scholarly journals Potential of Intestinal Current Measurement for Personalized Treatment of Patients with Cystic Fibrosis

2021 ◽  
Vol 11 (5) ◽  
pp. 384
Author(s):  
Simon Y. Graeber ◽  
Constanze Vitzthum ◽  
Marcus A. Mall
Keyword(s):  
Cystic Fibrosis ◽  
Diagnostic Testing ◽  
Current Measurement ◽  
Personalized Treatment ◽  
Transmembrane Conductance Regulator ◽  
New Era ◽  
Intestinal Epithelia ◽  
Transport Defect ◽  
Culture Models ◽  
Cftr Mutations

Refinement of personalized treatment of cystic fibrosis (CF) with emerging medicines targeting the CF basic defect will likely benefit from biomarkers sensitive to detect improvement of cystic fibrosis transmembrane conductance regulator (CFTR) function in individual patients. Intestinal current measurement (ICM) is a technique that enables quantitative assessment of CFTR chloride channel function in rectal tissues or other intestinal epithelia. ICM was originally developed to study the CF ion transport defect in the intestine and has been established as a sensitive biomarker of CFTR function and diagnostic test for CF. With the emergence of CFTR-directed therapeutics, ICM has become an important tool to estimate the level of rescue of CFTR function achieved by approved CFTR modulators, both at the level of CFTR genotype groups, as well as individual patients with CF. In combination with preclinical patient-derived cell culture models, ICM may aid the development of targeted therapies for patients with rare CFTR mutations. Here, we review the principles of ICM and examine how this CFTR biomarker may be used to support diagnostic testing and enhance personalized medicine for individual patients with common as well as rare CFTR mutations in the new era of medicines targeting the underlying cause of CF.

scholarly journals Animal Models of Cystic Fibrosis Pathology: Phenotypic Parallels and Divergences

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Gillian M. Lavelle ◽  
Michelle M. White ◽  
Niall Browne ◽  
Noel G. McElvaney ◽  
Emer P. Reeves
Keyword(s):  
Cystic Fibrosis ◽  
Animal Models ◽  
Mouse Models ◽  
Animal Studies ◽  
Mucociliary Clearance ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Bacterial Colonisation ◽  
Transport Defect ◽  
Cystic Fibrosis Transmembrane

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The resultant characteristic ion transport defect results in decreased mucociliary clearance, bacterial colonisation, and chronic neutrophil-dominated inflammation. Much knowledge surrounding the pathophysiology of the disease has been gained through the generation of animal models, despite inherent limitations in each. The failure of certain mouse models to recapitulate the phenotypic manifestations of human disease has initiated the generation of larger animals in which to study CF, including the pig and the ferret. This review will summarise the basic phenotypes of three animal models and describe the contributions of such animal studies to our current understanding of CF.

scholarly journals Interleukin 8 Secretion from Monocytes of Subjects Heterozygous for the ΔF508 Cystic Fibrosis Transmembrane Conductance Regulator Gene Mutation Is Altered

2004 ◽  
Vol 11 (5) ◽  
pp. 819-824 ◽  
Author(s):  
Munir M. Zaman ◽  
Andres Gelrud ◽  
Omer Junaidi ◽  
Meredith M. Regan ◽  
Michel Warny ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Mapk Signaling ◽  
Receptor Expression ◽  
Interleukin 8 ◽  
Healthy Controls ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Surface Receptors ◽  
Cftr Mutations ◽  
Cystic Fibrosis Transmembrane

ABSTRACT Patients with cystic fibrosis (CF) exhibit an excessive host inflammatory response. The aim of this study was to determine (i) whether interleukin 8 (IL-8) secretion is increased from monocytes from subjects heterozygous as well as homozygous for cystic fibrosis transmembrane conductance regulator (CFTR) mutations and (ii) whether this is due to increased cell surface lipopolysaccharide (LPS) receptors or, alternatively, increased activation of mitogen-activated protein kinases (MAPK). The basal level of IL-8 secretion was higher from monocytes from CF patients than from monocytes from healthy controls (P = 0.02) and obligate heterozygotes (parents of the CF patients). The 50% effective concentrations for LPS-induced IL-8 production for monocytes from both CF patients and obligate heterozygotes were 100-fold lower than those for monocytes from healthy controls (P < 0.05). No differences in the levels of IL-1β production were seen between these groups. Expression of the LPS surface receptors CD14 and Toll-like receptor 4 were not different between CF patients and healthy controls. In contrast, phosphorylation of the MAPKs p38 and ERK occurred at lower doses of LPS in monocytes from patients heterozygous and homozygous for CFTR mutations. These results indicate that a single allelic CFTR mutation is sufficient to augment IL-8 secretion in response to LPS. This is not a result of increased LPS receptor expression but, rather, is associated with alterations in MAPK signaling.

scholarly journals Amniotic Fluid Digestive Enzyme Analysis Is Useful for Identifying CFTR Gene Mutations of Unclear Significance

2009 ◽  
Vol 55 (12) ◽  
pp. 2214-2217 ◽  
Author(s):  
Florine Oca ◽  
Sophie Dreux ◽  
Bénédicte Gérard ◽  
Brigitte Simon-Bouy ◽  
Alix de Becdelièvre ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Amniotic Fluid ◽  
Digestive Enzyme ◽  
Gene Mutations ◽  
Diagnostic Sensitivity ◽  
Enzyme Analysis ◽  
Transmembrane Conductance Regulator ◽  
Diagnostic Specificity ◽  
Cftr Mutations ◽  
Severity Of The Disease

