Ion Channel Modulators in Cystic Fibrosis

doi:10.1016/j.chest.2018.04.036

Chest

Volume 154, Issue 2, August 2018, Pages 383-393

https://doi.org/10.1016/j.chest.2018.04.036 Get rights and content

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and remains one of the most common life-shortening genetic diseases affecting the lung and other organs. CFTR functions as a cyclic adenosine monophosphate-dependent anion channel that transports chloride and bicarbonate across epithelial surfaces, and disruption of these ion transport processes plays a central role in the pathogenesis of CF. These findings provided the rationale for pharmacologic modulation of ion transport, either by targeting mutant CFTR or alternative ion channels that can compensate for CFTR dysfunction, as a promising therapeutic approach. High-throughput screening has supported the development of CFTR modulator compounds. CFTR correctors are designed to improve defective protein processing, trafficking, and cell surface expression, whereas potentiators increase the activity of mutant CFTR at the cell surface. The approval of the first potentiator ivacaftor for the treatment of patients with specific CFTR mutations and, more recently, the corrector lumacaftor in combination with ivacaftor for patients homozygous for the common F508del mutation, were major breakthroughs on the path to causal therapies for all patients with CF. The present review focuses on recent developments and remaining challenges of CFTR-directed therapies, as well as modulators of other ion channels such as alternative chloride channels and the epithelial sodium channel as additional targets in CF lung disease. We further discuss how patient-derived precision medicine models may aid the translation of emerging next-generation ion channel modulators from the laboratory to the clinic and tailor their use for optimal therapeutic benefits in individual patients with CF.

Section snippets

Development of CFTR Modulators

Basic CF research has paved the way for a better molecular understanding of CFTR mutations by providing cell-based in vitro assays to measure CFTR function17, 18 and, moreover, structural homology models,¹⁹ molecular dynamics simulations,²⁰ and biophysical domain studies of CFTR.²¹ Recent novel cryo-electron microscopy structures of the dephosphorylated and phosphorylated channel state added intriguing insights into the mechanism of channel opening.22, 23 The detailed knowledge of CFTR

New-Generation Combination Treatments

Current strategies to enhance the efficacy of CFTR modulator therapy in patients with the F508del mutation focus on the development of amplifier compounds that increase the amount of CFTR molecules available as a therapeutic target.⁵⁶ They also focus on next-generation correctors that can stabilize other portions of the F508del molecule and thus help to overcome its multiple folding defects that may be responsible for the efficacy ceiling observed with current correctors.24, 25, 57 Successful

Patient-Derived Models to Enhance Precision Medicine for CF

Despite substantial progress in the development of therapies targeting the root cause of CF, many patients who have one or two copies of F508del or two untreatable CFTR mutations still await more effective drug treatments for their basic CF defect.⁵⁵ Because approximately 50% of patients carry two different CFTR mutations, these individuals will require addressing more than just one defect with combined treatments. Thus, personalized combination therapies will be needed. Furthermore, it is

Alternative Targets for Ion Channel Modulation in CF

Targeting of alternative ion channels that may compensate for CFTR dysfunction is advantageous in that this approach might be used to treat all patients with CF irrespective of their CFTR genotype (Fig 2C). In addition, pharmacologic modulation of alternative ion channels could augment benefits of CFTR modulator therapies in patients with CF and modulator-responsive CFTR mutations (Fig 2D). Promising epithelial ion channels that may be exploited as alternative targets are the ENaC and

Conclusions and Outlook

The identification of the CFTR gene in 1989 paved the way for unraveling the structure, processing, and function of CFTR in health, which has consequently revealed how multiple mutations in this epithelial anion channel cause CF multiorgan disease. With the advent of high-throughput screening technologies, this knowledge base generated by basic CF research enabled the identification of small-molecule compounds that act directly on mutant CFTR to restore its activity in the airways and other

Acknowledgments

Financial/nonfinancial disclosures: The authors have reported to CHEST the following: M. G. reports funding from grants and contracts from the Cystic Fibrosis Foundation, Cystic Fibrosis Foundation Therapeutics, Cystic Fibrosis Research, Inc., Catabasis Pharmaceuticals, Corbus Pharmaceuticals, GlaxoSmithKline, the National Institutes of Health, NC TraCS Institute, Path BioAnalytics, Reoxcyn Discoveries Group, Spirovation, and Theravance Biopharma; and is an inventor of the technology “airway

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Cited by (114)

