Local delivery of beta interferon using an adeno-associated virus type 5 effectively inhibits adjuvant arthritis in rats.
Beta interferon (IFN-beta) is a cytokine with potent immunomodulatory properties and has been described as a promising therapeutic molecule for the treatment of rheumatoid arthritis (RA). IFN-beta was previously overexpressed intra-articularly using an adenoviral vector in rats with adjuvant arthritis (AA) as a model of RA. This effect was powerful, albeit transient due to the vector chosen. Therefore, in the context of pre-clinical development, a delivery vector optimized for intra-articular gene transfer, recombinant adeno-associated virus type 5 (rAAV5), was selected. To exert an optimal effect, protein production should parallel the course of the disease. For this reason, the gene for IFN-beta was placed under the control of an inflammation-responsive [nuclear factor (NF)-kappaB] promoter. After intra-articular injection of the rAAV5 constructs in rats with AA, local transcription of the transgene and production of the IFN-beta protein was found, leading to a pronounced and sustained effect on paw swelling when the expression was under the control of the NF-kappaB-responsive promoter. Additionally, a significant beneficial effect was observed on proteoglycan depletion and erosions. Thus, intra-articular overexpression of IFN-beta using a rAAV5 vector exhibits potential as an innovative therapy for the treatment of RA.
Adriaansen
J
J
Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.
Fallaux
F J
FJ
Arthrogen BV, Amsterdam, The Netherlands.
de Cortie
C J
CJ
Arthrogen BV, Amsterdam, The Netherlands.
Vervoordeldonk
M J
MJ
Arthrogen BV, Amsterdam, The Netherlands.|Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.
Tak
P P
PP
Arthrogen BV, Amsterdam, The Netherlands.|Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.
D000818:Animals; D001169:Arthritis, Experimental / Q000628:therapy*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006651:Histocytochemistry; D007155:Immunologic Factors / Q000096:biosynthesis / Q000235:genetics; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics*; D051381:Rats
D007155:Immunologic Factors; D016899:Interferon-beta