scholarly journals Fertility, Pregnancy and Lactation Considerations for Women with CF in the CFTR Modulator Era

2021 ◽  
Vol 11 (5) ◽  
pp. 418
Author(s):  
Raksha Jain ◽  
Jennifer L. Taylor-Cousar
Keyword(s):  
Cystic Fibrosis ◽  
Genetic Disorder ◽  
Signs And Symptoms ◽  
Bicarbonate Transport ◽  
New Class ◽  
Pregnancy And Lactation ◽  
Infection And Inflammation ◽  
Protein Dysfunction ◽  
The Impact ◽  
Cftr Modulators

Cystic fibrosis (CF) is an autosomal recessive genetic disorder impacting approximately 80,000 people of all races and ethnicities world-wide. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene which encodes a protein of the same name. Protein dysfunction results in abnormal chloride and bicarbonate transport in mucus membranes, including those in the respiratory, gastrointestinal and reproductive tracts. Abnormal anion transport causes viscous secretions at the site of involvement. The majority of people with CF succumb to respiratory failure following recurrent cycles of infection and inflammation in the airways. Historically, providers treated the signs and symptoms of CF, but since 2012, have been able to impact the basic defect for the subset of people with CF who have mutations that respond to the new class of drugs, CFTR protein modulators. With the improved health and longevity afforded by CFTR modulators, more women are interested in parenthood and are becoming pregnant. Furthermore, this class of drugs likely increases fertility in women with CF. However, the safety of CFTR modulators in pregnancy and lactation is only beginning to be established. We summarize available data on the impact of CFTR modulators on fertility, pregnancy and lactation in women with CF.

scholarly journals CFTR Modulators: Impact on Fertility, Pregnancy, and Lactation in Women with Cystic Fibrosis

2020 ◽  
Vol 9 (9) ◽  
pp. 2706 ◽  
Author(s):  
Jennifer L. Taylor-Cousar
Keyword(s):  
Quality Of Life ◽  
Cystic Fibrosis ◽  
Genetic Disorder ◽  
Safety Data ◽  
Single Copy ◽  
The Body ◽  
Pregnancy And Lactation ◽  
The Impact ◽  
Cftr Modulators

Cystic fibrosis (CF) is a life-shortening genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. These mutations lead to abnormal ion transport in mucous membranes throughout the body, including in the respiratory and gastrointestinal and reproductive tracts. Improvements in care and therapy have led to substantial increases in the quantity and quality of life for those with CF. Consequently, women with CF are increasingly interested in having families. Although pregnancy was once discouraged for women with CF, at this point, even women with moderately severe lung disease can successfully navigate pregnancy. With the recent approval of a triple combination CFTR modulator therapy that improves lung function, nutritional status, and quality of life for people with a single copy of the most common CFTR mutation, it is expected that the number of women with CF who choose to become pregnant will continue to increase. Although animal reproduction models show no alarming signals for use during pregnancy at normal human doses, there is a paucity of human safety data in pregnancy and lactation. This review summarizes what is currently known about the impact of use of CFTR modulators on fertility, pregnancy, and lactation in women with CF.

scholarly journals Impact of Airway Inflammation on the Efficacy of CFTR Modulators

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3260
Author(s):  
Carla M. P. Ribeiro ◽  
Martina Gentzsch
Keyword(s):  
Cystic Fibrosis ◽  
Airway Inflammation ◽  
Primary Cultures ◽  
Lavage Fluid ◽  
Improved Outcomes ◽  
Inflammatory Stimuli ◽  
Infection And Inflammation ◽  
The Impact ◽  
Cftr Modulators

Defective CFTR biogenesis and activity in cystic fibrosis airways leads to airway dehydration and impaired mucociliary clearance, resulting in chronic airway infection and inflammation. Most cystic fibrosis patients have at least one copy of the F508del CFTR mutation, which results in a protein retained in the endoplasmic reticulum and degraded by the proteosomal pathway. CFTR modulators, e.g., correctors, promote the transfer of F508del to the apical membrane, while potentiators increase CFTR activity. Corrector and potentiator double therapies modestly improve lung function, whereas triple therapies with two correctors and one potentiator indicate improved outcomes. Enhanced F508del rescue by CFTR modulators is achieved by exposing F508del/F508del primary cultures of human bronchial epithelia to relevant inflammatory stimuli, i.e., supernatant from mucopurulent material or bronchoalveolar lavage fluid from human cystic fibrosis airways. Inflammation enhances the biochemical and functional rescue of F508del by double or triple CFTR modulator therapy and overcomes abrogation of CFTR correction by chronic VX-770 treatment in vitro. Furthermore, the impact of inflammation on clinical outcomes linked to CFTR rescue has been recently suggested. This review discusses these data and possible mechanisms for airway inflammation-enhanced F508del rescue. Expanding the understanding of how airway inflammation improves CFTR rescue may benefit CF patients.

