Therapeutic effect of CFTR modulators in cystic fibrosis patients with the 2789+5G>A splice variant in the genotype

About 13% of all variants causing cystic fibrosis are splice variants of the CFTR gene; at the moment, such variants are not well studied. The aim was to investigate the effect of the splicing variant 2789+5G>A on the phenotypic manifestations of cystic fibrosis and the effectiveness of targeted therapy in an intestinal organoids model in the patients with genotypes 2789+5G>A/L732X and 2789+5G>A/CFTRdele2,3. Methods. The medical history data, intestinal current measurement (ICM), and forskolin-induced swelling assay in the intestinal organoids were used. Results. The clinical features of the course of CF in 2 patients, carriers of the 2789+5G>A variant in a heterozygous state with genetic variants of the CFTR gene of classes I and VII, are presented. Clinical picture: the disease is of moderate severity; the pancreas is sufficient. The ICM method demonstrated the preservation of the chloride channel function. Assays on the cultured organoids obtained from the intestinal tissue showed moderate residual functional activity of the chloride channels. In addition, the 2789+5G>A variant is sensitive to all tested CFTR modulators. Conclusions. The splicing variant 2789+5G>A is characterized by moderate residual functional activity of the CFTR channel and is sensitive to all targeted treatments. However, the most effective CFTR modulator for this genetic variant is tezacaftor.