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- Title
1067. Amelioration of Arthritis after Local Delivery of an Adeno-Associated Virus Type 6 Expressing a TNF-Blocking Agent under a Disease-Inducible Promoter.
- Authors
Khoury, Maroun; Adriaansen, Jan; Louis-Plence, Pascale; Noel, Danièle; Bigey, Pascal; de Cortie, C.; Gould, David; Vervoordeldonk, Margriet; Scherman, Daniel; Tak, Paul-Peter; Jorgensen, Christian; Apparailly, Florence
- Abstract
Aim: Intra-articular gene delivery using adeno-associated virus (AAV) vectors has great potential for the treatment of rheumatoid arthritis (RA). We found that direct injection of recombinant (r)AAV5 into the knee joints of DBA/1 mice with collagen-induced arthritis (CIA) resulted in the highest synovial transduction. Since anti-TNF strategies have proven effective for the treatment of RA, we studied the potential of intra-articular gene delivery using a rAAV5 encoding a chimeric human TNF-α soluble receptor I variant (TNFR- Ig) in CIA. Moreover, the therapeutic gene was expressed under a chimeric disease-inducible NF-κB and IL-6-responsive promoter (NL6).Methods: Transduced COS cells were used to validate in vitro the promoter responsiveness to LPS. The induced TNFR-Ig secretion was measured by ELISA and its potential to block TNF-α was assessed using the TNF-α sensitive WEHI-164 cell bio-assay. Both knee joints of mice were injected 2 weeks after immunization with increasing doses of rAAV5-CMV-TNFR-Ig or rAAV5-NL6-TNFR- Ig vectors, and rAAV5-CMV-GFP was used as control. Clinical course of the disease was assessed by paw thickness measuring over time, radiological and histological scores were obtained at euthanasia. The TNFR-Ig and TNF-α were measured by ELISA in sera and knee-joint conditioned media. The disease-inducibility after repetitive LPS challenges was investigated in Balbc mice following rAAV5-NL6-TNFR-Ig vector injection into knee joints.Results: Proteins transcribed from both constructs were proven bioactive in vitro and transcription was responsive to LPS (68 fold increase after stimulation). In the mice treated with both the rAAV5- CMV- and rAAV5-NL6-TNFR-Ig vectors a significant reduction of paw swelling and arthritis incidence was observed. The expression of the transgene in the injected joints was stable or transient depending on the used promoter, and associated with decreased local and systemic TNF-α production. While the TNF-α expression was stably maintained low for 8 weeks when the transgene was driven by the CMV promoter, it peaks 1 week after intra-articular injection of LPS and drops to the basal levels 3 weeks after when the transgene was driven by the NL6 promoter.Conclusion: These results show that rAAV5 may be a useful method for local delivery of cytokine or anti-cytokine therapy in RA. In addition, disease-regulated transgene expression for physiologically responsive gene therapy of arthritis seems feasible.Molecular Therapy (2006) 13, S409–S409; doi: 10.1016/j.ymthe.2006.08.1165
- Subjects
RHEUMATOID arthritis; RECOMBINANT viruses; KNEE; TUMOR necrosis factors; THERAPEUTICS; GENES
- Publication
Molecular Therapy, 2006, Vol 13, pS409
- ISSN
1525-0016
- Publication type
Article
- DOI
10.1016/j.ymthe.2006.08.1165