In utero and postnatal VX-770 administration rescues multiorgan disease in a ferret model of cystic fibrosis
Sun, Xingshen; Yi, Yaling; Yan, Ziying; Rosen, Bradley H.; Liang, Bo; Winter, Michael C.; Evans, T. Idil Apak; Rotti, Pavana G.; Yang, Yu; Gray, Jaimie S.; Park, Soo Yeun; Zhou, Weihong; Zhang, Yulong; Moll, Shashanna R.; Woody, Lisa; Tran, Dao M.; Jiang, Licong; Vonk, Annelotte M.; Beekman, Jeffrey M.; Negulescu, Paul; Van Goor, Fred; Fiorino, Dennis F.; Gibson-Corley, Katherine N.; Engelhardt, John F.
(2019) Science Translational Medicine, volume 11, issue 485
(Article)
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
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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.
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Keywords: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
ISSN: 1946-6234
Publisher: American Association for the Advancement of Science
Note: Funding Information: This work was supported by NIH grants R24 DK096518, R24 HL123482, P30 DK054759, R01 DK047967, R01 DK115791, and P01 HL051670 (to J.F.E.); the Cystic Fibrosis Foundation (CFF) ENGELH0XX0 (to J.F.E.); the Carver Chair in Molecular Medicine (to J.F.E.); a Vertex Pharmaceuticals Sponsored Research Agreement (to J.F.E.); and ZonMW 91214103 and NCFS HIT-CF2 (to J.M.B.). Funding contributions were as follows: (i) NIH and the CFF supported creation and generation of the G551D ferrets; (ii) NIH, CFF, and Vertex supported their characterization; and (iii) Vertex provided the VX-770 (ivacaftor). Publisher Copyright: © 2019 American Association for the Advancement of Science. All Rights Reserved.
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