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

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 Signaling. Annals of the Rheumatic Diseases (1-6). pp. 1-6.

Abstract

Objectives. Wnt signaling has been implicated in activating a fibrogenic program 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 anti-fibrotic effects of pharmacologic 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 (Tsk1) mice, in murine sclerodermatous chronic-graft-versus-host disease (cGvHD) and in fibrosis induced by a constitutively-active TGFbeta-receptor I (TBR).

Results. Treatment with pharmacologically relevant and well tolerated doses of GNF6231 inhibited the activation of Wnt signaling 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, not only did GNF6231 prevent progression of fibrosis, it also 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 analog of GNF6231 has already demonstrated robust pathway inhibition and tolerability in humans and could be available for clinical trials.

Item Type: Article
Date Deposited: 22 Feb 2017 00:45
Last Modified: 22 Feb 2017 00:45
URI: https://oak.novartis.com/id/eprint/29769

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