Pharmacological Blockade of Canonical Wnt Signaling for the Treatment of Systemic Sclerosis and Other Fibrotic Diseases

• Applicant: Dr. Christian Beyer
• Subject Area: Rheumatology
• Term: from 2012 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 227045208

Fibrosis results from the excessive accumulation of extracellular matrix, which leads to the disruption of the physiologic tissue architecture and failure of the affected organs. In systemic sclerosis (SSc), a prototypical fibrotic disease, fibrosis of the skin, lungs, gastrointestinal tract and the cardiovascular system leads to high morbidity and mortality among patients. Canonical Wnt signaling has a central role in the development of fibrosis. We have shown that overexpression of Wnt-1 and Wnt-10b leads to accumulation of beta-catenin and increased transcription of pro-fibrotic target genes in SSc. The development of massive fibrosis of the skin and internal organs upon overexpression of Wnt-10b or stabilization of beta-catenin in fibroblasts further highlights the crucial role of canonical Wnt signaling in fibrogenesis. By contrast, fibroblast-specific deletion of beta-catenin significantly inhibits experimental dermal fibrosis suggesting a therapeutic potential of canonical Wnt signaling. The canonical Wnt signaling pathway offers several therapeutic targets that we will study in the proposed project. This includes inhibition of Wnt secretion by porcupine inhibitors, stabilization of Axin via Tankyrase inhibitors, inhibition of beta-catenin-cofactor-binding and blockade of beta-catenin-dependent transcription of target genes. The major goal of this pre-clinical project is selecting potent and tolerable therapies to block pro-fibrotic Wnt signaling in future clinical studies. We will test both the potency and tolerability of the above-mentioned therapeutic strategies in in vitro- and in vivo-models for different clinical scenarios, including (1) treatment of different fibrotic diseases (SSc, lung fibrosis, chronic Graft-versus-Host Disease), (2) early and inflammation-dependent stages as well as late and non-inflammatory stages of fibrotic diseases, and (3) prevention and treatment of fibrosis. Using genetic knock-out models as well as pharmacological inhibitors we will analyze the molecular signaling pathways in detail. As pharmacological inhibitors are available for all of the selected Wnt targets, with some of them having already entered clinical trials in oncology, our project has a great translational potential. Potent anti-fibrotic therapies to treat SSc and other fibrotic diseases are not available in clinical routine. Because of the high morbidity and mortality among patients suffering from these diseases, however, the clinical need is tremendous. Our comprehensive project shall path the way for clinical studies with Wnt inhibitors to treat fibrosis.

• DFG Programme: Research Grants