Personalized assessment of the effectiveness of targeted drugs for the treatment of cystic fibrosis in a patient with c.264_268delATATT and c.3139+1G>C rare variants of the <i>CFTR</i> gene

Abstract

When new, most often rare variants of the CFTR gene are detected in patients with cystic fibrosis, the method of intestinal organoids is used, which allows for a personalized assessment of the residual functional activity of the CFTR channel and the effect of targeted drugs to determine the possibility of further pathogenetic therapy. Objective: to study the effect of the CFTR potentiator ivacaftor, as well as ivacaftor in combination with the CFTR correctors lumacaftor, tezacaftor and elexacaftor on the restoration of CFTR-channel function on a culture of intestinal organoids obtained from a patient with two rare variants c.264_268delATATT and c.3139+1GC. To assess the activity of the CFTR channel, the forskolin-induced swelling assay on organoids and the intestinal current measurements on rectal biopsy samples method were used, a description of the clinical picture in a patient with the c.264_268delATATT/c.3139+1GC genotype was performed. Genetic variants c.264_268delATATT and c. 3139+1GC are classified as "severe" and cause complete loss of CFTR chloride channel function. The severity of the disease in a child is consistent with in vitro results. No effective CFTR modulators were found for the studied variants, so targeted therapy cannot be recommended to the patient.