RNA interference-mediated suppression of TNF-α converting enzyme as an alternative anti-TNF-α therapy for rheumatoid arthritis

Abstract

Excessive tumor necrosis factor-alpha (TNF-alpha) is associated with the pathogenesis of rheumatoid arthritis (RA). Approximately 90% of patients with RA, who have inadequate response to methotrexate, follow anti-TNF-alpha therapy as the first-line immuno-treatment. However, ineffective long-term anti-TNF-alpha antibody cycling for 40% of non-responders to anti-TNF-alpha antibodies is costly and associated with various side effects, which needs alternative mechanism of action therapies. In the present study, a novel strategy to down-regulate TNF-alpha level was developed by using an alternative method of suppressing TNF-alpha converting enzyme (TACE), a transmembrane enzyme involved in cleaving and releasing bioactive soluble TNF-alpha. TACE suppression can be an effective remedy to block the production of soluble TNF-alpha, leading to an increased sensitivity to anti-TNF-alpha nonresponders. A disease site-targeted RNA interference system was developed by forming non-viral complex between shRNA against TACE (shTACE) and bone resorption site-specific peptide carrier composed of aspartate repeating and arginine repeating sequences. The shTACE/peptide carrier complex alleviated arthritic symptoms in collagen induced arthritis (CIA) models by demonstrating enhanced anti-inflammatory and anti-osteoclastogenic effects. Similar results were obtained with human primary synovial cells and osteoclast precursor isolated from tissues and synovial fluids of RA patients. Taken together, the shTACE/targeting peptide complex provides a strong potential as an alternative anti-TNF-alpha therapeutic for RA treatment.