Journal article
In utero and postnatal ivacaftor/lumacaftor therapy rescues multiorgan disease in CFTR-F508del ferrets
JCI insight, Vol.9(8), e157229
04/22/2024
DOI: 10.1172/jci.insight.157229
PMCID: PMC11141870
PMID: 38646935
Abstract
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.
Details
- Title: Subtitle
- In utero and postnatal ivacaftor/lumacaftor therapy rescues multiorgan disease in CFTR-F508del ferrets
- Creators
- Idil Apak Evans - University of IowaXingshen Sun - University of IowaBo Liang - University of IowaAmber R Vegter - University of IowaLydia Guo - University of IowaThomas J Lynch - University of IowaYan Zhang - University of IowaYulong Zhang - University of IowaYaling Yi - University of IowaYu Yang - University of IowaZehua Feng - University of IowaSoo Yeun Park - University of IowaAmanita Shonka - University of IowaHannah McCumber - University of IowaLisi Qi - University of IowaPeipei Wu - University of IowaGuangming Liu - University of IowaAllison Lacina - University of IowaKai Wang - Department of Biostatistics, University of Iowa College of Public Health, Iowa City, Iowa, USAKatherine N Gibson-Corley - Vanderbilt University Medical CenterDavid K Meyerholz - University of IowaDominique H Limoli - University of IowaBradley H Rosen - University of IowaZiying Yan - University of IowaDouglas J Bartels - University of IowaJohn F Engelhardt - University of Iowa
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.9(8), e157229
- DOI
- 10.1172/jci.insight.157229
- PMID
- 38646935
- PMCID
- PMC11141870
- NLM abbreviation
- JCI Insight
- eISSN
- 2379-3708
- Language
- English
- Date published
- 04/22/2024
- Academic Unit
- Molecular Physiology and Biophysics; Microbiology and Immunology; Anatomy and Cell Biology; The University of Iowa Institute for Vision Research; Pathology; Biostatistics; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984618625102771
Metrics
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