scholarly journals Use of a High-Throughput Phenotypic Screening Strategy to Identify Amplifiers, a Novel Pharmacological Class of Small Molecules That Exhibit Functional Synergy with Potentiators and Correctors

2017 ◽  
Vol 23 (2) ◽  
pp. 111-121 ◽  
Author(s):  
Kenneth A. Giuliano ◽  
Shinichiro Wachi ◽  
Lawrence Drew ◽  
Danijela Dukovski ◽  
Olivia Green ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Small Molecules ◽  
High Throughput ◽  
Stress Responses ◽  
Genetic Disorder ◽  
Screening Strategy ◽  
New Class ◽  
Cftr Mutations ◽  
Cellular Stress Responses ◽  
Cftr Modulators

Cystic fibrosis (CF) is a lethal genetic disorder caused by mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Despite recent groundbreaking approval of genotype-specific small-molecule drugs, a significant portion of CF patients still lack effective therapeutic options that address the underlying cause of the disease. Through a phenotypic high-throughput screen of approximately 54,000 small molecules, we identified a novel class of CFTR modulators called amplifiers. The identified compound, the characteristics of which are represented here by PTI-CH, selectively increases the expression of immature CFTR protein across different CFTR mutations, including F508del-CFTR, by targeting the inefficiencies of early CFTR biosynthesis. PTI-CH also augments the activity of other CFTR modulators and was found to possess novel characteristics that distinguish it from CFTR potentiator and corrector moieties. The PTI-CH–mediated increase in F508del-CFTR did not elicit cytosolic or endoplasmic reticulum–associated cellular stress responses. Based on these data, amplifiers represent a promising new class of CFTR modulators for the treatment of CF that can be used synergistically with other CFTR modulators.

scholarly journals The effects of nano-curcumin as a nutritional strategy on clinical and inflammatory factors in children with cystic fibrosis: the study protocol for a randomized controlled trial

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Saeedeh Talebi ◽  
Mahammad Safarian ◽  
Mahmood Reza Jaafari ◽  
Seyed Javad Sayedi ◽  
Zahra Abbasi ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Controlled Trial ◽  
Genetic Disorder ◽  
The Body ◽  
Inflammatory Factors ◽  
Secondary Outcome ◽  
Nasopharyngeal Swab ◽  
Nutritional Strategy ◽  
Cftr Protein ◽  
The Impact

Abstract Background Cystic fibrosis (CF) is a genetic disorder, which is caused by the CFTR protein defects. Along with CFTR dysfunction, inflammation plays a key role in the disease outcomes. Inflammation may develop due to the internal dysfunction of the CFTR protein or external factors. Curcumin affects the CFTR protein function primarily as a corrector and potentiator and secondary as an anti-inflammatory and antimicrobial agent. The present study aims to assess the impact of nano-curcumin on clinical and inflammatory markers in children with CF. Methods This prospective, double blind control trial will be conducted at the Akbar Children’s Hospital in Mashhad, Iran. Children with CF will be enrolled based on the eligibility criteria. Placebo and curcumin with the maximum dose of 80 mg considering the body surface of the patients will be administrated for 3 months. The primary outcome is to evaluate inflammation based on serum interleukin-6, interleukin-10, and hs-CRP, stool calprotectin, and neutrophil count of nasopharyngeal swab. The secondary outcome involved clinical assessment via spirometry, anthropometrics, and quality of life. They will be assessed before and after 3 months. Discussion Due to the multifarious effects of curcumin on CF disease, it could be proposed as a nutritional strategy in the treatment of cystic fibrosis. Trial registration Iranian Registry of Clinical Trials IRCT20200705048018N1. Registered on July 10, 2020.

scholarly journals Stressors and Stress Responses in Cystic Fibrosis

2018 ◽  
Vol 5 (1) ◽  
pp. 11-29 ◽  
Author(s):  
Zsuzsa Bebok ◽  
Lianwu Fu
Keyword(s):  
Cystic Fibrosis ◽  
Stress Response ◽  
Stress Responses ◽  
Genetic Disorder ◽  
Cellular Stress ◽  
Cellular Stress Response ◽  
Bicarbonate Transport ◽  
Persistent Infections ◽  
Human Disorders ◽  
The Unfolded Protein Response

