Journal Article

In utero and postnatal ivacaftor/lumacaftor therapy rescues multiorgan disease in CFTR-F508del ferrets

Zhang, Yulong, Liu, Guangming, Vegter, Amber R., Park, Soo Yeun, McCumber, Hannah, Lynch, Thomas J., Evans, Idil Apak, Zhang, Yan, Limoli, Dominique H., Bartels, Douglas J., Yan, Ziying, Sun, Xingshen, Liang, Bo, Guo, Lydia, Feng, Zehua, Wu, Peipei, Shonka, Amanita, Yang, Yu, Rosen, Bradley H., Engelhardt, John F., Lacina, Allison, Gibson-Corley, Katherine N., Qi, Lisi, Meyerholz, David K., Wang, Kai, Yi, Yaling

2024

Overview

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, with F508del being the most prevalent mutation. The combination of CFTR modulators (potentiator and correctors) has provided benefit to CF patients carrying the F508del mutation; however, the safety and effectiveness of in utero combination modulator therapy remains unclear. We created a F508del ferret model to test whether ivacaftor/lumacaftor (VX-770/VX-809) therapy can rescue in utero and postnatal pathologies associated with CF. Using primary intestinal organoids and air-liquid interface cultures of airway epithelia, we demonstrate that the F508del mutation in ferret CFTR results in a severe folding and trafficking defect, which can be partially restored by treatment with CFTR modulators. In utero treatment of pregnant jills with ivacaftor/lumacaftor prevented meconium ileus at birth in F508del kits and sustained postnatal treatment of CF offspring improved survival and partially protected from pancreatic insufficiency. Withdrawal of ivacaftor/lumacaftor treatment from juvenile CF ferrets reestablished pancreatic and lung diseases, with altered pulmonary mechanics. These findings suggest that in utero intervention with a combination of CFTR modulators may provide therapeutic benefits to individuals with F508del. This CFTR-F508del ferret model may be useful for testing therapies using clinically translatable endpoints.

• Publisher: American Society for Clinical Investigation,American Society for Clinical investigation
• Subject: Aminophenols - pharmacology / Aminophenols - therapeutic use / Aminopyridines - pharmacology / Aminopyridines - therapeutic use / Animals / Benzodioxoles - pharmacology / Benzodioxoles - therapeutic use / Chloride Channel Agonists - pharmacology / Chloride Channel Agonists - therapeutic use / Cystic fibrosis / Cystic Fibrosis - drug therapy / Cystic Fibrosis - genetics / Cystic Fibrosis Transmembrane Conductance Regulator - genetics / Disease Models, Animal / Drug Combinations / FDA approval / Feces / Female / Ferrets / Lung diseases / Meconium / Mustela / Mutation / Newborn babies / Organoids / Pancreas / Pathophysiology / Postpartum period / Pregnancy / Proteins / Pulmonology / Quinolones - pharmacology / Quinolones - therapeutic use / Therapeutics