Roxadustat (FG-4592) accelerates pulmonary growth, development, and function in a compensatory lung growth model

Area of Science:

• Pulmonary Medicine
• Developmental Biology
• Pharmacology

Background:

• Congenital diaphragmatic hernia (CDH) causes hypoplastic lungs, leading to high morbidity and mortality in children.
• Current treatments for severe CDH are largely supportive, with unchanged mortality rates over decades.
• Vascular endothelial growth factor (VEGF)-mediated angiogenesis is crucial for compensatory lung growth.

Purpose of the Study:

• To evaluate Roxadustat, a prolyl hydroxylase inhibitor, for its potential to accelerate compensatory lung growth.
• To investigate the role of VEGF and pigment epithelium-derived factor (PEDF) in Roxadustat's effect on lung development.

Main Methods:

• Roxadustat treatment was administered following left pneumonectomy in a preclinical model.
• Lung volume, total lung capacity, alveolarization, and exercise tolerance were assessed.
• VEGF and PEDF expression levels were analyzed to understand the underlying mechanisms.

Main Results:

• Roxadustat significantly increased lung volume, total lung capacity, alveolarization, and exercise tolerance.
• The therapeutic effect involved increased VEGF and decreased PEDF, an anti-angiogenic factor.
• Vadadustat, a similar drug, did not show comparable benefits, suggesting a specific mechanism for Roxadustat.

Conclusions:

• Roxadustat demonstrates potential in accelerating compensatory lung growth in the context of pulmonary hypoplasia.
• The dual modulation of pro-angiogenic (VEGF) and anti-angiogenic (PEDF) factors may underlie Roxadustat's efficacy.
• Given its established safety profile in clinical trials, Roxadustat could offer a promising therapeutic avenue for CDH-related lung disease.