WS14.02 Cystic fibrosis personalised medicine; paediatric in vitro airway cell models to predict CFTR modulator patient outcomes

Objectives: CF is a multisystemic genetic disease with early mortality due to respiratory failure from obstructive lung disease. CFTR modulator drugs that target the dysfunctional disease causing chloride channel, demonstrated efficacy in improving clinical biomarkers. However, heterogeneity of response to drug was seen in clinical trials. Primary cell models, created from a patient’s own stem cells, have been proposed as an in vitro test to predict an individuals’ response to treatment. We aimed to investigate the relationship between matched paediatric in vitro cell models and the in vivo response to a CFTR modulator. Methods: F508del-CFTR homozygous patients from Sydney Children’s Hospital CF clinic with acceptable spirometry (FEV1) data pre and post treatment with CFTR modulator were included. Nasal cell models were created from cryopreserved conditionally reprogrammed nasal epithelial cells, treated with CFTR modulators and CFTR ion transport activity assessed in an Ussing Chamber. Retrospective review of medical records was conducted to collect sweat chloride and FEV1 percent predicted(pp) results. Results: 24 patients (mean age 12.61 years ±3.376) met inclusion criteria and had successful in vitro testing performed. Sweat chloride and FEV1 significantly improved following modulator treatment (–22.5 ± 11.2 mmol/L, n = 15, p < 0.001, 3.558 ± 7.48 pp, n = 24, p = 0.029). Heterogenous response to drug was seen in vitro (Range 2.77–62.00%WT). Regression analysis demonstrated a significant relationship between in vitro modulator response and in vivo sweat chloride change (R2 = 0.541 (p = 0.007)) but no significant relationship with FEV1 for all patients (R2 = 0.652(p = 0.133)). Subgroup analysis demonstrated a significant linear relationship in patients with a baseline FEV1 <90 pp (R2 = 0.875(p = 0.002) n = 12). Conclusion: Our data demonstrate CFTR activity in vitro may predict CFTR activity in vivo as well as lung function response measured by FEV1pp in those with a reduced baseline FEV1.