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. 2021 Jul 7;10(7):828.
doi: 10.3390/antibiotics10070828.

Elexacaftor-Tezacaftor-Ivacaftor Therapy for Cystic Fibrosis Patients with The F508del/Unknown Genotype

Marika Comegna  1   2 , Vito Terlizzi  3 , Donatello Salvatore  4 , Carmela Colangelo  4 , Antonella Miriam Di Lullo  5 , Immacolata Zollo  1   2 , Giovanni Taccetti  3 , Giuseppe Castaldo  1   2 , Felice Amato  1   2
Affiliations

Elexacaftor-Tezacaftor-Ivacaftor Therapy for Cystic Fibrosis Patients with The F508del/Unknown Genotype

Marika Comegna et al. Antibiotics (Basel). .

Abstract

The new CFTR modulator combination, elexacaftor/tezacaftor/ivacaftor (Trikafta) was approved by the FDA in October 2019 for treatment of Cystic Fibrosis in patients 6 years of age or older who have at least one F508del mutation in one allele and a minimal-function or another F508del mutation in the other allele. However, there is a group of patients, in addition to those with rare mutations, in which despite the presence of a F508del in one allele, it was not possible to identify any mutation in the other allele. To date, these patients are excluded from treatment with Trikafta in Italy, where the CF patients carrying F508del/unknown represent about 1.3% (71 patients) of the overall Italian CF patients. In this paper we show that the Trikafta treatment of nasal epithelial cells, derived from F508del/Unknown patients, results in a significant rescue of CFTR activity. Based on our findings, we think that the F508del/Unknown patients considered in this study could obtain clinical benefits from Trikafta treatment, and we strongly suggest their eligibility for this type of treatment. This study, adding further evidence in the literature, once again confirms the validity of functional studies on nasal cells in the cystic fibrosis theratyping and personalized medicine.

Keywords: CFTR; cystic fibrosis; functional characterization; personalized medicine; rare mutation; theratyping.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Short-circuit current (Isc) recording experiments on brushed nasal epithelial cells. Case 1 to 3 are short-circuit currents from CF patients with F508del/Unknown genotype treated with KaftrioTM. Cells were treated with (green line) or without (dark red line) a combination of VX-445 (3 μM), VX-661 (3 μM) and VX-770 (100 nM) for 24 h. The black arrows indicate: A = addition of Amiloride (100 μM) for ENaC channel activity inhibition, F = addition of Forskolin (10 μM), IBMX (3-Isobutyl-1-methylxanthine) (100 μM) for activation of the transepithelial cAMP-dependent current (including CFTR channel activity) and I = addition of Inh-172 (5 μM) for CFTR specific inhibition. All chemicals were added to the apical/mucosal side of cells.
Figure 2
Figure 2
KaftrioTM effect on CFTR-dependent Cl-secretion. Isc response to FSK Forskolin (10 μM), IBMX (100 μM) (ΔIscF/I) after treatment for 24 h with DMSO (No-treated) or a combination of VX-445 (3 μM), VX-661 (3 μM) and VX-770 (100 nM) (Treated). ΔIscF/I recording experiments on brushed nasal epithelial cells from CF patients (two filters per patients, n = 3) with F508del/Unknown genotype and control subjects (two filters per subject, n = 6). CF NT: Cystic Fibrosis patients Non Treated (white circles), CF Treated (black circles), CTR NT: Control subjects Non Treated (white squares), CTR Treated (black squares). The p-values for statistically significant differences are indicated as * <0.031. In the Table 2 are presented the statistical analysis of the samples analyzed.
See this image and copyright information in PMC

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