Advances in Preclinical In Vitro Models for the Translation of Precision Medicine for Cystic Fibrosis

The development of preclinical in vitro models has provided significant progress to the studies of cystic fibrosis (CF), a frequently fatal monogenic disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein. Numerous cell lines were generated over the last 30 years and they have been instrumental not only in enhancing the understanding of CF pathological mechanisms but also in developing therapies targeting the underlying defects in CFTR mutations with further validation in patient-derived samples. Furthermore, recent advances toward precision medicine in CF have been made possible by optimizing protocols and establishing novel assays using human bronchial, nasal and rectal tissues, and by progressing from two-dimensional monocultures to more complex three-dimensional culture platforms. These models also enable to potentially predict clinical efficacy and responsiveness to CFTR modulator therapies at an individual level. In parallel, advanced systems, such as induced pluripotent stem cells and organ-on-a-chip, continue to be developed in order to more closely recapitulate human physiology for disease modeling and drug testing. In this review, we have highlighted novel and optimized cell models that are being used in CF research to develop novel CFTR-directed therapies (or alternative therapeutic interventions) and to expand the usage of existing modulator drugs to common and rare CF-causing mutations.

Automated summary

The development of preclinical in vitro models has significantly advanced the studies of cystic fibrosis (CF), a fatal monogenic disease caused by mutations in the CFTR gene. These models have improved our understanding of CF pathological mechanisms and have been instrumental in developing therapies targeting CFTR mutations. Recent progress in precision medicine has allowed the use of human tissues to predict clinical efficacy and responsiveness to CFTR modulator therapies. Furthermore, more advanced systems, such as induced pluripotent stem cells and organ-on-a-chip, are being developed for disease modeling and drug testing.