Objectives 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 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Considering that pwCF carrying rare variants may benefit from ETI, including variants already validated by the Food and Drug Administration (FDA), a compassionate use program 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.Methods CFTR activity correction was studied by short-circuit current in HNEC cultures at basal state (DMSO) and after ETI incubation and expressed as % of normal CFTR activity after sequential addition of Forskolin and Inh-172 (Delta I-ETI/DMSO%WT).Results Eleven pwCF carried variants eligible for ETI according to the FDA label and twenty-eight variants not listed by the FDA. ETI significantly increased CFTR activity of FDA-approved CFTR variants (I601F, G85E, S492F, M1101 K, R347P, R74W;V201M;D1270N, and H1085R). We point out ETI correction of non FDA-approved variants including N1303 K, R334W, R1066C, Q552P and terminal splicing variants (4374+1G>A, 4096-3C>G). Delta I-ETI/DMSO%WT was significantly correlated to change in ppFEV(1) and sweat chloride concentration (p<0.0001 for both). R74W; V201M; D1270N; G85E, Q552P and M1101 K were rescued more efficiently by other CFTR modulator combinations than ETI.Conclusion Primary nasal epithelial cells hold promise for expanding CFTR modulators prescription in pwCF carrying rare mutants. Additional variants should be discussed for ETI indication.
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