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Pharmacological inhibition of porcupine induces regression of experimental skin fibrosis by targeting Wnt signalling

Chen, Chih-wei and Beyer, Christian and Liu, Jun and Maier, Christiane and Li, Chun and Trinh-Minh, Thuong and Xu, Xiaohan and Cole, Stuart and Hsieh, Mindy Hsieh and Ng, Nicholas and Althage, Alana and Meeusen, Shelly and Pan, Shifeng and Svensson, Eric and Seidel, Martin and Schett, Georg and Gergely, Peter and Harris, Jennifer and Distler , Jorg (2017) Pharmacological inhibition of porcupine induces regression of experimental skin fibrosis by targeting Wnt signalling. Annals of the Rheumatic Diseases, 76 (4). pp. 773-778. ISSN 1468-2060

Abstract

Objectives Wnt signalling has been implicated in activating a fibrogenic programme in fibroblasts in systemic sclerosis (SSc). Porcupine is an O-Acyltransferase required for secretion of Wnt proteins in mammals. Here, we aimed to evaluate the antifibrotic effects of pharmacological inhibition of porcupine in preclinical models of SSc. Methods The porcupine inhibitor GNF6231 was evaluated in the mouse models of bleomycin-induced skin fibrosis, in tight-skin-1 mice, in murine sclerodermatous chronic-graft-versus-host disease (cGvHD) and in fibrosis induced by a constitutively active transforming growth factor-β-receptor I. Results Treatment with pharmacologically relevant and well-Tolerated doses of GNF6231 inhibited the activation of Wnt signalling in fibrotic murine skin. GNF6231 ameliorated skin fibrosis in all four models. Treatment with GNF6231 also reduced pulmonary fibrosis associated with murine cGvHD. Most importantly, GNF6231 prevented progression of fibrosis and showed evidence of reversal of established fibrosis. Conclusions These data suggest that targeting the Wnt pathway through inhibition of porcupine provides a potential therapeutic approach to fibrosis in SSc. This is of particular interest, as a close analogue of GNF6231 has already demonstrated robust pathway inhibition in humans and could be available for clinical trials.

Item Type: Article
Keywords: Fibroblasts Systemic Sclerosis Treatment
Date Deposited: 21 Nov 2017 00:45
Last Modified: 25 Jan 2019 00:45
URI: https://oak.novartis.com/id/eprint/31830

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