Potential systemic effects of acquired CFTR dysfunction in COPD
2024, Respiratory Medicine
Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation, respiratory symptoms, inflammation of the airways, and systemic manifestations of the disease. Genetic susceptibility and environmental factors are important in the development of the disease, particularly exposure to cigarette smoke which is the most notable risk factor. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are the cause of cystic fibrosis (CF), which shares several pathophysiological pulmonary features with COPD, including airway obstruction, chronic airway inflammation and bacterial colonization; in addition, both diseases also present systemic defects leading to comorbidities such as pancreatic, gastrointestinal, and bone-related diseases. In patients with COPD, systemic CFTR dysfunction can be acquired by cigarette smoking, inflammation, and infection. This dysfunction is, on average, about half of that found in CF. Herein we review the literature focusing on acquired CFTR dysfunction and the potential role in the pathogenesis of comorbidities associated with COPD and chronic bronchitis.
The future of cystic fibrosis treatment: from disease mechanisms to novel therapeutic approaches
2023, The Lancet
With the 2019 breakthrough in the development of highly effective modulator therapy providing unprecedented clinical benefits for over 90% of patients with cystic fibrosis who are genetically eligible for treatment, this rare disease has become a front runner of transformative molecular therapy. This success is based on fundamental research, which led to the identification of the disease-causing CFTR gene and our subsequent understanding of the disease mechanisms underlying the pathogenesis of cystic fibrosis, working together with a continuously evolving clinical research and drug development pipeline. In this Series paper, we focus on advances since 2018, and remaining knowledge gaps in our understanding of the molecular mechanisms of CFTR dysfunction in the airway epithelium and their links to mucus dysfunction, impaired host defences, airway infection, and chronic inflammation of the lungs of people with cystic fibrosis. We review progress in (and the remaining obstacles to) pharmacological approaches to rescue CFTR function, and novel strategies for improved symptomatic therapies for cystic fibrosis, including how these might be applicable to common lung diseases, such as bronchiectasis and chronic obstructive pulmonary disease. Finally, we discuss the promise of genetic therapies and gene editing approaches to restore CFTR function in the lungs of all patients with cystic fibrosis independent of their CFTR genotype, and the unprecedented opportunities to transform cystic fibrosis from a fatal disease to a treatable and potentially curable one.
Identification of single nucleotide variants in SLC26A9 gene in patients with cystic fibrosis (p.Phe508del homozygous) and its association to Orkambi® (Lumacaftor and Ivacaftor) response in vitro
2023, Gene
Since patients with cystic fibrosis with different Cystic Fibrosis Transmembrane Regulator (CFTR) genotypes present a wide response variability for modulator drugs such as Orkambi®, it is important to screen variants in candidate genes with an impact on precision and personalized medicine, such as Solute Carrier Family 26, member 9 (SLC26A9) gene.
Sanger sequencing for the exons and intron–exon boundary junctions of the SLC26A9 gene was employed in nine individuals with p.Phe508del homozygous genotype for the CFTR gene who were not under CFTR modulators therapy. The sequencing variants were evaluated by in silico prediction tools. The CFTR function was measured by cAMP–stimulated current (ΔIsc-eq-FSK) in polarized CFTR of human nasal epithelial cells cultured in micro–Ussing chambers with Orkambi®.
We found 24 intronic variants, three in the coding region (missense variants – rs74146719 and rs16856462 and synonymous – rs33943971), and three in the three prime untranslated region (3′ UTR) region in the SLC26A9 gene. Twenty variants were considered benign according to American College of Medical Genetics and Genomics guidelines, and ten were classified as uncertain significance. Although some variants had deleterious predictions or possible alterations in splicing, the majority of predictions were benign or neutral. When we analyzed the ΔIsc-eq-FSK response to Orkambi®, there were no significant differences within the genotypes and alleles for all 30 variants in the SLC26A9 gene.
Among the nine individuals with p.Phe508del homozygous genotype for the CFTR gene, no pathogenic SLC26A9 variants were found, and we did not detect associations from the 30 SLC26A9 variants and the response to the Orkambi® in vitro.
Cystic fibrosis prevalence in the United States and participation in the Cystic Fibrosis Foundation Patient Registry in 2020
2023, Journal of Cystic Fibrosis
The Cystic Fibrosis Foundation Patient Registry (CFFPR) collects data on individuals with cystic fibrosis (CF) in the United States (US). In 2012, the US CF population was estimated at 33,292 to 34,327 individuals, with 81-84% CFFPR participation.
In this study, we update these estimates via simulation to account for uncertainty in CF incidence by race or Hispanic ethnicity, initiation of CF newborn screening (NBS) programs by state, and updated cumulative survival for CF births 1968-2020. We defined registry participation as the proportion of individuals alive as of 2020 with any prior CFFPR participation as well as the proportion with contributing data in 2019 or 2020; we summarize CFFPR participation for those born prior to 1968.
We estimated the 2020 prevalent CF population between 1968-2020 to be 38,804 (95% Uncertainty Interval (UI): 38,532 to 39,065) individuals, with 77% of the prevalent CF population contributing recent data. CFFPR participation differs by age (54% of those born in 1968) and exceeds >90% of the population born in 2009 or later.
We demonstrate that the CFFPR remains a valid data source generalizable to the CF population. High participation among younger individuals may reflect the success of newborn screening programs and early referral to CF care. If engagement can be sustained, the percentage of individuals participating in the CFFPR will grow over time and there is an opportunity to identify factors associated with loss to follow up among older individuals to optimize the quality of the CFFPR data.
Patient-derived cell models for personalized medicine approaches in cystic fibrosis
2023, Journal of Cystic Fibrosis
Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) channel that perturb anion transport across the epithelia of the airways and other organs. To treat cystic fibrosis, strategies that target mutant CFTR have been developed such as correctors that rescue folding and enhance transfer of CFTR to the apical membrane, and potentiators that increase CFTR channel activity. While there has been tremendous progress in development and approval of CFTR therapeutics for the most common (F508del) and several other CFTR mutations, around 10-20% of people with cystic fibrosis have rare mutations that are still without an effective treatment. In the current decade, there was an impressive evolution of patient-derived cell models for precision medicine. In cystic fibrosis, these models have played a crucial role in characterizing the molecular defects in CFTR mutants and identifying compounds that target these defects. Cells from nasal, bronchial, and rectal epithelia are most suitable to evaluate treatments that target CFTR. In vitro assays using cultures grown at an air-liquid interface or as organoids and spheroids allow the diagnosis of the CFTR defect and assessment of potential treatment strategies. An overview of currently established cell culture models and assays for personalized medicine approaches in cystic fibrosis will be provided in this review. These models allow theratyping of rare CFTR mutations with available modulator compounds to predict clinical efficacy. Besides evaluation of individual personalized responses to CFTR therapeutics, patient-derived culture models are valuable for testing responses to developmental treatments such as novel RNA- and DNA-based therapies.
Elexacaftor-Tezacaftor-Ivacaftor in 2 cystic fibrosis adults homozygous for M1101K with end-stage lung disease
2023, Respiratory Medicine Case Reports
Elexacaftor-tezacaftor-ivacaftor (ETI) therapy is shown to improve the health of individuals with cystic fibrosis (CF) who have the F508del variant. There are in vitro studies showing benefit with ETI for select rare CF variants. Limited data exists on the use of ETI in individuals with rare CF variants, particularly in those with advanced lung disease. We present 2 cases of CF individuals homozygous for the rare M1101K variant with end-stage lung disease who demonstrated sustained improvements in lung function, pulmonary exacerbation frequency, respiratory symptoms, and body mass index after 6 months of ETI treatment – similar to that expected with F508del.

