AI Article Synopsis
- Mutation-targeted therapy for cystic fibrosis (CF) is not suitable for all patients, particularly those with rare CFTR gene variants like W57G/A234D.
- Researchers analyzed how these variants affect CFTR protein stability using colonoids and nasal epithelial cells, utilizing methods like western blotting and Ussing chamber analysis.
- Treatment with CFTR modulators (VX661, VX445, VX770) showed improved CFTR function, reduced sweat chloride levels, and an increase in lung function (FEV1%) after 27 weeks, highlighting the importance of personalized treatment approaches for CF.
Article Abstract
Mutation targeted therapy in cystic fibrosis (CF) is still not eligible for all CF subjects, especially for cases carrying rare variants such as the CFTR genotype W57G/A234D (c.169T>G/c.701C>A). We performed analysis of the effects of these variants on protein stability, which we functionally characterized using colonoids and reprogrammed nasal epithelial cells. The effect of mutations on cystic fibrosis transmembrane conductance regulator (CFTR) protein was analyzed by western blotting, forskolin-induced swelling (FIS), and Ussing chamber analysis. We detected a residual CFTR function that increases following treatment with the CFTR modulators VX661±VX445±VX770, correlates among models, and is associated with increased CFTR protein levels following treatment with CFTR correctors. treatment with VX770 reduced sweat chloride concentration to non-CF levels, increased the number of CFTR-dependent sweat droplets, and induced a 6% absolute increase in predicted FEV1% after 27 weeks of treatment indicating the relevance of theratyping with patient-derived cells in CF.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10660498 | PMC |
| http://dx.doi.org/10.1016/j.isci.2023.108180 | DOI Listing |
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