Personalized Selection of a CFTR Modulator for a Patient with a Complex Allele [L467F;F508del]

Abstract

The presence of complex alleles in the CFTR gene can lead to difficulties in diagnosing cystic fibrosis and cause resistance to therapy with CFTR modulators. Tezacaftor/ivacaftor therapy for 8 months in a patient with the initially established F508del/F508del genotype did not lead to an improvement in her condition—there was no change in spirometry and an increase in the patient’s weight, while there was only a slight decrease in NaCl values, measured by a sweat test. The intestinal current measurements of the patient’s rectal biopsy showed no positive dynamics in the rescue of CFTR function while taking tezacaftor/ivacaftor. The assumption that the patient had an additional mutation in the cis position was confirmed by sequencing the CFTR gene, and the complex allele [L467F;F508del] was identified. Based on the rescue of CFTR function by elexacaftor/tezacaftor/ivacaftor obtained using forskolin-induced swelling on intestinal organoids, the patient was prescribed therapy with this targeted drug. The use of elexacaftor/tezacaftor/ivacaftor for 7 months resulted in a significant improvement in the patient’s clinical condition.

Post-approval studies with the CFTR modulators Elexacaftor-Tezacaftor—Ivacaftor

“…Thus, to address this unresolved issue, researchers have characterized the association between CFTR genotype, phenotype and its modulation by ELX/TEZ/IVA in recombinant cells ( Laselva et al, 2021 ; Borgo et al, 2022 ; Tomati et al, 2022 ) or patient-derived epithelial cells in vitro ( Veit et al, 2021b ; Borgo et al, 2022 ; Shaughnessy et al, 2022b ; Furstova et al, 2022 ; Tomati et al, 2022 ). Alternatively, they combined the cell culture work with the examination of CFTR biomarkers and clinical characteristics prior and during treatment with ELX/TEZ/IVA ( Anderson et al, 2021 ; Comegna et al, 2021 ; Huang et al, 2021 ; Terlizzi et al, 2021 ; Aalbers et al, 2022 ; Kondratyeva et al, 2022a ; 2022b ; Ciciriello et al, 2022 ; Sondo et al, 2022 ). A peculiar challenge are complex alleles not yet documented in the databases.…”

“…A peculiar challenge are complex alleles not yet documented in the databases. Characterization of p.[Leu467Phe-Phe508del] in patient-derived organoids and primary intestinal epithelium demonstrated a more compromised CFTR function than p.Phe508del, but fortunately was susceptible to modulation by ELX/TEZ/IVA both in vitro and in the patient in vivo ( Kondratyeva et al, 2022a ; Kondratyeva et al, 2022b ).…”

The Effect of Complex Alleles of the CFTR Gene on the Clinical Manifestations of Cystic Fibrosis and the Effectiveness of Targeted Therapy

“…At the same time, the clinical course of the disease in groups with genotypes p.Phe508del/p. [Leu467Phe;Phe508del] and p.Phe508del/p.Phe508del did not differ in age of diagnosis, characteristics of respiratory function, nutritional and microbiological status, frequency of exacerbations, or therapy, including courses of intravenous antibacterial therapy [ 20 , 21 ].…”

“…Previously, it was found that the p.Leu467Phe variant does not lead to the development of CF, but reduces the amount of functional (fully glycosylated) CFTR by two times compared to the norm [ 55 ], but p.Leu467Phe in combination with p.Phe508del causes a lack of response to treatment with CFTR correctors [ 20 ]. Variants of p.Leu467Phe and p.Phe508del have an additive pathogenic effect, which can no longer be eliminated by the lumacaftor corrector.…”

“…However, the authors also note that the effect was not observed only by this criterion [ 50 ]. The search for a variant of p.Leu467Phe is crucial in Russian patients with cystic fibrosis with p.Phe508del who do not respond to therapy with thezacaftor/ivacaftor and lumacaftor/ivacaftor, given the high frequency of the complex allele of p.[Leu467Phe;Phe508del]) [ 20 ].…”