View all citing articles on Scopus

: FUNDING/SUPPORT: M. G. has been supported by the National Institutes of Health [Grant P30 DK065988 CFRTCC] and the Cystic Fibrosis Foundation [BOUCHE15R0 RDP Program], and M. A. M. has been supported by the German Ministry for Education and Research [Grant FKZ 82DZL004A1] and the Einstein Foundation Berlin.

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Chest

Translating Basic Research Into Clinical PracticeIon Channel Modulators in Cystic Fibrosis

Section snippets

Development of CFTR Modulators

New-Generation Combination Treatments

Patient-Derived Models to Enhance Precision Medicine for CF

Alternative Targets for Ion Channel Modulation in CF

Conclusions and Outlook

Acknowledgments

Lancet

J Cyst Fibros

Pharmacol Ther

J Biol Chem

J Biol Chem

Cell

Cell

Lancet Respir Med

Chest

J Cyst Fibros

J Cyst Fibros

J Cyst Fibros

Lancet Respir Med

Lancet Respir Med

Gastroenterology

Lancet Respir Med

Cell

J Cyst Fibros

J Cyst Fibros

Stem Cell Reports

J Cyst Fibros

Curr Opin Pharmacol

J Cyst Fibros

J Pediatr

J Cyst Fibros

Chest

Curr Opin Pharmacol

CFTR: cystic fibrosis and beyond

Eur Respir J

Managing cystic fibrosis: strategies that increase life expectancy and improve quality of life

Am J Respir Crit Care Med

Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA

Science

A CFTR potentiator in patients with cystic fibrosis and the G551D mutation

N Engl J Med

Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR

N Engl J Med

Rescue of DeltaF508-CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small molecules

Am J Physiol Lung Cell Mol Physiol

Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene

Nat Genet

Unraveling the complex genetic model for cystic fibrosis: pleiotropic effects of modifier genes on early cystic fibrosis-related morbidities

Hum Genet

Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis

Nat Commun

From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations

Mol Biol Cell

Phosphorylation-regulated Cl- channel in CHO cells stably expressing the cystic fibrosis gene

Nature

Expression of cystic fibrosis transmembrane conductance regulator corrects defective chloride channel regulation in cystic fibrosis airway epithelial cells

Nature

Phenylalanine-508 mediates a cytoplasmic-membrane domain contact in the CFTR 3D structure crucial to assembly and channel function

Proc Natl Acad Sci U S A

Molecular modelling and molecular dynamics of CFTR

Cell Mol Life Sci

Thermal unfolding studies show the disease causing F508del mutation in CFTR thermodynamically destabilizes nucleotide-binding domain 1

Protein Sci

Molecular structure of the human CFTR ion channel

Cell

Conformational changes of CFTR upon phosphorylation and ATP binding

Cell

Mechanism-based corrector combination restores DeltaF508-CFTR folding and function

Nat Chem Biol

Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del

N Engl J Med

Translating Basic Research Into Clinical Practice
Ion Channel Modulators in Cystic Fibrosis