Inhibition of Wnt/β-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis

WR Henderson Jr, EY Chi, X Ye… - Proceedings of the …, 2010 - National Acad Sciences
WR Henderson Jr, EY Chi, X Ye, C Nguyen, Y Tien, B Zhou, Z Borok, DA Knight, M Kahn
Proceedings of the National Academy of Sciences, 2010National Acad Sciences
Idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia is a ravaging condition of
progressive lung scarring and destruction. Anti-inflammatory therapies including
corticosteroids have limited efficacy in this ultimately fatal disorder. An important unmet need
is to identify new agents that interact with key molecular pathways involved in the
pathogenesis of pulmonary fibrosis to prevent progression or reverse fibrosis in these
patients. Because aberrant activation of the Wnt/β-catenin signaling cascade occurs in lungs …
Idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia is a ravaging condition of progressive lung scarring and destruction. Anti-inflammatory therapies including corticosteroids have limited efficacy in this ultimately fatal disorder. An important unmet need is to identify new agents that interact with key molecular pathways involved in the pathogenesis of pulmonary fibrosis to prevent progression or reverse fibrosis in these patients. Because aberrant activation of the Wnt/β-catenin signaling cascade occurs in lungs of patients with IPF, we have targeted this pathway for intervention in pulmonary fibrosis using ICG-001, a small molecule that specifically inhibits T-cell factor/β-catenin transcription in a cyclic AMP response-element binding protein binding protein (CBP)-dependent fashion. ICG-001 selectively blocks the β-catenin/CBP interaction without interfering with the β-catenin/p300 interaction. We report here that ICG-001 (5 mg/kg per day) significantly inhibits β-catenin signaling and attenuates bleomycin-induced lung fibrosis in mice, while concurrently preserving the epithelium. Administration of ICG-001 concurrent with bleomycin prevents fibrosis, and late administration is able to reverse established fibrosis and significantly improve survival. Because no effective treatment for IPF exists, selective inhibition of Wnt/β-catenin-dependent transcription suggests a potential unique therapeutic approach for pulmonary fibrosis.
National Acad Sciences