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EBSCO

https://doi.org/10.14300/mnnc.2025.20081

Impact of the [L467F;F508del] complex allele on the response to targeted therapy in cystic fibrosis. Exploring new possibilities. Clinical observation

[Notes from practice]
Elena Ivanovna Kondratieva; Anna Sergeevna Efremova; Julia Leonidovna Melyanovskaya; Ekaterina Aleksandrovna Ovsyannikova; Olga Anatolyevna Schagina; Anna Yuryevna Voronkova; Maria Gennadyevna Krasnova; Anna Aleksandrovna Stepanova;

The item contains a clinical case presentation of a patient with cystic fibrosis with genotype [L467F;F508del]/CFTRdele2,3, where, against the background of therapy with the CFTR modulator elexacaftor/tezacaftor/ivacaftor, a stable increase in body weight and height was observed, yet no improvement in lung function; a high concentration of sweat chlorides persisted with sinusitis progressing. An analysis of the results obtained through determining the difference in intestinal current measurement and forskolin-induced swelling of intestinal organoids revealed a pronounced CFTR defect and low sensitivity to standard combinations of modulators. The most significant restoration of CFTR function was obtained with the combination of vanzacaftor/tezacaftor/ivacaftor (VX-121/VX-661/VX-770). The data obtained point at potential effectiveness of the new triple scheme for this type of the complex allele, as well as stress the importance of employing functional tests for individual selection of therapy when dealing patients featuring rare and complex CFTR genotypes.

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References:
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https://doi.org/10.1016/S0140-6736(20)32542-3
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7. Efremova A., Melyanovskaya Y., Krasnova M., Voronkova A., Mokrousova D. [et al.]. Estimation of chloride channel residual function and assessment of targeted drugs efficiency in the presence of a complex allele [L467F;F508del] in the CFTR gene. Int. J. Mol. Sci. 2024;25(19):10424. https://doi.org/10.3390/ijms251910424
8. Register of Patients with cystic fibrosis in the Russian Federation. 2023 / edited by E. L. Amelina [et al.]. Moscow: MEDPRAKTIKA-M, 2025. (In Russ.). https://doi.org/10.61726/1981.2025.26.16.001
9. Sondo E., Cresta F., Pastorino C., Tomati V., Capurro V. [et al.]. The L467F-F508del complex allele hampers pharmacological rescue of mutant CFTR by elexacaftor/tezacaftor/ivacaftor in cystic fibrosis patients: the value of the ex vivo nasal epithelial model to address non-responders to CFTR-modulating drugs. Int. J. Mol. Sci. 2022;23(6):3175. https://doi.org/10.3390/ijms23063175
10. Krasnova M. G., Mokrousova D. O., Efremova A. S., Melyanovskaya Yu. L., Sherman V. D. [et al.]. Study of CFTR channel functional activity in a patient with the genotype [L467F;F508del]/W1310X. Pul’monologiya. – Pulmonology. 2024;34(2):264-270. (In Russ.). https://doi.org/10.18093/0869-0189-2024-34-2-264-270

Keywords: cystic fibrosis, CFTR gene, intestinal current measurement, intestinal organoids, complex allele [L467F;F508del]