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Antifibrotic Effects of the Dual CCR2/CCR5 Antagonist Cenicriviroc in Animal Models of Liver and Kidney Fibrosis

Eric Lefebvre ; Graeme Moyle ; Ran Reshef ; Lee P Richman ; Melanie Thompson ; Feng Hong ; Hsin-L Chou ; Taishi Hashiguchi ; Craig Plato ; Dominic Poulin ; Toni Richards ; Hiroyuki Yoneyama ; Helen Jenkins ; Grushenka Wolfgang ; Scott L Friedman

PLoS ONE, 01 January 2016, Vol.11(6), p.e0158156 [Peer Reviewed Journal]

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  • Title:
    Antifibrotic Effects of the Dual CCR2/CCR5 Antagonist Cenicriviroc in Animal Models of Liver and Kidney Fibrosis
  • Author: Eric Lefebvre ; Graeme Moyle ; Ran Reshef ; Lee P Richman ; Melanie Thompson ; Feng Hong ; Hsin-L Chou ; Taishi Hashiguchi ; Craig Plato ; Dominic Poulin ; Toni Richards ; Hiroyuki Yoneyama ; Helen Jenkins ; Grushenka Wolfgang ; Scott L Friedman
  • Description: Interactions between C-C chemokine receptor types 2 (CCR2) and 5 (CCR5) and their ligands, including CCL2 and CCL5, mediate fibrogenesis by promoting monocyte/macrophage recruitment and tissue infiltration, as well as hepatic stellate cell activation. Cenicriviroc (CVC) is an oral, dual CCR2/CCR5 antagonist with nanomolar potency against both receptors. CVC's anti-inflammatory and antifibrotic effects were evaluated in a range of preclinical models of inflammation and fibrosis.Monocyte/macrophage recruitment was assessed in vivo in a mouse model of thioglycollate-induced peritonitis. CCL2-induced chemotaxis was evaluated ex vivo on mouse monocytes. CVC's antifibrotic effects were evaluated in a thioacetamide-induced rat model of liver fibrosis and mouse models of diet-induced non-alcoholic steatohepatitis (NASH) and renal fibrosis. Study assessments included body and liver/kidney weight, liver function test, liver/kidney morphology and collagen deposition, fibrogenic gene and protein expression, and pharmacokinetic analyses.CVC significantly reduced monocyte/macrophage recruitment in vivo at doses ≥20 mg/kg/day (p < 0.05). At these doses, CVC showed antifibrotic effects, with significant reductions in collagen deposition (p < 0.05), and collagen type 1 protein and mRNA expression across the three animal models of fibrosis. In the NASH model, CVC significantly reduced the non-alcoholic fatty liver disease activity score (p < 0.05 vs. controls). CVC treatment had no notable effect on body or liver/kidney weight.CVC displayed potent anti-inflammatory and antifibrotic activity in a range of animal fibrosis models, supporting human testing for fibrotic diseases. Further experimental studies are needed to clarify the underlying mechanisms of CVC's antifibrotic effects. A Phase 2b study in adults with NASH and liver fibrosis is fully enrolled (CENTAUR Study 652-2-203; NCT02217475).
  • Is Part Of: PLoS ONE, 01 January 2016, Vol.11(6), p.e0158156
  • Identifier: E-ISSN: 1932-6203 ; DOI: 10.1371/journal.pone.0158156
  • Subjects: Sciences (General)
  • Language: English
  • Source: Directory of Open Access Journals (DOAJ)

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