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.
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Handling editor Tore K Kvien
JL, JLH and JHWD are co-corresponding authors.
Contributors Design of the study: C-WC, CB, JL, JLH and JHWD. Acquisition of data: C-WC, CB, JL, CM, CL, TT-M, XX, SHC, MHH, NN, AA, SM, SP, ECS, HMS, JLH and JHWD. Interpretation of data: CWC, CB, JL, CM, DL, TTM, XX, SHC, MHH, NN, AA, SM, SP, ECS, HMS, JLH and JHWD. Manuscript preparation: C-WC, CB, JL, CM, JLH and JHWD.
Funding Grant support was provided by the Erlanger Leistungsbezogene Anschubfinanzierung und Nachwuchsförderung (ELAN), grants J29 and A40 of the Interdisciplinary Center of Clinical Research (IZKF) in Erlangen and grants DI 1537/1-1, DI 1537/2-1, DI 1537/4-1, AK 144/1-1, BE 5191/1-1 and SCHE 1583/7-1 from the Deutsche Forschungsgemeinschaft. In addition, the study was supported by the Career Support Award of Medicine of the Ernst Jung Foundation (to JHWD).
Competing interests JHWD has consultancy relationships and/or has received research funding from Actelion, Pfizer, Ergonex, BMS, Celgene, Bayer Pharma, JB Therapeutics, Sanofi-Aventis, Novartis, Array Biopharma and Active Biotec in the area of potential treatments of systemic sclerosis and is stock owner of 4D Science. JL, CL, SHC, MHH, NN, AA, MS, SM, SP, ECS, HMS, PG and JLH are employees of Novartis.
Provenance and peer review Not commissioned; externally peer reviewed.
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