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

Abstract

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.

Additive Potentiation of R334W-CFTR Function by Novel Small Molecules

“…Numerous screening campaigns have been carried out to identify CFTR potentiators in libraries of drug-like small molecules, which have resulted in the discovery of several compounds with distinct chemical structures that are able to potentiate CFTR function [ 11 , 25 , 27 , 29 , 52 ]. Nevertheless, few potentiators achieved clinical investigation and up to recently, only the potentiator VX-770 was clinically approved for PwCF carrying specific mutations [ 5 , 6 , 7 , 8 , 9 , 10 ]. ABBV-974 (formerly GLPG-1837) has the same binding site as VX-770 in the transmembrane domains of CFTR [ 53 , 54 ] and acts by facilitating the channel gating in a phosphorylation-dependent and ATP-independent fashion [ 12 , 55 ].…”

“…The potentiator VX-770 (also termed ivacaftor) was the first CFTR-modulator drug approved for clinical use initially for people with CF (PwCF) carrying the G551D mutation [ 5 ]. Subsequent studies led to label extensions of VX-770 monotherapy for several other gating and residual function mutations [ 6 , 7 , 8 , 9 , 10 ]. VX-770 acts by increasing the function of mutant CFTR channels present at the plasma membrane [ 11 ].…”

Elexacaftor-Tezacaftor-Ivacaftor: A Life-Changing Triple Combination of CFTR Modulator Drugs for Cystic Fibrosis

“…These include inhaled and physical therapies and various daily medications, including conventional mucolytics, antibiotics, anti-inflammatory agents, and pancreatic enzymes, and monitoring by a multidisciplinary healthcare team (physicians, nurse, nutritionist, physiotherapist, and psychologist) [ 1 , 3 , 11 ]. With the advances in fundamental and translational research by developing preclinical cell models and by implementing cell-based high-throughput screening assays, novel therapies that directly target the primary CFTR defect(s) were discovered [ 10 , 12 ]. These are CFTR modulator drugs that can restore the folding and trafficking of mutant CFTR protein (correctors) or enhance the channel open probability (potentiators) when the protein is located at the plasma membrane [ 2 , 11 ].…”

Clinical Advances in Cystic Fibrosis

“…It is most common in Caucasian people and in Europe (with an incidence of 1:3000 births), whereas in African and Asian populations, the birth prevalence is lower, at 1:15,000 and 1:30,000, respectively [ 7 ]. The relatively high incidence of CF among Europeans may be related to the increased number (>2000) of CFTR genetic variants reported to date [ 8 ]; however, only about 500 variants have been recognized as responsible for causing this disease [ 9 ].…”

“…So-called CFTR modulators have been developed in order to potentiate, correct, stabilize or amplify CFTR functionality [ 11 ]. To date, there are four CFTR modulator drugs approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), but they are used in clinical practice only for specific genotypes and, as a consequence, for a small CF sub-population [ 9 ].…”