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

Yoonsung Song, Sungsin Jo, Jee Young Chung, Younseo Oh, Subin Yoon, Young Lim Lee, Seong Su Kim, Jae Hyuk Yang, Kiseok Jang, Chul Su Yang, Tae Hwan Kim, Yong Hee Kim

Research output: Contribution to journalArticlepeer-review

Abstract

Excessive tumor necrosis factor-α (TNF-α) is associated with the pathogenesis of rheumatoid arthritis (RA). Approximately 90% of patients with RA, who have inadequate response to methotrexate, follow anti-TNF-α therapy as the first-line immuno-treatment. However, ineffective long-term anti-TNF-α antibody cycling for 40% of non-responders to anti-TNF-α 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-α level was developed by using an alternative method of suppressing TNF-α converting enzyme (TACE), a transmembrane enzyme involved in cleaving and releasing bioactive soluble TNF-α. TACE suppression can be an effective remedy to block the production of soluble TNF-α, leading to an increased sensitivity to anti-TNF-α non-responders. 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-α therapeutic for RA treatment.

Original languageEnglish
Pages (from-to)1300-1312
Number of pages13
JournalJournal of Controlled Release
Volume330
DOIs
StatePublished - 2021 Feb 10

Keywords

  • Gene therapy
  • Human primary synovial cells and osteoclast precursor
  • Rheumatoid arthritis
  • TNF-α converting enzyme

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