CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine

Abstract

Cystic fibrosis (CF) is a lethal inherited disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, which result in impairment of CFTR mRNA and protein expression, function, stability or a combination of these. Although CF leads to multifaceted clinical manifestations, the respiratory disorder represents the major cause of morbidity and mortality of these patients. The life expectancy of CF patients has substantially lengthened due to early diagnosis and improvements in symptomatic therapeutic regimens. Quality of life remains nevertheless limited, as these individuals are subjected to considerable clinical, psychosocial and economic burdens. Since the discovery of the CFTR gene in 1989, tremendous efforts have been made to develop therapies acting more upstream on the pathogenesis cascade, thereby overcoming the underlying dysfunctions caused by CFTR mutations. In this line, the advances in cell-based high-throughput screenings have been facilitating the fast-tracking of CFTR modulators. These modulator drugs have the ability to enhance or even restore the functional expression of specific CF-causing mutations, and they have been classified into five main groups depending on their effects on CFTR mutations: potentiators, correctors, stabilizers, read-through agents, and amplifiers. To date, four CFTR modulators have reached the market, and these pharmaceutical therapies are transforming patients' lives with short-and long-term improvements in clinical outcomes. Such breakthroughs have paved the way for the development of novel CFTR modulators, which are currently under experimental and clinical investigations. Furthermore, recent insights into the CFTR structure will be useful for the rational design of next-generation modulator drugs. This review aims to provide a summary of recent developments in CFTR-directed therapeutics. Barriers and future directions are also discussed in order to optimize treatment adherence, identify feasible and sustainable solutions for equitable access to these therapies, and continue to expand the pipeline of novel modulators that may result in effective precision medicine for all individuals with CF.

The Effect of Sodium Bicarbonate, a Beneficial Adjuvant Molecule in Cystic Fibrosis, on Bronchial Epithelial Cells Expressing a Wild-Type or Mutant CFTR Channel

“…Used in triple combination, small molecular CFTR modulators, like correctors, which act as pharmacological chaperones or proteostasis regulators, and potentiators, which directly improve CFTR channel functions, now offer a breakthrough therapy for the most common CFTR mutations [3,4]. Patients carrying the most common ∆F508-CFTR mutations can benefit from these new drugs, however these therapies are either not suitable for all patients, who might be unresponsive due to rare or unique CFTR mutations, or they cannot afford them due to their excessive cost [5].…”

Adherence and barriers to general and respiratory exercises in cystic fibrosis

“…Cystic fibrosis (CF) is a life-limiting autosomal recessive genetic illness caused by mutation of the CF transmembrane conductance regulator gene on chromosome 7. 1 Although CF leads to multisystem involvement (eg, respiratory, gastrointestinal, hepatic, and genitourinary), the respiratory impairments are the most common causes of morbidity and mortality. 2,3 The respiratory impairments result in dehydration of mucus, which causes increased viscidity, inefficient airway clearance, and recurrent infections.…”

The Role of Specialized Pro-Resolving Mediators in Cystic Fibrosis Airways Disease

“…High-throughput screening has allowed to identify small molecules, such as lumacaftor (VX809) tezacaftor (VX661), and elexacaftor (VX-445) to modulate processing and trafficking of CFTR (CFTR correctors) and ivacaftor (VX770) to potentiate its activity as a chloride channel (CFTR potentiator) providing the first drugs to specifically target the CFTR protein defect. Associations of these molecules, the first ones being currently prescribed in routine since the mid-2010s, restore chloride transport and normalizing sweat test results ( Lopes-Pacheco, 2019 ). Beside their main action on epithelial chloride transport and encouraging results on disease progression, their impact on inflammatory cytokine production are controversial and their long term immunomodulatory effects are still discussed ( Jarosz-Griffiths et al, 2020 ; Volkova et al, 2020 ).…”

“…The prognosis for CF has greatly improved but it remains a severe and lethal disease. One promising therapy recently emerged, with small molecule correctors of mutated CFTR, which improve CFTR function and trafficking to the plasma-membrane [for recent review, see ( Lopes-Pacheco, 2019 )]. However, these therapies are gene mutation specific and their long-term impact on airway inflammation is still controversial ( Jarosz-Griffiths et al, 2020 ; Volkova et al, 2020 ).…”