Patient-derived cell models for personalized medicine approaches in cystic fibrosis

Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation. In a phase 2 trial involving patients who were heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators correct the basic defect caused by CFTR mutations. Improvements in health outcomes have been achieved using the combination of a CFTR corrector and potentiator in people with CF (pwCF) homozygous for F508del . The addition of elexacaftor (ELX; VX-445), a next-generation CFTR corrector, to tezacaftor/ivacaftor (TEZ/IVA) further improved F508del-CFTR function and clinical outcomes in a phase 2 study in pwCF homozygous for F508del . A phase 3, multi-centre, randomised, double-blind, active-controlled trial of ELX in triple combination with TEZ/IVA (ELX/TEZ/IVA) in pwCF homozygous for F508del was conducted. Eligible participants were aged ≥12 years with stable disease and percent predicted forced expiratory volume in 1 second (ppFEV 1 ) of 40 to 90, inclusive. After a four-week TEZ/IVA run-in, participants were randomised 1:1 to four weeks of ELX/TEZ/IVA versus TEZ/IVA alone. The primary endpoint was absolute change from baseline (measured at the end of the TEZ/IVA run-in) in ppFEV 1 at week 4. Key secondary endpoints were absolute change in sweat chloride and CF Questionnaire–Revised respiratory domain (CFQ-R RD) score. ClinicalTrials.gov , number NCT03525548 . Between August and December 2018, 113 participants were enrolled. Following the run-in, 107 participants were randomised and completed the 4-week treatment period. The ELX/TEZ/IVA group had improvements in ppFEV 1 (10·0 percentage points, 95% CI 7·4 to 12·6, p<0·0001), sweat chloride concentration (−45·1 mmol/L, 95% CI −50·1 to −40·1, p<0·0001), and CFQ-R RD score (17·4 points, 95% CI 11·8 to 23·0, p<0·0001) compared with the TEZ/IVA group. ELX/TEZ/IVA was well tolerated, with no discontinuations. Most adverse events were mild or moderate; serious adverse events occurred in 4% (n=2) of participants receiving ELX/TEZ/IVA and 2% (n=1) receiving TEZ/IVA. ELX/TEZ/IVA provided clinically robust benefit vs TEZ/IVA alone with a favourable safety profile and demonstrates the potential to lead to transformative improvements in the lives of pwCF homozygous for F508del .

We recently established conditions allowing for long-term expansion of epithelial organoids from intestine, recapitulating essential features of the in vivo tissue architecture. Here we apply this technology to study primary intestinal organoids of people suffering from cystic fibrosis, a disease caused by mutations in CFTR, encoding cystic fibrosis transmembrane conductance regulator. Forskolin induces rapid swelling of organoids derived from healthy controls or wild-type mice, but this effect is strongly reduced in organoids of subjects with cystic fibrosis or in mice carrying the Cftr F508del mutation and is absent in Cftr-deficient organoids. This pattern is phenocopied by CFTR-specific inhibitors. Forskolin-induced swelling of in vitro-expanded human control and cystic fibrosis organoids corresponds quantitatively with forskolin-induced anion currents in freshly excised ex vivo rectal biopsies. Function of the CFTR F508del mutant protein is restored by incubation at low temperature, as well as by CFTR-restoring compounds. This relatively simple and robust assay will facilitate diagnosis, functional studies, drug development and personalized medicine approaches in cystic fibrosis.