Local delivery of beta interferon using an adeno-associated virus type 5 effectively inhibits adjuvant arthritis in rats

Abstract

Beta interferon (IFN-β) is a cytokine with potent immunomodulatory properties and has been described as a promising therapeutic molecule for the treatment of rheumatoid arthritis (RA). IFN-β 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-β was placed under the control of an inflammation-responsive [nuclear factor (NF)-κB] promoter. After intra-articular injection of the rAAV5 constructs in rats with AA, local transcription of the transgene and production of the IFN-β protein was found, leading to a pronounced and sustained effect on paw swelling when the expression was under the control of the NF-κB-responsive promoter. Additionally, a significant beneficial effect was observed on proteoglycan depletion and erosions. Thus, intra-articular overexpression of IFN-β using a rAAV5 vector exhibits potential as an innovative therapy for the treatment of RA.