Targeting of Liver Mannan-Binding Lectin-Associated Serine Protease-3 with RNA Interference Ameliorates Disease in a Mouse Model of Rheumatoid Arthritis
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Targeting of Liver Mannan-Binding Lectin-Associated Serine Protease-3 with RNA Interference Ameliorates Disease in a Mouse Model of Rheumatoid Arthritis. / Banda, Nirmal K; Desai, Dhruv; Scheinman, Robert I; Pihl, Rasmus; Sekine, Hideharu; Fujita, Teizo; Sharma, Vibha; Hansen, Annette G; Garred, Peter; Thiel, Steffen; Borodovsky, Anna; Holers, V Michael.
In: ImmunoHorizons, Vol. 2, No. 8, 2018, p. 274-295.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Targeting of Liver Mannan-Binding Lectin-Associated Serine Protease-3 with RNA Interference Ameliorates Disease in a Mouse Model of Rheumatoid Arthritis
AU - Banda, Nirmal K
AU - Desai, Dhruv
AU - Scheinman, Robert I
AU - Pihl, Rasmus
AU - Sekine, Hideharu
AU - Fujita, Teizo
AU - Sharma, Vibha
AU - Hansen, Annette G
AU - Garred, Peter
AU - Thiel, Steffen
AU - Borodovsky, Anna
AU - Holers, V Michael
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
U2 - 10.4049/immunohorizons.1800053
DO - 10.4049/immunohorizons.1800053
M3 - Journal article
C2 - 30417171
VL - 2
SP - 274
EP - 295
JO - ImmunoHorizons
JF - ImmunoHorizons
SN - 2573-7732
IS - 8
ER -
ID: 218726013