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

Abstract

Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) channel that perturb anion transport across the epithelia of the airways and other organs. To treat cystic fibrosis, strategies that target mutant CFTR have been developed such as correctors that rescue folding and enhance transfer of CFTR to the apical membrane, and potentiators that increase CFTR channel activity. While there has been tremendous progress in development and approval of CFTR therapeutics for the most common (F508del) and several other CFTR mutations, around 10-20% of people with cystic fibrosis have rare mutations that are still without an effective treatment. In the current decade, there was an impressive evolution of patient-derived cell models for precision medicine. In cystic fibrosis, these models have played a crucial role in characterizing the molecular defects in CFTR mutants and identifying compounds that target these defects. Cells from nasal, bronchial, and rectal epithelia are most suitable to evaluate treatments that target CFTR. In vitro assays using cultures grown at an air-liquid interface or as organoids and spheroids allow the diagnosis of the CFTR defect and assessment of potential treatment strategies. An overview of currently established cell culture models and assays for personalized medicine approaches in cystic fibrosis will be provided in this review. These models allow theratyping of rare CFTR mutations with available modulator compounds to predict clinical efficacy. Besides evaluation of individual personalized responses to CFTR therapeutics, patient-derived culture models are valuable for testing responses to developmental treatments such as novel RNA- and DNA-based therapies.

Keywords: CFTR; Modulator; Organoid; Primary human epithelial cells; Spheroid; Theratyping.

Figure 1.. Human CF models for personalized medicine.

A. Illustrations of cell collection for patient-derived models. B. Cartoon depicting culturing and standard assays for nasal, bronchial, and GI/rectal 2D and 3D patient-derived cell models (PDCM).

Figure 2.. Cartoon depicting suitability of PDCM.

Discussed cell models are suitable for biobanking, diagnosis, obtaining information on molecular defects (CFTR or modifier genes) and therapeutic testing and drug screening. Created with BioRender.com.