Pulmonary fibrosis, particularly idiopathic pulmonary fibrosis (IPF), represents a significant challenge in healthcare due to its detrimental impact on lung function and limited treatment options. While WNT/β-catenin signaling plays a crucial role in lung development and maintenance of adult lung stem cells, its dysregulation has been associated with pulmonary fibrosis. However, recent research has revealed a potential therapeutic avenue through the modulation of this signaling pathway.

WNT ligands bind to Frizzled (FZD) and LRP receptors, initiating canonical WNT/β-catenin signaling. Additionally, RSPO enhances this signaling by removing surface E3 ubiquitin ligases, which would otherwise target WNT receptors for degradation. Recent developments in antibody-based modulators of WNT signaling have shown promise in promoting tissue repair in various organ damages. Particularly, a multi-FZD-specific WNT mimetic demonstrated the expansion of alveolar cells in vitro, sparking interest in its therapeutic potential for pulmonary fibrosis.

Patel, M., et al (2024) conducted a recent study to investigate the effects of WNT pathway modulation in an acute bleomycin mouse model of pulmonary fibrosis. They employed antibody-based platform modulators to test the efficacy of pathway antagonists and activators. The study also involved functional tests to assess lung function such as flexiVent and vivoFlow, along with histological analyses to evaluate pulmonary inflammation and fibrosis.

The study revealed that a broad-spectrum WNT mimetic, targeting multiple FZD receptors, reduced pulmonary inflammation and fibrosis while improving lung function in the dual bleomycin administration mice model, developed by IPS Therapeutique, Inc., (Figure 1; improved elastance, compliance, inspiratory capacity, respiratory rate, expiratory time). Additionally, the mimetic expanded alveolar organoids, indicating its potential in tissue repair.

These findings highlight the unexpected efficacy of a broad-spectrum WNT mimetic in mitigating fibrosis and improving lung function. Further research will focus on improving the understanding of responsive cell types, which will open avenues for developing targeted therapies with limited systemic side effects. This approach holds promise for developing regenerative therapies that address the underlying pathology of pulmonary fibrosis, potentially transforming patient outcomes and quality of life.

References

• A WNT mimetic with broad spectrum FZD-specificity decreases fibrosis and improves function in a pulmonary damage model. (2024). Patel, M., et al. Respiratory Research, 25(153)
• flexiVent & vivoFlow in vivo work conducted by IPS Therapeutique, Inc.