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

Autor:	Sun X; Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA., Yi Y; Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA., Yan Z; Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA., Rosen BH; Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.; Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA., Liang B; Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA., Winter MC; Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA., Evans TIA; Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA., Rotti PG; Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA., Yang Y; Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA., Gray JS; Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA., Park SY; Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA., Zhou W; Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA., Zhang Y; Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA., Moll SR; Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA., Woody L; Vertex Pharmaceuticals Incorporated, San Diego, CA 92121, USA., Tran DM; Vertex Pharmaceuticals Incorporated, San Diego, CA 92121, USA., Jiang L; Vertex Pharmaceuticals Incorporated, San Diego, CA 92121, USA., Vonk AM; Pediatric Pulmonology and Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, Netherlands., Beekman JM; Pediatric Pulmonology and Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, Netherlands., Negulescu P; Vertex Pharmaceuticals Incorporated, San Diego, CA 92121, USA., Van Goor F; Vertex Pharmaceuticals Incorporated, San Diego, CA 92121, USA., Fiorino DF; Vertex Pharmaceuticals Incorporated, San Diego, CA 92121, USA., Gibson-Corley KN; Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA., Engelhardt JF; Department of Anatomy & Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA. john-engelhardt@uiowa.edu.; Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2019 Mar 27; Vol. 11 (485).
DOI:	10.1126/scitranslmed.aau7531
Abstrakt:	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. (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze:	MEDLINE
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