作者
Elise Dréano,Pierre‐Régis Burgel,Aurélie Hatton,Naïm Bouazza,B. Chevalier,Julie Macey,Sylvie Leroy,I. Durieu,Laurence Weiss,Dominique Grenet,Nathalie Stremler,Camille Ohlmann,Philippe Reix,Michele Porzio,Pierre Claudé,Natacha Rémus,B. Douvry,Sylvie Montcouquiol,Laure Cosson,Julie Mankikian,Jeanne Languepin,Véronique Houdouin,L. Le Clainche,Anne Guillaumot,Delphine Pouradier,Adrien Tissot,Pascaline Priou,Laurent Mély,F. Chedevergne,Muriel Lebourgeois,Jean Lebihan,Clémence Martin,Flora Zavala,Jennifer Da Silva,Lydie Lemonnier,Mairead Kelly‐Aubert,Anita Golec,P. Foucaud,Christophe Marguet,Aleksander Edelman,Alexandre Hinzpeter,P Carli,Emmanuelle Girodon,Isabelle Sermet-Gaudelus,Iwona Pranke
摘要
Around 20% of people with cystic fibrosis (pwCF) do not have access to the triple combination elexacaftor/tezacaftor/ivacaftor (ETI) in Europe because they do not carry the F508del allele on the CF transmembrane conductance regulator (CFTR) gene. Considering that pwCF carrying rare variants may benefit from ETI, including variants already validated by the US Food and Drug Administration (FDA), a compassionate use programme was launched in France. PwCF were invited to undergo a nasal brushing to investigate whether the pharmacological rescue of CFTR activity by ETI in human nasal epithelial cell (HNEC) cultures was predictive of the clinical response.CFTR activity correction was studied by short-circuit current in HNEC cultures at basal state (dimethyl sulfoxide (DMSO)) and after ETI incubation and expressed as percentage of normal (wild-type (WT)) CFTR activity after sequential addition of forskolin and Inh-172 (ΔIETI/DMSO%WT).11 pwCF carried variants eligible for ETI according to the FDA label and 28 carried variants not listed by the FDA. ETI significantly increased CFTR activity of FDA-approved CFTR variants (I601F, G85E, S492F, M1101K, R347P, R74W;V201M;D1270N and H1085R). We point out ETI correction of non-FDA-approved variants, including N1303K, R334W, R1066C, Q552P and terminal splicing variants (4374+1G>A and 4096-3C>G). ΔIETI/DMSO%WT was significantly correlated to change in percentage predicted forced expiratory volume in 1 s and sweat chloride concentration (p<0.0001 for both). G85E, R74W;V201M;D1270N, Q552P and M1101K were rescued more efficiently by other CFTR modulator combinations than ETI.Primary nasal epithelial cells hold promise for expanding the prescription of CFTR modulators in pwCF carrying rare mutants. Additional variants should be discussed for ETI indication.