Gathering real-world compassionate data to expand eligibility for elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis with N1303K or other rare<i>CFTR</i>variants: a viewpoint

Burgel, Pierre-Régis; Sermet-Gaudelus, Isabelle; Girodon, Emmanuelle; Kanaan, Reem; Le Bihan, Jean; Remus, Natascha; Ravoninjatovo, Bruno; Grenet, Dominique; Porzio, Michele; Houdouin, Véronique; Le Clainche-Viala, Laurence; Durieu, Isabelle; Nove-Josserand, Raphaele; Languepin, Jeanne; Coltey, Bérangère; Guillaumot, Anne; Audousset, Camille; Chiron, Raphaël; Weiss, Laurence; Fajac, Isabelle; Da Silva, Jennifer; Martin, Clémence

doi:10.1183/13993003.01959-2023

Cited by 7 publications

(4 citation statements)

References 25 publications

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“…In the respiratory epithelium, N1303K-CFTR activity restoration by ETI is variable and can be increased with API, consistent with a strong gating defect and this is clinically relevant. ETI has proved efficient for pwCF carrying N1303K and non-eligible mutations (14,15,17,18,19,20,21). The level of improvement was similar to that observed for F508del patients.…”

Section: Discussionsupporting

confidence: 66%

“…Importantly, N1303K-CFTR rescue was also observed in patient-derived primary cell models (13–16). Results of a placebo-controlled clinical study, as well as registry and real-world data provided evidence that pwCF carrying N1303K in the absence of F508del responded to ETI and support the request to EMA of ETI label expansion for pwCF carrying this mutation (14,17,18,19,20,21).…”

Section: Introductionmentioning

confidence: 69%

“…Supplemental table 2 shows data reported in 13 N1303K/N1303K and 23 N1303K/MF pwCF in France (14, 18, 21), combined with other published cases in Israel and Germany (15, 17, 19, 22). At follow-up, sweat test decreased by a mean of 11 mmol/L (−38-+31) (p<0.0001, paired t-test), and most remained elevated above 60 mmol/L ( Supplemental Figure 7a ).…”

Section: Resultsmentioning

confidence: 99%

“…ETI has proved efficient for pwCF carrying N1303K and non-eligible mutations (14,15,17,18,19,20,21). The level of improvement was similar to that observed for F508del patients.…”

Section: Discussionmentioning

confidence: 99%

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Beyond Kaftrio : mechanistic insights to maximize N1303K-CFTR rescue

Pranke,

Capurro,

Chevalier

et al. 2024

Preprint

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IntroductionN1303K is the fourth most frequent Cystic Fibrosis (CF) causing mutation. People with CF (pwCF) clinical status can be improved by Elexacaftor(ELX)/Tezacaftor(TEZ)/Ivacaftor (ETI) combotherapy. We investigated the mechanism underlying N1303K-CFTR rescue.MethodsN1303K-CFTR expression and maturation was evaluated by Western Blot in cell lines and Human Nasal Epithelial Primary Cells (HNECs). Cell surface expression was studied by nanoluciferase complementation assay and TurboID proximity labeling. Functional rescue was testedin vitroby YFP-Based Assay and Short Circuit Current.ResultsCorrection by ELX/TEZ increases N1303K-CFTR amounts, but not its maturation in CFTR-expressing HEK and 16HBEge cell lines and in HNECs. In control conditions, N1303K-CFTR is more distributed at the cell surface and significantly more surface partners are identified in the N1303K-CFTR interactome as compared to F508del-CFTR in HEK cells. ELX/TEZ induces a global stabilization of N1303K-CFTR without favoring its plasma membrane relocation in contrast to F508del-CFTR which is redistributed to the membrane. ETI increases N1303K-CFTR activity in HNECs and can be increased by API co-potentiation with a predicted increase in Forced Expiratory Volume in 1 second (ppFEV1) by respectively 13(2)% and 18%(3). This is consistent with a gain in ppFEV1 reported in pwCF carrying the N1303K mutation and additional improvement by API in a patient.ConclusionThese results support the expansion of ETI approval to N1303K mutation but highlight different mechanisms of action than for F508del.

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Section: Discussionsupporting

confidence: 66%

Section: Introductionmentioning

confidence: 69%

Section: Resultsmentioning

confidence: 99%

“…ETI has proved efficient for pwCF carrying N1303K and non-eligible mutations (14,15,17,18,19,20,21). The level of improvement was similar to that observed for F508del patients.…”

Section: Discussionmentioning

confidence: 99%

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