RT Journal Article
SR Electronic
T1 Airway morphogenesis in wild type and heterozygous F508del mouse embryonic lungs treated by Elexacaftor/Tezacaftor/Ivacaftor
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 4330
DO 10.1183/13993003.congress-2022.4330
VO 60
IS suppl 66
A1 A Hadchouel-Duvergé
A1 M Lhuillier
A1 L Aoust
A1 E Dreano
A1 K Landry Truchon
A1 C Delacourt
A1 L Jeanotte
A1 I Sermet Gaudelus
YR 2022
UL http://erj.ersjournals.com/content/60/suppl_66/4330.abstract
AB Background: CFTR modulators combo-therapy Elexacaftor/Tezacaftor/Ivacaftor (ETI) is efficient in cystic fibrosis patients bearing a least one F508del mutation. An increasing number of pregnancies in treated women is expected. Safety data during pregnancy are lacking.Aims: To study the potential impact of ETI treatment on airway development in a murine model at the pseudo-glandular stage.Methods: Branching morphogenesis and expression of Fgf10, Fgfr2IIIb, Shh, and Hhip were analysed in lung explants sampled at E12.5 from heterozygous F508del and wild-type mouse embryos after 24, 48 and 72h of culture in different conditions: standard culture medium, treatment with ETI or with Forskolin ± the inhibitor of CFTR Inh-172.Results: After 72h of culture and in comparison to control medium, ETI induced a decrease of 78% in lung branching in heterozygous F508del lungs (p<0.0001) and of 79% in wild-type lungs (p<0.0001), and a significant increase of the percentage of terminal bud dilations, by 5.3 fold (p<0.001) for heterozygous F508del lungs and by 5.7 fold (p=0.004) in wild-type lungs. These results were recapitulated by cAMP-dependent CFTR activation by Forskolin and reversed by addition of Inh-172. ETI induced a significant decrease in Fgf10, Fgfr2IIIb, Shh and Hhip expression in lung explants of both groups treated with ETI for 72h.Conclusion: Our results show that ETI alters lung branching morphogenesis of control and heterozygous F508del mouse embryos during the pseudo-glandular stage. Those alterations are related, at least in part, to CFTR activation. This call for caution and suggest that ETI exposure during pregnancy could interfere with airway morphogenesis.FootnotesCite this article as Eur Respir J 2022; 60: Suppl. 66, 4330.This article was presented at the 2022 ERS International Congress, in session “-”.This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only).