Emerging Cystic Fibrosis Transmembrane Conductance Regulator Modulators as New Drugs for Cystic Fibrosis: A Portrait of in Vitro Pharmacology and Clinical Translation

Abstract

Pharmacological correction of the defective ion channel with cystic fibrosis transmembrane conductance regulator (CFTR) has become an attractive approach to therapy directed at the root cause of the life-limiting disease cystic fibrosis (CF). CFTR defects range from absence, misfolding, and resulting degradation to functional defects of the CFTR protein. The discovery and development of the CFTR potentiator ivacaftor was a major break-through in CF therapy and has triggered an enormous incentive for seeking effective modulators such as lumacaftor, tezacaftor or elexacaftor for all patients with CF. A number of emerging CFTR modulators are currently in the development pipeline, and rescue levels of CFTR protein approach a cure for cystic fibrosis. In this review, we identify and characterize all preclinical and clinical emerging CFTR modulators and discuss the in vitro pharmacology, looking at CFTR protein expression and chloride transport and the translation to the clinic. The new emerging CFTR modulators could offer new therapeutic solutions for CF patients.

HMGB1: A Possible Crucial Therapeutic Target for COVID-19?

“…Target for COVID-19? 3 Horm Res Paediatr DOI: 10.1159/000508291 sion and/or specific polymorphisms could play a role, particularly in the lung, and some of the new CFTR modulators should be considered for treatment if this were indeed the case [25,26]. Furthermore, diabetes is a recognized risk factor for Sars-CoV2 infection [27], and HMGB1 is known to be increased in diabetes [8].…”

“…Finally, my research group previously showed that cystic fibrosis transductance regulator (CFTR) malfunction, as found in cystic fibrosis, increases HMGB1 serum concentrations, along with inflammation, and further increases are observed at the onset of the specifically related diabetes [24]. This suggests that changes in CFTR expression and/or specific polymorphisms could play a role, particularly in the lung, and some of the new CFTR modulators should be considered for treatment if this were indeed the case [25, 26]. Furthermore, diabetes is a recognized risk factor for Sars-CoV2 infection [27], and HMGB1 is known to be increased in diabetes [8].…”

Anti-Inflammatory Influences of Cystic Fibrosis Transmembrane Conductance Regulator Drugs on Lung Inflammation in Cystic Fibrosis

“…G551D is a missense mutation affecting approximately 4% of the global CF population and causes impaired CFTR channel gating [ 60 ]. Ivacaftor monotherapy approval was later extended to include additional gating mutations, including G1244E, G1349D, G178R, G551S, S1252N, S1255P, S549N, S549R, and R117H [ 7 ]. Ivacaftor (VX-770) targets the dysfunctional CFTR and increases the time in which these channels remain open, allowing for sufficient anion transport ( Figure 7 ).…”

“…The recent development of CFTR modulators, namely ivacaftor, lumacaftor, tezacaftor and elexacaftor, has reinvigorated therapeutic potential of resolving CFTR dysfunction directly as previous treatment options were only targeting secondary manifestations and symptoms [ 7 ]. This review aims to summarise the relationship between CF and lung inflammation, to explore current literature on the anti-inflammatory effects of CFTR modulators, and to propose future research avenues, all aimed to refine our understanding of this life-threatening disease and improve patient outcome.…”

Synthesis and Therapeutic Applications of Iminosugars in Cystic Fibrosis

“…Currently, researchers are working on different approaches, some of them aimed to handle the basic molecular defect in CF, by restoring proper function to the CFTR protein or correcting its production process so that a normal protein can be build up [50][51][52][53][54], others directed to controlling the clinical manifestations of the diseases, including inflammation, infection and mucociliary clearance, mostly for patients with irreversible lung damage [55][56][57][58][59]. The iminosugar class has representative examples in both fields of application and the results obtained in the last decades have been examined below.…”