CFTR Modulators: Shedding Light on Precision Medicine for Cystic Fibrosis.

Miquéias Lopes-Pacheco

doi:10.3389/fphar.2016.00275

Abstract

Cystic fibrosis (CF) is the most common life-threatening monogenic disease aﬄicting Caucasian people. It affects the respiratory, gastrointestinal, glandular and reproductive systems. The major cause of morbidity and mortality in CF is the respiratory disorder caused by a vicious cycle of obstruction of the airways, inflammation and infection that leads to epithelial damage, tissue remodeling and end-stage lung disease. Over the past decades, life expectancy of CF patients has increased due to early diagnosis and improved treatments; however, these patients still present limited quality of life. Many attempts have been made to rescue CF transmembrane conductance regulator (CFTR) expression, function and stability, thereby overcoming the molecular basis of CF. Gene and protein variances caused by CFTR mutants lead to different CF phenotypes, which then require different treatments to quell the patients’ debilitating symptoms. In order to seek better approaches to treat CF patients and maximize therapeutic effects, CFTR mutants have been stratified into six groups (although several of these mutations present pleiotropic defects). The research with CFTR modulators (read-through agents, correctors, potentiators, stabilizers and amplifiers) has achieved remarkable progress, and these drugs are translating into pharmaceuticals and personalized treatments for CF patients. This review summarizes the main molecular and clinical features of CF, emphasizes the latest clinical trials using CFTR modulators, sheds light on the molecular mechanisms underlying these new and emerging treatments, and discusses the major breakthroughs and challenges to treating all CF patients.

Highlights

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF) – the most common life-limiting autosomal recessive inherited disorder in Caucasian people
CF transmembrane conductance regulator (CFTR) encodes an anion channel expressed in several cell types that: (1) transports chloride across the apical membrane; (2) modulates the activity of other ion channels, thereby regulating fluid and electrolyte balance in the mucosal membranes; and (3) secretes bicarbonate, which is crucial for pH regulation, host defense and protection against noxious stimuli (Gadsby et al, 2006; Gentzsch et al, 2010; Gustafsson et al, 2012)
As a protein of the adenosine triphosphate (ATP)-binding cassette (ABC) family, CFTR is comprised of two transmembrane domains (TMDs), two nucleotide-binding domains (NBDs) and a unique regulatory domain (RD) (Gadsby et al, 2006) (Figure 1)

Summary

INTRODUCTION

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF) – the most common life-limiting autosomal recessive inherited disorder in Caucasian people. It is noteworthy that during infection by P. aeruginosa, the bacterial population can segregate and evolve differently according to the lung microenvironment, leading to differences in the bacterial characteristics, such as nutritional requirements, defense and microbial resistance This may explain, partly, why this pathogen is so prevalent and difficult to eradicate from CF patient lungs (Jorth et al, 2015; LaFayette et al, 2015). Risk of gastrointestinal cancer compared to an age-matched non-CF population (Maisonneuve et al, 2013), which may be explained by the fact that CFTR is a tumor suppressor gene (Than et al, 2016) Another severe complication is the allergic bronchopulmonary aspergillosis, which is correlated to accelerated decline of lung function in adult CF patients (Armstead et al, 2014). The knowledge obtained about the molecular scenario in which CFTR mutants are degraded has contributed to understanding the different defects caused by different mutants, and to developing drugs that rectify the primary defect of specific mutations

A PROTEOSTASIS NETWORK ENGAGED IN CFTR DEGRADATION

Findings

CONCLUSION