Study of the effect of targeted therapy on the restoration of the functional CFTR channel in a patient with the E403D/CFTRdele2,3 genotype

Background. Cystic fibrosis (CF) is a systemic hereditary disease caused by a mutation in the CFTR gene and characterized by damage to the glands of external secretion, severe respiratory dysfunction. It is believed that with a «severe» genotype, clinical manifestations are more pronounced and manifest early. Variant E403D is included in the list of variants sensitive to CFTR modulators (ivacaftor-tezacaftorelexacaftor). However, its use in clinical practice in a patient – a carrier of this variant E403D, did not lead to the expected effect.

Methods. The medical history of a patient with CF with the genotype E403D/CFTRdele2,3 was analyzed. Biopsy material from the rectum was used to intestinal current measurement (ICM) and forskolin-induced swelling assay in intestinal organoids. DNA for sequencing was isolated from venous blood leukocytes.

Results. The patient (11-year-old girl) with the E403D/CFTRdele2.3 genotype was diagnosed based on neonatal screening. The ICM method revealed reduced CFTR channel function before the start of CFTR modulator therapy. According to the forskolininduced swelling assay in intestinal organoids, it was shown that the amount of functional protein on the apical membrane of the intestinal epithelium did not increase under the action of either the potentiator or the corrector in the patient. Clinically, no positive dynamics were obtained from taking the drug for 1.5 years.

Conclusion. For the first time, an analysis of the functional state of the chloride channel of a patient with the E403D/CFTRdele2,3 genotype was performed using the ICM method before therapy and during CFTR modulator therapy. A relationship was shown between severe manifestations of the disease and the absence of CFTR chloride channel function, both according to the sweat test and the absence of a response to forskolin during the ICM method. Forskolin-induced swelling of intestinal organoids showed that therapy with the tested CFTR modulators cannot be recommended for a patient with the E403D variant in a compound heterozygous state with a class I or VII variant.

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