Targeting of Liver Mannan-Binding Lectin-Associated Serine Protease-3 with RNA Interference Ameliorates Disease in a Mouse Model of Rheumatoid Arthritis

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  • Nirmal K Banda, Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
  • ,
  • Dhruv Desai, Alnylam Pharmaceuticals Inc., Boston, MA 02142.
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  • Robert I Scheinman, Skaggs School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
  • ,
  • Rasmus Pihl
  • Hideharu Sekine, Department of Immunology, Fukushima Medical University, Fukushima 960-1295, Japan; and.
  • ,
  • Teizo Fujita, Department of Immunology, Fukushima Medical University, Fukushima 960-1295, Japan; and.
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  • Vibha Sharma, Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
  • ,
  • Annette G Hansen
  • Peter Garred, Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, University Hospital of Copenhagen, 2200 Copenhagen, Denmark.
  • ,
  • Steffen Thiel
  • Anna Borodovsky, Alnylam Pharmaceuticals Inc., Boston, MA 02142.
  • ,
  • V Michael Holers, Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.

Mannan-binding lectin-associated serine protease 3 (MASP-3) regulates the alternative pathway of complement and is predominantly synthesized in the liver. The role of liver-derived MASP-3 in the pathogenesis of rheumatoid arthritis (RA) is unknown. We hypothesized that liver-derived MASP-3 is essential for the development of joint damage and that targeted inhibition of MASP-3 in the liver can attenuate arthritis. We used MASP-3-specific small interfering RNAs (siRNAs) conjugated to N-acetylgalactosamine (GalNAc) to specifically target the liver via asialoglycoprotein receptors. Active GalNAc-MASP3-siRNA conjugates were identified, and in vivo silencing of liver MASP-3 mRNA was demonstrated in healthy mice. The s.c. treatment with GalNAc-MASP-3-siRNAs specifically decreased the expression of MASP-3 in the liver and the level of MASP-3 protein in circulation of mice without affecting the levels of the other spliced products. In mice with collagen Ab-induced arthritis, s.c. administration of GalNAc-MASP-3-siRNA decreased the clinical disease activity score to 50% of controls, with decrease in histopathology scores and MASP-3 deposition. To confirm the ability to perform MASP-3 gene silencing in human cells, we generated a lentivirus expressing a short hairpin RNA specific for human MASP-3 mRNA. This procedure not only eliminated the short-term (at day 15) expression of MASP-3 in HepG2 and T98G cell lines but also diminished the long-term (at day 60) synthesis of MASP-3 protein in T98G cells. Our study demonstrates that isoform-specific silencing of MASP-3 in vivo modifies disease activity in a mouse model of RA and suggests that liver-directed MASP3 silencing may be a therapeutic approach in human RA.

Original languageEnglish
JournalImmunoHorizons
Volume2
Issue8
Pages (from-to)274-295
Number of pages22
ISSN2573-7732
DOIs
Publication statusPublished - 1 Sep 2018

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