In utero and postnatal VX-770 administration rescues multiorgan disease in a ferret model of cystic fibrosis

Xingshen Sun; Yaling Yi; Ziying Yan; Bradley H Rosen; Bo Liang; Michael C Winter; T Idil Apak Evans; Pavana G Rotti; Yu Yang; Jaimie S Gray; Soo Yeun Park; Weihong Zhou; Yulong Zhang; Shashanna R Moll; Lisa Woody; Dao M Tran; Licong Jiang; Annelotte M Vonk; Jeffrey M Beekman; Paul Negulescu; Fred Van Goor; Dennis F Fiorino; Katherine N Gibson-Corley; John F Engelhardt

doi:10.1126/scitranslmed.aau7531

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In utero and postnatal VX-770 administration rescues multiorgan disease in a ferret model of cystic fibrosis

Journal article

Open access

Peer reviewed

In utero and postnatal VX-770 administration rescues multiorgan disease in a ferret model of cystic fibrosis

Xingshen Sun, Yaling Yi, Ziying Yan, Bradley H Rosen, Bo Liang, Michael C Winter, T Idil Apak Evans, Pavana G Rotti, Yu Yang, Jaimie S Gray, …

Science translational medicine, Vol.11(485), p.eaau7531

03/27/2019

DOI: 10.1126/scitranslmed.aau7531

PMCID: PMC6489481

PMID: 30918114

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https://doi.org/10.1126/scitranslmed.aau7531View

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Abstract

Cystic fibrosis (CF) is a multiorgan disease caused by mutations in the cystic fibrosis transmembrane conductance regulator ( ). 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 mutation. In utero VX-770 administration provided partial protection from developmental pathologies in the pancreas, intestine, and male reproductive tract. Homozygous 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.

Mutation

Pregnancy

Genitalia, Male - abnormalities

Cystic Fibrosis - physiopathology

Humans

Pancreas, Exocrine - pathology

Respiratory Tract Infections - prevention & control

Male

Pancreas, Exocrine - drug effects

Female

Respiratory Tract Infections - etiology

Disease Models, Animal

Animals, Newborn

Animals, Genetically Modified

Translational Medical Research

Ferrets

Gestational Age

Disease Progression

Gene Knock-In Techniques

Quinolones - administration & dosage

Animals

Genitalia, Male - drug effects

Chloride Channel Agonists - administration & dosage

Cystic Fibrosis - genetics

Cystic Fibrosis Transmembrane Conductance Regulator - genetics

Pancreas, Exocrine - physiopathology

Blood Glucose - metabolism

Aminophenols - administration & dosage

Cystic Fibrosis - drug therapy

Details

Title: Subtitle: In utero and postnatal VX-770 administration rescues multiorgan disease in a ferret model of cystic fibrosis
Creators: Xingshen Sun - Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Yaling Yi - Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Ziying Yan - Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Bradley H Rosen - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Bo Liang - Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Michael C Winter - Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
T Idil Apak Evans - Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Pavana G Rotti - Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Yu Yang - Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Jaimie S Gray - Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Soo Yeun Park - Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Weihong Zhou - Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Yulong Zhang - Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Shashanna R Moll - Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Lisa Woody - Vertex Pharmaceuticals Incorporated, San Diego, CA 92121, USA
Dao M Tran - Vertex Pharmaceuticals Incorporated, San Diego, CA 92121, USA
Licong Jiang - Vertex Pharmaceuticals Incorporated, San Diego, CA 92121, USA
Annelotte M Vonk - Pediatric Pulmonology and Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, Netherlands
Jeffrey M Beekman - Pediatric Pulmonology and Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, Netherlands
Paul Negulescu - Vertex Pharmaceuticals Incorporated, San Diego, CA 92121, USA
Fred Van Goor - Vertex Pharmaceuticals Incorporated, San Diego, CA 92121, USA
Dennis F Fiorino - Vertex Pharmaceuticals Incorporated, San Diego, CA 92121, USA
Katherine N Gibson-Corley - Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
John F Engelhardt - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Resource Type: Journal article
Publication Details: Science translational medicine, Vol.11(485), p.eaau7531
Publisher: United States
DOI: 10.1126/scitranslmed.aau7531
PMID: 30918114
PMCID: PMC6489481
ISSN: 1946-6234
eISSN: 1946-6242
Grant note: R24 HL123482 / NHLBI NIH HHS P30 ES005605 / NIEHS NIH HHS R24 DK096518 / NIDDK NIH HHS S10 OD018526 / NIH HHS R01 DK115791 / NIDDK NIH HHS KL2 TR002536 / NCATS NIH HHS P01 HL051670 / NHLBI NIH HHS R01 DK047967 / NIDDK NIH HHS P30 DK054759 / NIDDK NIH HHS
Language: English
Date published: 03/27/2019
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Pulmonary, Critical Care, and Occupational Medicine; Anatomy and Cell Biology; Pathology; Radiation Oncology; Internal Medicine; Ophthalmology and Visual Sciences
Record Identifier: 9984025368102771

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