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Applications of RNA interference in the treatment of arthritis

  • Muhammad Farooq Rai
    Affiliations
    Department of Orthopedic Surgery, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, Missouri

    Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, Missouri
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  • Hua Pan
    Affiliations
    Department of Cardiovascular Sciences, University of South Florida Health Heart Institute, Morsani School of Medicine, Tampa, Florida
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  • Huimin Yan
    Affiliations
    Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, Missouri, USA
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  • Linda J. Sandell
    Affiliations
    Department of Orthopedic Surgery, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, Missouri

    Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, Missouri
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  • Christine T.N. Pham
    Correspondence
    Reprint requests: Christine Pham, Washington University School of Medicine, 660 South Euclid Avenue, Box 8045, Saint Louis, MO 63110;
    Affiliations
    Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, Missouri, USA

    Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri
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  • Samuel A. Wickline
    Affiliations
    Department of Cardiovascular Sciences, University of South Florida Health Heart Institute, Morsani School of Medicine, Tampa, Florida
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      RNA interference (RNAi) is a cellular mechanism for post-transcriptional gene regulation mediated by small interfering RNA (siRNA) and microRNA. siRNA-based therapy holds significant promise for the treatment of a wide-range of arthritic diseases. siRNA selectively suppresses the expression of a gene product and can thus achieve the specificity that is lacking in small molecule inhibitors. The potential use of siRNA-based therapy in arthritis, however, has not progressed to clinical trials despite ample evidence for efficacy in preclinical studies. One of the main challenges to clinical translation is the lack of a suitable delivery vehicle to efficiently and safely access diverse pathologies. Moreover, the ideal targets in treatment of arthritides remain elusive given the complexity and heterogeneity of these disease pathogeneses. Herein, we review recent preclinical studies that use RNAi-based drug delivery systems to mitigate inflammation in models of rheumatoid arthritis and osteoarthritis. We discuss a self-assembling peptide-based nanostructure that demonstrates the potential of overcoming many of the critical barriers preventing the translation of this technology to the clinic.

      Abbreviations:

      ADAM (a disintegrin and metalloproteinase), ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs), Ago2 (argonaute RNA-induced silencing complex catalytic component 2), C5aR1 (C5a receptor 1), CAIA (collagen antibody induced arthritis), CCR5 (C-C motif chemokine receptor 5), CH (chitosan), CIA (collagen induced arthritis), FDA (Food and Drug Administration), GalNAc (N-acetylgalactosamine), Hif2a (Hypoxia-induced factor 2a), hnRNP (heterogeneous nuclear RNP), Ihh (Indian hedgehog), IL (interleukin), MASP (mannan-binding lectin-associated serine protease), MMP (matrix metalloproteinase), MPS (macrophage phagocytic system), NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), OA (osteoarthritis), PCL (ε-polycaprolactone), PDAPEI (2,6-pyridinedicarboxaldehyde polyethyleneimine), PEG (polyethylene glycol), PEG-PLL-PLeu (Poly(ethylene glycol)-b-poly(L-lysine)-b-poly(L-leucine)), PEI (polyethyleneimine), PFC NP (perfluorocarbon nanoparticle), PTOA (post-traumatic OA), RA (rheumatoid arthritis), RISC (RNA induced silencing complex), RNAi (RNA interference), RORγT (retinoic acid-related orphan receptor gamma t), siRNA (small interfering RNA), SPIO (superparamagnetic iron oxide), TNF (tumor necrosis factor), YAP (Yes-associated protein)
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