Abstract Cystic fibrosis (CF) is a life-shortening, genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). The primary cause of CF is reduced CFTR-mediated chloride and bicarbonate transport, due to mutations in CFTR. However, inflammation and persistent infections influence clinical outcome. Cellular stress response pathways, such as the unfolded protein response (UPR) and the integrated stress response (ISR), referred to here as cellular stress response pathways (SRPs), contribute to the pathology of human disorders. Multiple studies have indicated activation of SRPs in CF tissues. We review our present understanding of how SRPs are activated in CF and their contribution to pathology. We conclude that reduced CFTR function in CF organs establishes a tissue environment in which internal or external insults activate SRPs. SRPs contribute to CF pathogenesis by reducing CFTR expression, enhancing inflammation with consequent tissue remodeling. Understanding the contribution of SRPs to CF pathogenesis is crucial even in the era of CFTR “modulators” that are designed to potentiate, correct or amplify CFTR function, since there is an urgent need for supportive treatments. Importantly, CF patients with established pathology could benefit from the targeted use of drugs that modulate SRPs to reduce the symptoms.

scholarly journals Airway Inflammation and Host Responses in the Era of CFTR Modulators

2020 ◽  
Vol 21 (17) ◽  
pp. 6379
Author(s):  
Karen Keown ◽  
Ryan Brown ◽  
Declan F. Doherty ◽  
Claire Houston ◽  
Michael C. McKelvey ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Function ◽  
Lung Disease ◽  
Airway Inflammation ◽  
Host Responses ◽  
Current Evidence ◽  
Future Research ◽  
Clinical Endpoints ◽  
New Class ◽  
Cftr Modulators

The arrival of cystic fibrosis transmembrane conductance regulator (CFTR) modulators as a new class of treatment for cystic fibrosis (CF) in 2012 represented a pivotal advance in disease management, as these small molecules directly target the upstream underlying protein defect. Further advancements in the development and scope of these genotype-specific therapies have been transformative for an increasing number of people with CF (PWCF). Despite clear improvements in CFTR function and clinical endpoints such as lung function, body mass index (BMI), and frequency of pulmonary exacerbations, current evidence suggests that CFTR modulators do not prevent continued decline in lung function, halt disease progression, or ameliorate pathogenic organisms in those with established lung disease. Furthermore, it remains unknown whether their restorative effects extend to dysfunctional CFTR expressed in phagocytes and other immune cells, which could modulate airway inflammation. In this review, we explore the effects of CFTR modulators on airway inflammation, infection, and their influence on the impaired pulmonary host defences associated with CF lung disease. We also consider the role of inflammation-directed therapies in light of the widespread clinical use of CFTR modulators and identify key areas for future research.

scholarly journals Choice of Differentiation Media Significantly Impacts Cell Lineage and Response to CFTR Modulators in Fully Differentiated Primary Cultures of Cystic Fibrosis Human Airway Epithelial Cells

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2137
Author(s):  
Vinciane Saint-Criq ◽  
Livia Delpiano ◽  
John Casement ◽  
Jennifer C. Onuora ◽  
JinHeng Lin ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
Cell Lineage ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Functional Responses ◽  
Human Airway ◽  
The Impact ◽  
Cftr Modulators ◽  
Human Airway Epithelial Cells

In vitro cultures of primary human airway epithelial cells (hAECs) grown at air–liquid interface have become a valuable tool to study airway biology under normal and pathologic conditions, and for drug discovery in lung diseases such as cystic fibrosis (CF). An increasing number of different differentiation media, are now available, making comparison of data between studies difficult. Here, we investigated the impact of two common differentiation media on phenotypic, transcriptomic, and physiological features of CF and non-CF epithelia. Cellular architecture and density were strongly impacted by the choice of medium. RNA-sequencing revealed a shift in airway cell lineage; one medium promoting differentiation into club and goblet cells whilst the other enriched the growth of ionocytes and multiciliated cells. Pathway analysis identified differential expression of genes involved in ion and fluid transport. Physiological assays (intracellular/extracellular pH, Ussing chamber) specifically showed that ATP12A and CFTR function were altered, impacting pH and transepithelial ion transport in CF hAECs. Importantly, the two media differentially affected functional responses to CFTR modulators. We argue that the effect of growth conditions should be appropriately determined depending on the scientific question and that our study can act as a guide for choosing the optimal growth medium for specific applications.

scholarly journals Modulation of Ion Transport to Restore Airway Hydration in Cystic Fibrosis

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 453
Author(s):  
James A. Reihill ◽  
Lisa E. J. Douglas ◽  
S. Lorraine Martin
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
Genetic Disorder ◽  
Airway Epithelial Cells ◽  
Transmembrane Conductance Regulator ◽  
Airway Epithelial ◽  
Loss Of Function ◽  
Transmembrane Conductance ◽  
Infection And Inflammation ◽  
Cf Transmembrane Conductance Regulator

Cystic fibrosis (CF) is a life-limiting genetic disorder caused by loss-of-function mutations in the gene which codes for the CF transmembrane conductance regulator (CFTR) Cl− channel. Loss of Cl− secretion across the apical membrane of airway lining epithelial cells results in dehydration of the airway surface liquid (ASL) layer which impairs mucociliary clearance (MCC), and as a consequence promotes bacterial infection and inflammation of the airways. Interventions that restore airway hydration are known to improve MCC. Here we review the ion channels present at the luminal surface of airway epithelial cells that may be targeted to improve airway hydration and MCC in CF airways.

