

Application des techniques de thérapie génique aux maladies ostéo-articulaires

“…Face à la chronicité des processus impliqués dans la PR, une stratégie bloquant les phases de poussées inflammatoires constitue une autre approche thérapeutique. Chez le rat, l'administration intra-articulaire ou systémique d'un adeno-associated virus de type 2 (AAV-2) exprimant le récepteur du TNFα (p75, TNFR) couplé à une immunoglobuline (TNFR:Fc) (Ethanercept) dans un modèle d'arthrite induite par le streptocoque se traduit par une très forte diminution de l'infiltration cellulaire, de la formation du pannus, de la dégradation des tissus cartilagineux et osseux et de l'expression des ARN messagers de différentes cytokines pro-inflammatoires [11]. Des résultats similaires ont été obtenus après administration intra-articulaire de la forme soluble du TNFR à des souris transgéniques arthritiques exprimant le TNFα [12].…”