Established and novel human translational models to advance cystic fibrosis research, drug discovery, and optimize CFTR-targeting therapeutics

Abstract

To find a cure for cystic fibrosis, there has been tremendous progress in the development of treatments that target the basic defect in the protein channel, CFTR. However, 10% of cystic fibrosis patients have rare CFTR mutations that are still without an approved CFTR-targeting drug. To identify relevant therapies for these patients, culture models using nasal, bronchial, and rectal tissue from individual patients allow functional, biochemical, and cellular detection of drug-rescued CFTR. Additionally, novel systems such as induced pluripotent stem cell-derived models are utilized to characterize CFTR mutations and identify treatments. State-of-the-art translational models were instrumental for CFTR modulator development and may become important for gene-based drug discovery and other novel therapeutic strategies.

Figure 1:. Translational human in vitro models for CF research and drug discovery.

Processing and expansion of nasal bronchial and GI epithelial tissues to form 2D planar and 3D spheroid cultures. Expanded HNE and HBE cells are either seeded on membranes form planar cultures or in matrigel to form spheroids. GI organoids develop directly from partially digested tissues. Planar and spheroid cultures can be utilized to evaluate pharmacological rescue of CFTR rescue by various assays that evaluate CFTR function and maturation. Some image panels were obtained from Servier Medical Art (smart.servier.com).