# Beyond Trikafta: new models to assess tissue dependent rescue of N1303K-CFTR

## TL;DR

This study explores why the drug ETI improves lung function but not sweat test results in Cystic Fibrosis patients with the N1303K mutation.

## Contribution

The paper introduces new cell models to assess tissue-specific responses of N1303K-CFTR to therapies.

## Key findings

- ETI improves CFTR maturation and Cl− transport in airway and sweat gland cells with F508del-CFTR.
- N1303K-CFTR in respiratory cells shows partial correction by ETI but not full maturation.
- Apigenin enhances N1303K-CFTR activity in respiratory cells but not in sweat gland cells.

## Abstract

Respiratory status of people with Cystic Fibrosis (pwCF) carrying N1303K is improved by Elexacaftor/Tezacaftor/Ivacaftor (ETI) but, contrary to other mutations, the impact on sweat test results is limited.

To explore this discrepancy, we implemented new sweat gland and respiratory cell lines stably expressing Wild type (WT)-, F508del- and N1303K-CFTR. CFTR dependent chloride (Cl−) and bicarbonate (HCO3-) transport was measured by short circuit current in these new models and in primary Human Nasal Epithelial Cells (HNECs). CFTR expression was evaluated by Western blot.

In the airway and the sweat gland cells expressing F508del-CFTR, ETI induced maturation of CFTR and increased Cl− transport. In the respiratory cell lines and HNECs, N1303K-CFTR generated both immature and mature forms of CFTR. Correction by ETI increased CFTR amounts without promoting its maturation and improved Cl− secretion. N1303K-CFTR channel activity was markedly increased by co-potentiation of IVA with Apigenin. In the sweat gland, N1303K-CFTR was expressed as a globally misfolded protein, non-rescuable by ETI. API treatment to 2 patients improved FEV1 without lowering sweat Cl- content.

N1303K-CFTR shows tissue specific correction and suboptimal response to ETI which can be improved by API.