In utero and postnatal ivacaftor/lumacaftor therapy rescues multiorgan disease in CFTR-F508del ferrets
Idil Apak Evans, Xingshen Sun, Bo Liang, Amber R. Vegter, Lydia Guo, Thomas J. Lynch, Yan Zhang, Yulong Zhang, Yaling Yi, Yu Yang, Zehua Feng, Soo Yeun Park, Amanita Shonka, Hannah McCumber, Lisi Qi, Peipei Wu, Guangming Liu, Allison Lacina, Kai Wang, Katherine N. Gibson-Corley, David K. Meyerholz, Dominique H. Limoli, Bradley H. Rosen, Ziying Yan, Douglas J. Bartels, John F. Engelhardt
Idil Apak Evans, Xingshen Sun, Bo Liang, Amber R. Vegter, Lydia Guo, Thomas J. Lynch, Yan Zhang, Yulong Zhang, Yaling Yi, Yu Yang, Zehua Feng, Soo Yeun Park, Amanita Shonka, Hannah McCumber, Lisi Qi, Peipei Wu, Guangming Liu, Allison Lacina, Kai Wang, Katherine N. Gibson-Corley, David K. Meyerholz, Dominique H. Limoli, Bradley H. Rosen, Ziying Yan, Douglas J. Bartels, John F. Engelhardt
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Research Article Pulmonology Therapeutics

In utero and postnatal ivacaftor/lumacaftor therapy rescues multiorgan disease in CFTR-F508del ferrets

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.

Authors

Idil Apak Evans, Xingshen Sun, Bo Liang, Amber R. Vegter, Lydia Guo, Thomas J. Lynch, Yan Zhang, Yulong Zhang, Yaling Yi, Yu Yang, Zehua Feng, Soo Yeun Park, Amanita Shonka, Hannah McCumber, Lisi Qi, Peipei Wu, Guangming Liu, Allison Lacina, Kai Wang, Katherine N. Gibson-Corley, David K. Meyerholz, Dominique H. Limoli, Bradley H. Rosen, Ziying Yan, Douglas J. Bartels, John F. Engelhardt

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Figure 7

In utero and postnatal LUM/IVA treatment of CFTR-F508del ferrets partially protects from pancreatitis.

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In utero and postnatal LUM/IVA treatment of CFTR-F508del ferrets partial...
(A) Masson’s trichrome–stained section of the pancreas from a CFTR-F508del ferret treated in utero and postnatally with LUM/IVA until 45 days of age and sacrificed at 101 days of age. There is marked pancreatic fibrosis (blue staining), adipose replacement (†), duct plugging (#), and islet aggregation (arrows). (B and C) Masson’s trichrome– (B) and H&E-stained (C) sections of the pancreas from a CFTR-F508del ferret treated in utero and postnatally with LUM/IVA until sacrificed at 51 days of age. The H&E-stained section highlights a localized area with cystic dilatation of acini and inflammatory infiltrates (*) in the animal continuously treated with LUM/IVA. When quantified, this type of pathology was observed in 4.1% of the area of the entire pancreas. Islets are marked by arrows and have normal architecture. (D) H&E-stained section of the pancreas from the 223-day-old CFTR-F508del ferret continuously treated with LUM/IVA. This ferret had normal fecal elastase levels at 140 days (4,682 μg EL-1/g feces) and showed no areas of acinar loss in the head, body, and tail of the pancreas and normal islet architecture (arrow). (E–G) Islet organization shown by histochemical staining of pancreatic sections for insulin (brown) in adult (E) WT (500 days old), (F) CFTR-F508del (505 days old) removed from LUM/IVA at 117 days, and (G) CFTR-F508del (223 days old) reared on LUM/IVA until euthanized. (H–J) Pancreatic sections stained with (H) H&E, (I) for insulin, and (J) for insulin with Masson’s trichrome from a CFTR-F508del ferret treated in utero and postnatally with LUM/IVA until 45 days of age and euthanized at 296 days of age. This ferret had undetectable fecal elastase levels before the necropsy. Aggregated islets are marked by an arrow and † marks fat. (a–i) Higher-power magnification images of the boxed regions in the main panels (A–I). Scale bars: 1 mm (A, B, D, H, and J), 500 μm (C, E–G, and I), 250 μm (a–d and h), and 100 μm (e–g and i).