CFTR Modulators: Shedding Light on Precision Medicine for Cystic Fibrosis

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.

Combination of Correctors Rescues CFTR Transmembrane-Domain Mutants by Mitigating their Interactions with Proteostasis

“…Proteostasis networks interconnect gene expression, signaling pathways, molecular chaperones, and degradation systems to maintain a healthy proteome [1, 4]. The wt-CFTR and ΔF508 interact differently with proteostasis components that enable wt-CFTR maturation and preclude ΔF508 exit from the ER [2].…”

“…CFTR mutants have been segregated into groups to aid the search for treatments that could rectify mutants with similar defects; however, some of the mutants may present differing structural characteristics or even be unique, responding very differently to the same treatment. In working toward effective approaches, precision medicine is trying to find appropriate pharmacological treatments to overcome the debilitating symptoms in all CF patients [4]. …”

“…Worldwide, about 80% of CF patients possess the mutant ΔF508, with only half of them homozygous for this mutant and the remainder bearing other (non-ΔF508) mutants on the second allele [4, 8]. Nearly 2,000 mutations have been reported in the CF Mutation Database (CFTR1) (see [9]) including the TMD mutants G85E, E92K, L1077P, and M1101K.…”

“…CFTR encodes a chloride channel located at the apical membrane of several epithelial tissues, and its loss of activity impairs the ionic and fluid transcellular balance, resulting in dehydration of the epithelial lining and triggering the progressive pathological cascade of the disease. The major cause of CF morbidity and mortality is the pulmonary disorder caused by an accumulation of thick and tenacious mucus, inflammation, and recurrent infections that impair lung function and end in respiratory failure [4]. …”

Highlights from the 2016 North American Cystic Fibrosis Conference

“…Currently, CFTR modulators are available for approximately 50-55% of people with CF. 7,8 In 2016, lumacaftor/ivacaftor approval by the FDA was expanded to include children with CF ages 6-11 years, homozygous for the F508del-CFTR mutation. Studies are on-going to extend this approval into younger age groups.…”