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Selection of CFTR modulators for children with the W1282R variant

Objective. To study the clinical manifestations of W1282R variant, functional activity of the cystic fibrosis transmembrane conductance regulator (CFTR) channel, and effectiveness of CFTR modulator therapy in patients with the W1282R variant. Materials and methods included medical records, intestinal current measurement method (ICM) and method of intestinal organoids (IO). Results. The c.3844T>C (p.Trp1282Arg, W1282R) variant refers to missense mutations. The Cystic Fibrosis (CF) Patient Registry of the Russian Federation (2019) provides the data on 34 patients with the W1282R variant in the genotype. Clinical manifestations in two patients with the W1282R variant corresponds to the severe course of CF. ICM method revealed the loss of CFTR function. The effect of VX-809 corrector, VX-770 potentiator and their combined use were assessed in each patient using the method of IO. Conclusion. The results indicated a “severe” W1282R variant. The application of VX-809 corrector had no effect on the restoration of chloride channel function, unlike the F508del homozygous control sample (class II mutations). The VX-770 potentiator had no effect on the kinetic properties of CFTR protein. But in both patients, a significant restoration of lost channel function (~45%) was recorded with the combined use of VX-809 corrector and VX-770 potentiator, which is typical for class III and class IV variants. This challenges the conclusions that the W1282R variant has class II characteristics only. Combination therapy with VX-809 and VX-770 may be recommended for patients with the W1282R/CFTRdel2,3 and W1282R/F508del genotypes. Key words: cystic fibrosis, CFTR gene, W1282R pathogenic variant, intestinal current measurement method, intestinal organoids, forskolin-induced swelling assay, correctors, potentiators, target therapy, ivacaftor, lumacaftor