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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).

An in vivo method for adenovirus-mediated transduction of thick ascending limbs. The thick ascending limb of the loop of Henle (THAL) plays an important role in the maintenance of salt, water, and acid-base balance. While techniques for gene transfer of renal vascular cells and some tubular segments have been described, in vivo transduction of THALs has not been successful. We hypothesized that in vivo injection of adenoviral vectors into the renal medulla would result in efficient transduction of THALs. We injected recombinant adenoviruses containing the reporter gene, green fluorescent protein (GFP), driven by either the cytomegalovirus promoter (Ad-CMVGFP) or the promoter for the Na/K/2 Cl cotransporter (Ad-NKCC2GFP), which is THAL-specific, into the outer medullary interstitium of Sprague-Dawley rat kidneys. Kidneys were removed at various times after viral injection and analyzed for GFP expression. Western blots revealed strong GFP expression in the outer medulla (which is composed primarily of THALs) 5 days after Ad-CMVGFP injection. We quantified THAL transduction efficiency by scoring the number of fluorescent tubules in THALs suspensions, which showed that at least 77 ± 3% of THAL expressed GFP. To specifically transduce THALs, we injected Ad-NKCC2GFP into the medullary interstitium. As determined by Western blot, GFP expression was only detected in the outer medulla. Immunohistochemistry and confocal microscopy showed that GFP was localized to tubular cells positive for Tamm-Horsfall protein. Thus, GFP fluorescence was only detected in THALs, not in cortical, inner medulla or vascular cells. Time-course studies showed that GFP expression in THALs was measurable from 4 to 14 days, peaked at 7 days, and had returned to background levels by 21 days. This method facilitates highly efficient, THAL-specific transduction. While application of this technique for gene therapy in humans is unlikely due to the transient gene expression observed and the impossibility for repeated injections of adenoviral vectors, this method provides a valuable tool for investigators studying regulation and mechanisms of THAL ion transport and its relationship to whole-kidney physiology and pathophysiology.