Состояние здоровья близнецов с генотипом F508del/R334W при муковисцидозе и возможности таргетной терапии

Abstract

The CFTR gene contains 27 exons and is located at position 31.1 of the long arm of chromosome 7 (7q31.1). More than 2000 variants of the CFTR gene have been described so far. The R334W variant is associated with the mild disease course. Objective. To perform comprehensive assessment of the health status, functional CFTR activity, and efficacy of CFTR modulators in twins with the F508del/R334W genotype. Materials and methods. Data from medical records, intestinal current measurement (ICM), intestinal organoid culture. Results. We examined two twins with moderate cystic fibrosis who had similar clinical manifestations, including rhinosinusitis with nasal polyps and respiratory infections caused by gram-negative bacteria. Both patients also had polyvalent allergy. One child presented with a decrease of pancreatic elastase 1 in stool from 500 μg/g to 125 500 μg/g, which required administration of pancreatin and dosage increase later. Both children had reduced chloride channel function as demonstrated by ICM. The administration of a corrector (VX-809) and a potentiator (VX-770) effectively restored the channel function; their simultaneous use ensured an additive effect. The quantitative results obtained in both cultures of intestinal organoids were very similar. Key words: cystic fibrosis, CFTR gene, pathogenic variant R334W, intestinal current measurement, intestinal organoids, forskolin-induced swelling assay, correctors, potentiators, targeted therapy, ivacaftor, lumacaftor