Novel Correctors and Potentiators Enhance Translational Readthrough in CFTR Nonsense Mutations

Premature-termination codons (PTCs) in CFTR (cystic fibrosis [CF] transmembrane conductance regulator) lead to nonfunctional CFTR protein and therefore are the proximate reason for ~11% of CF-causing alleles, that no treatments exist. The CFTR corrector lumacaftor and also the potentiator ivacaftor improve CFTR function with terminal PTC mutations and boost the aftereffect of readthrough agents. Novel correctors GLPG2222 (corrector 1 [C1]), GLPG3221 (corrector 2 [C2]), and potentiator GLPG1837 compare favorably with lumacaftor and ivacaftor in vitro. Here, we evaluated the result of correctors C1a and C2a (derivatives of C1 and C2) and GLPG1837 alone or in conjunction with the readthrough compound G418 on CFTR function using heterologous Fischer rat thyroid (FRT) cells, the genetically engineered human bronchial epithelial (HBE) 16HBE14o- cell lines, and first human cells with PTC mutations. In FRT lines pretreated with G418, GLPG1837 elicited dose-dependent increases in CFTR activity that exceeded individuals from ivacaftor in FRT-W1282X and FRT-R1162X cells. A 3-mechanism strategy composed of G418, GLPG1837, and 2 correctors (C1a   C2a) produced the finest functional enhancements in FRT and 16HBE14o- PTC variants, noting that correction and potentiation without readthrough was sufficient to stimulate CFTR activity for W1282X cells. GLPG1837   C1a   C2a restored substantial function in G542X/F508del HBE cells and restored much more function for W1282X/F508del cells, mainly due to the corrector/potentiator effect, without any additional take advantage of G418. In G542X/R553X or R1162X/R1162X organoids, enhanced forskolin-caused swelling was observed with G418   GLPG1837   C1a   C2a, although GLPG1837   C1a   C2a alone was sufficient to enhance forskolin-caused swelling in W1282X/W1282X organoids. Mixture of CFTR correctors, potentiators, and readthrough compounds augments the running repair of CFTR Galicaftor nonsense mutations, indicating the opportunity of novel correctors and potentiators to revive function to truncated W1282X CFTR.

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