WS14.01Primary nasal epithelial cells for personalized medicine in non-eligible cystic fibrosis patients

Objective

Patients with cystic fibrosis (pwCF) without any F508del allele in the cystic fibrosis transmembrane conductance regulator (CFTR) have currently no access to CFTR modulator therapy in Europe. To test the potential of pharmacological rescue of CFTR by ETI in non-eligible pwCF, we tested the in vitro and in vivo effects of ETI in non-F508del pwCF.

Methods

Highly differentiated primary human nasal epithelial cultures (pHNECs) were cultivated from nasal swabs of 39 pwCF and non-F508del CFTR mutations and 29 healthy controls. CFTR activity was assessed by short-circuit currents in non-perfused Ussing chamber after ETI or DMSO incubation. In 10 pwCF, who received ETI therapy after a preclinical response in pHNECs, we assessed lung function (FEV₁% predicted) and the in vivo CFTR biomarkers sweat chloride concentration (SCC) and intestinal current measurements (ICM) or nasal potential difference (NPD) at baseline and 1 to 3 months after ETI.

Results

Twenty-five pwCF showed no increased CFTR activity in pHNECs after treatment with ETI compared to DMSO. However, pHNECs from 14 pwCF showed a response to ETI with a mean correction of CFTR activity of 20% of the healthy level. The 10 pwCF who received ETI showed a mean improvement in FEV₁% predicted by 12%. All 10 pwCF showed a pathological SCC above 60 mmol/L, which was reduced by at least 5 mmol/L after ETI. In ICM, the cAMP-dependent chloride secretory response increased from -12 µA/cm² to 32 µA/cm² after ETI and the total chloride secretory response increased from -16 µA/cm² to 123 µA/cm². A subgroup of 6 pwCF, where NPD was performed, showed an increase in total chloride response in NPD from -0.25 mV to -14 mV after ETI.

Conclusion

We identified non-F508del CFTR mutations responding to ETI in vitro with improvements in FEV₁%, SSC, ICM, and NPD. Our data show that in vitro CFTR modulator testing in pHNECs, confirmed by in vivo biomarkers, is a promising approach for personalized medicine in non-eligible pwCF.