CFTR Functional Rescue and Heterogeneous Clinical Outcomes Following Elexacaftor/Tezacaftor/Ivacaftor Therapy in People with Cystic Fibrosis Carrying the W1282R Variant
- 1Research Centre for Medical Genetics,1 Moskvorechye St., 115552 Moscow, Russia
- 2Independent Researcher, Moscow 121108, Russia
Abstract
The clinical response to elexacaftor/tezacaftor/ivacaftor (ETI) in people with cystic fibrosis carrying the rare cystic fibrosis transmembrane conductance regulator (CFTR) variant W1282R has not been well characterized. We retrospectively analyzed 12 people with cystic fibrosis treated with ETI for 3–36 months in addition to ongoing standard CF therapy. Baseline lung function was generally preserved in patients with available spirometry (median percent predicted forced expiratory volume in 1 s (ppFEV1), 110%; interquartile range (IQR), 93–123), limiting the potential for further improvement in ppFEV1; no statistically significant change in ppFEV1 was detected during ETI therapy (p = 0.328). Paired data for ppFEV1, body mass index (BMI), and sweat conductivity were available for 8, 12, and 9 patients, respectively. CFTR function was assessed by intestinal current measurement (ICM; n = 4) and patient-derived intestinal organoids (n = 2). Functional testing demonstrated markedly reduced baseline CFTR activity. In the patient with paired ICM measurements before and during ETI therapy, restoration of CFTR-mediated chloride transport was observed, whereas ETI significantly increased forskolin-induced swelling (FIS) in both patient-derived organoid cultures (p < 0.001 for each culture). BMI did not change significantly during ETI therapy (p = 0.269). Sweat conductivity showed a statistically significant overall reduction (median change, −3 mmol/L; p = 0.031); however, marked reductions were observed in only two of nine patients. Interpretation is limited by the small retrospective cohort and incomplete availability of paired clinical and functional data. These findings indicate that functional responsiveness of W1282R-CFTR to ETI may not be accompanied by consistent improvement across the clinical outcomes assessed.
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BibTeX
@article{kondratyeva2026cftr,
title = {{CFTR Functional Rescue and Heterogeneous Clinical Outcomes Following Elexacaftor/Tezacaftor/Ivacaftor Therapy in People with Cystic Fibrosis Carrying the W1282R Variant}},
author = {Elena Kondratyeva and Anna Efremova and Yuliya Melyanovskaya and Elena Zhekaite and Maria Sapelnikova and Michael Milovanov and Olga Shchagina and Anna Voronkova and Victoria Sherman and Stanislav Krasovsky and Sergey Kutsev and Dmitry Goldshtein},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27198896},
url = {https://www.mdpi.com/1422-0067/27/19/8896},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - CFTR Functional Rescue and Heterogeneous Clinical Outcomes Following Elexacaftor/Tezacaftor/Ivacaftor Therapy in People with Cystic Fibrosis Carrying the W1282R Variant
AU - Elena Kondratyeva
AU - Anna Efremova
AU - Yuliya Melyanovskaya
AU - Elena Zhekaite
AU - Maria Sapelnikova
AU - Michael Milovanov
AU - Olga Shchagina
AU - Anna Voronkova
AU - Victoria Sherman
AU - Stanislav Krasovsky
AU - Sergey Kutsev
AU - Dmitry Goldshtein
PY - 2026
DA - 2026/10/07
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27198896
UR - https://www.mdpi.com/1422-0067/27/19/8896
AB - The clinical response to elexacaftor/tezacaftor/ivacaftor (ETI) in people with cystic fibrosis carrying the rare cystic fibrosis transmembrane conductance regulator (CFTR) variant W1282R has not been well characterized. We retrospectively analyzed 12 people with cystic fibrosis treated with ETI for 3–36 months in addition to ongoing standard CF therapy. Baseline lung function was generally preserved in patients with available spirometry (median percent predicted forced expiratory volume in 1 s (ppFEV1), 110%; interquartile range (IQR), 93–123), limiting the potential for further improvement in ppFEV1; no statistically significant change in ppFEV1 was detected during ETI therapy (p = 0.328). Paired data for ppFEV1, body mass index (BMI), and sweat conductivity were available for 8, 12, and 9 patients, respectively. CFTR function was assessed by intestinal current measurement (ICM; n = 4) and patient-derived intestinal organoids (n = 2). Functional testing demonstrated markedly reduced baseline CFTR activity. In the patient with paired ICM measurements before and during ETI therapy, restoration of CFTR-mediated chloride transport was observed, whereas ETI significantly increased forskolin-induced swelling (FIS) in both patient-derived organoid cultures (p < 0.001 for each culture). BMI did not change significantly during ETI therapy (p = 0.269). Sweat conductivity showed a statistically significant overall reduction (median change, −3 mmol/L; p = 0.031); however, marked reductions were observed in only two of nine patients. Interpretation is limited by the small retrospective cohort and incomplete availability of paired clinical and functional data. These findings indicate that functional responsiveness of W1282R-CFTR to ETI may not be accompanied by consistent improvement across the clinical outcomes assessed.
SN - 1422-0067
ER -