MP: Tankyrase inhibition as a therapeutic principle in idiopathic lung fibrosis

Idiopathic pulmonary fibrosis (IPF) is a devastating and fatal type of lung disease that results in scarring (fibrosis) of the lungs for an unknown reason and with a median survival of only ~3 years after diagnosis. During IPF progression, alveolar epithelial cell injury and hyperplasia, enhanced extracellular matrix deposition, and fibroblast activation are common features. Currently, more than 80,000 adults in the United States have IPF, and more than 30,000 new cases are diagnosed each year. There is currently no cure for IPF. Applicable drugs for IPF are pirfenidone (Roche, Esbriet?) and nintedanib (Boehringer Ingelheim, Ofev?). These medications may help slow the progression of IPF but are of limited effect. Increasing lines of evidence show that a dysregulated activation of WNT signaling is involved in the pathogenesis of idiopathic pulmonary fibrosis and recently an experimental WNT/PORC inhibitior has shown promise in fibrosis models. We will test the proprietory WNT/TNKS inhibitor OM-153 on a mouse lung fibrosis model as a POC for therapeutic WNT inhibition in IPF.

In this Milestone Project the main aim was to evaluate if tankyrase inhibition (TNKSi), using OM-153, could lead to counteraction of fibrosis in introductory in vitro and in vivo experiments. First, we documented TNKSi-control of markers for fibrosis, WNT/?-catenin and YAP signaling in human fibroblasts (in vitro). Next, by employing the Chinese CRO Wuxi, we documented an anti-fibrotic effect of OM-153 in bleomycin-induced lung fibrosis model in mice. Our results show a clear potential for the use of TNKSi against fibrotic diseases and idiopathic pulmonary fibrosis (IPF). Further project progress is warranted and additional financial support will be the next objective for this highly promising project.