1. In utero and postnatal VX-770 administration rescues multiorgan disease in a ferret model of cystic fibrosis
- Author
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Lisa Woody, John F. Engelhardt, Annelotte M. Vonk, Yulong Zhang, Jaimie S. Gray, Xingshen Sun, Yaling Yi, Michael C. Winter, Shashanna R. Moll, Bradley H. Rosen, Dao M. Tran, Weihong Zhou, Ziying Yan, Paul A. Negulescu, Licong Jiang, Fred Van Goor, Bo Liang, Pavana G. Rotti, Jeffrey M. Beekman, Katherine N. Gibson-Corley, S. Park, T. Idil Apak Evans, Yu Yang, and Dennis F. Fiorino
- Subjects
Blood Glucose ,Male ,0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,Cystic Fibrosis ,Cystic Fibrosis Transmembrane Conductance Regulator ,Physiology ,Gestational Age ,Genitalia, Male ,Quinolones ,Aminophenols ,Cystic fibrosis ,Article ,Animals, Genetically Modified ,Translational Research, Biomedical ,Pathogenesis ,Ivacaftor ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,Animals ,Humans ,Medicine ,Gene Knock-In Techniques ,Chloride Channel Agonists ,Respiratory Tract Infections ,Lung ,biology ,business.industry ,Ferrets ,General Medicine ,medicine.disease ,Pancreas, Exocrine ,Cystic fibrosis transmembrane conductance regulator ,Pathophysiology ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Animals, Newborn ,030228 respiratory system ,In utero ,Mutation ,Disease Progression ,biology.protein ,Female ,business ,Pancreas ,medicine.drug - Abstract
Cystic fibrosis (CF) is a multiorgan disease caused by mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR ). In patients with CF, abnormalities initiate in several organs before birth. However, the long-term impact of these in utero pathologies on disease pathophysiology is unclear. To address this issue, we generated ferrets harboring a VX-770 (ivacaftor)–responsive CFTR G551D mutation. In utero VX-770 administration provided partial protection from developmental pathologies in the pancreas, intestine, and male reproductive tract. Homozygous CFTR G551D/G551D animals showed the greatest VX-770–mediated protection from these pathologies. Sustained postnatal VX-770 administration led to improved pancreatic exocrine function, glucose tolerance, growth and survival, and to reduced mucus accumulation and bacterial infections in the lung. VX-770 withdrawal at any age reestablished disease, with the most rapid onset of morbidity occurring when withdrawal was initiated during the first 2 weeks after birth. The results suggest that CFTR is important for establishing organ function early in life. Moreover, this ferret model provides proof of concept for in utero pharmacologic correction of genetic disease and offers opportunities for understanding CF pathogenesis and improving treatment.
- Published
- 2019