318 Novel eRF3 degrader monotherapy induces translational readthrough of CFTR nonsense mutations at therapeutically relevant levels

analyzer.After normalization to cell number, basal OCR results indicated that 16hBE cells with delF508-CFTR exhibited lower adenosine triphosphate-linked respiration than wt-CFTR cells.16hBE cells with delF508-CFTR had lower maximal respiration as well, especially than that of wt.VX-770 alone, without a corrector, significantly improved oxidative phosphorylation in 16hBE cells with delF508-CFTR but not in wt-CFTR cells.CB-839, the glutaminase-1 inhibitor, exerted a corrective effect on 16hBE cells with delF508-CFTR but not on cells with wt-CFTR.Our Ussing chamber data confirmed the results from the Seahorse analysis.We found that acute inhibition of glutaminase-1 by CB-839 slightly potentiates the function of CFTR.These data suggest that inhibition of specific metabolic pathways such as glutaminolysis could be beneficial to PwCF.Conclusions: Our study has established a rationale for testing the effect of glutaminase-1 inhibitors, particularly CB-839, in primary airway epithelial cells bearing mutant CFTR.