Treatment of cystic fibrosis airway cells with CFTR modulators reverses aberrant mucus properties via hydration

2021 ◽  
pp. 2100185
Author(s):  
Cameron B. Morrison ◽  
Kendall M. Shaffer ◽  
Kenza C. Araba ◽  
Matthew R. Markovetz ◽  
Jason A. Wykoff ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Short Circuit ◽  
Large Fraction ◽  
Cell Surfaces ◽  
Bronchial Epithelial ◽  
Cystic Fibrosis Airway ◽  
Surface Liquid ◽  
The Impact ◽  
Cftr Modulators ◽  
Short Circuit Currents

QuestionCystic fibrosis (CF) is characterised by the accumulation of viscous, adherent mucus in the lungs. While several hypotheses invoke a direct relationship with CFTR dysfunction (i.e., acidic airway surface liquid (ASL) pH, low [HCO3−], airway dehydration), the dominant biochemical alteration of CF mucus remains unknown.Materials/MethodsWe characterised a novel cell line (CFTR-KO Calu3 cells) and the responses of human bronchial epithelial (HBE) cells from subjects with G551D or F508del mutations to Ivacaftor and Elexacaftor-Tezacaftor-Ivacaftor (ETI). A spectrum of assays such as short-circuit currents (Isc), qPCR, ASL pH, western blotting (WB), light scattering/refractometry (SEC-MALS), scanning electron microscopy (SEM), % solids, and particle tracking were performed to determine the impact of CFTR function on mucus properties.ResultsLoss of CFTR function in Calu3 cells resulted in ASL pH acidification and mucus hyperconcentration (dehydration). Modulation of CFTR in CF HBE cells did not affect ASL pH or mucin mRNA expression, but decreased mucus concentration, relaxed mucus network ultrastructure, and improved mucus transport. In contrast with modulator-treated cells, a large fraction of airway mucins remained attached to naïve CF cells following short apical washes, as revealed by the use of reducing agents to remove residual mucus from the cell surfaces. Extended hydration, but not buffers alkalised with NaOH or HCO3−, normalised mucus recovery to modulator-treated cell levels.ConclusionThese results indicate that airway dehydration, not acidic pH and/or low [HCO3−], is responsible for abnormal mucus properties in CF airways and CFTR modulation predominantly restores normal mucin entanglement.

scholarly journals Effect of vitamin D on infection and inflammation in patients with cystic fibrosis: a systematic review and meta-analysis

2022 ◽  
Author(s):  
Nelufa Begum ◽  
Abdullah Al Tarique ◽  
Tamara Blake ◽  
Dwan Vilcins ◽  
Mohammad Zahirul Islam ◽  
...  
Keyword(s):  
Systematic Review ◽  
Cystic Fibrosis ◽  
Vitamin D ◽  
Tract Infection ◽  
Respiratory Tract ◽  
Respiratory Tract Infection ◽  
Meta Analysis ◽  
Genetic Disorder ◽  
Random Effect ◽  
Infection And Inflammation

Background Cystic fibrosis (CF) is a genetic disorder in which the respiratory system gets clogged with mucus leads to progressive lung damage. There is no known cure for CF but several treatments to manage symptoms and reduce complications. Vitamin D deficiency is common in CF associated with increased infection and inflammation. This systematic review and meta analysis will evaluate the effectiveness of vitamin D treatment in reducing respiratory tract infection and inflammation in patients with CF. Methods Randomized and quasi randomised studies in CF patients with control groups will be identified. The antibacterial activity of vitamin D supplementation will help in reducing respiratory tract infection and inflammation in CF. Overall effects of vitamin D in terms of infection and inflammatory markers such as C reactive protein, inflammatory cytokine interleukin (IL)6, IL8, IL17, IL23, antimicrobial peptide (LL37), lung function defined by forced expiratory volume in 1 second (FEV1)%, other assessed respiratory parameters will be calculated using random-effect models. Study quality will be assessed using RoB 2, A revised Cochrane Risk of Bias tool for randomised trials. The overall quality of evidence for each outcome will be summarised according to the Grading of Recommendations Assessment, Development, and Evaluations (GRADE) framework.

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