Abstract Background: The large number of CFTR [cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C, member 7)] mutations and the existence of variants of unclear significance complicate the prenatal diagnosis of cystic fibrosis (CF). The aim of this study was to determine whether the pattern of amniotic fluid digestive enzymes (AF-DEs) could be correlated with the severity of CFTR mutations. Methods: The AF-DE pattern (γ-glutamyltranspeptidase, aminopeptidase M, and the intestinal isoform of alkaline phosphatase) was retrospectively analyzed in 43 AF samples. All fetuses presented 2 CFTR mutations, which were classified according to the severity of the disease: CF/CF (n = 38); CF/CFTR-related disorders (n = 1); and CF/unknown variant (n = 4). The relationships between clinical CF status, CFTR mutations, and AF-DE pattern were studied. Results: Of 38 severely affected CF fetuses, an “obstructive” AF-DE pattern was observed in 15 of 15 samples collected before 22 weeks, irrespective of the CFTR mutation (diagnostic sensitivity, 100%; diagnostic specificity, 99.8%). In the 23 fetuses evaluated after 22 weeks, the AF-DE pattern was abnormal in 7 cases and noncontributive in 16 (diagnostic sensitivity, 30.4%; diagnostic specificity, 99.8%). Of the 5 questionable cases (F508del/N1224K, F508del/L73F, 3849+10kbC&gt;T/G1127E, F508del/S1235R, F508del/G622D), all were CF symptom free at 2–4 years of follow-up. The AF-DE pattern (&lt;22 weeks) was typical in 3 cases but abnormal in the last 2 cases. Conclusions: AF-DE analysis is of value for prenatal CF diagnosis in classic forms of CF and could be helpful in nonclassic CF.

scholarly journals Cystic Fibrosis Lung Disease Modifiers and Their Relevance in the New Era of Precision Medicine

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 562
Author(s):  
Afsoon Sepahzad ◽  
Deborah J. Morris-Rosendahl ◽  
Jane C. Davies
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Response To Treatment ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
New Era ◽  
Genome Wide ◽  
Cystic Fibrosis Lung Disease ◽  
Genomic Tools

Our understanding of cystic fibrosis (CF) has grown exponentially since the discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989. With evolving genetic and genomic tools, we have come to better understand the role of CFTR genotypes in the pathophysiology of the disease. This, in turn, has paved the way for the development of modulator therapies targeted at mutations in the CFTR, which are arguably one of the greatest advances in the treatment of CF. These modulator therapies, however, do not target all the mutations in CFTR that are seen in patients with CF and, furthermore, a variation in response is seen in patients with the same genotype who are taking modulator therapies. There is growing evidence to support the role of non-CFTR modifiers, both genetic and environmental, in determining the variation seen in CF morbidity and mortality and also in the response to existing therapies. This review focusses on key findings from studies using candidate gene and genome-wide approaches to identify CF modifier genes of lung disease in cystic fibrosis and considers the interaction between modifiers and the response to modulator therapies. As the use of modulator therapies expands and we gain data around outcomes, it will be of great interest to investigate this interaction further. Going forward, it will also be crucial to better understand the relative influence of genomic versus environmental factors. With this understanding, we can truly begin to deliver personalised care by better profiling the likely disease phenotype for each patient and their response to treatment.

scholarly journals Three Novel CFTR Polymorphic Repeats Improve Segregation Analysis for Cystic Fibrosis

2009 ◽  
Vol 55 (7) ◽  
pp. 1372-1379 ◽  
Author(s):  
Ausilia Elce ◽  
Angelo Boccia ◽  
Giuseppe Cardillo ◽  
Sonia Giordano ◽  
Rossella Tomaiuolo ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Prenatal Diagnosis ◽  
Large Scale ◽  
Segregation Analysis ◽  
Preimplantation Diagnosis ◽  
Cftr Gene ◽  
Transmembrane Conductance Regulator ◽  
Large Scale Analysis ◽  
Allelic Distribution ◽  
Cftr Mutations

Abstract Background: Molecular diagnosis for cystic fibrosis (CF) is based on the direct identification of mutations in the CFTR gene [cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C, member 7)] (detection rate about 90% with scanning procedures) and on segregation analysis of intragenic polymorphisms for carrier and prenatal diagnosis in about 20% of CF families in which 1 or both causal mutations are unknown. Methods: We identified 3 novel intragenic polymorphic repeats (IVS3polyA, IVS4polyA, and IVS10CA repeats) in the CFTR gene and developed and validated a procedure based on the PCR followed by capillary electrophoresis for large-scale analysis of these polymorphisms and the 4 previously identified microsatellites (IVS1CA, IVS8CA, IVS17bTA, and IVS17bCA repeats) in a single run. We validated the procedure for both single- and 2-cell samples (for a possible use in preimplantation diagnosis), and on a large number of CF patients bearing different genotypes and non-CF controls. Results: The allelic distribution and heterozygosity results suggest that the 3 novel polymorphisms strongly contribute to carrier and prenatal diagnosis of CF in families in which 1 or both causal mutations have not been identified. At least 1 of the 4 previously identified microsatellites was informative in 78 of 100 unrelated CF families; at least 1 of all 7 polymorphisms was informative in 98 of the families. Finally, the analysis of haplotypes for the 7 polymorphisms revealed that most CF mutations are associated with different haplotypes, suggesting multiple slippage events but a single origin for most CFTR mutations. Conclusions: The analysis of the 7 polymorphisms is a rapid and efficient tool for routine carrier, prenatal, and preimplantation diagnosis of CF.

scholarly journals Elexacaftor is a CFTR potentiator and acts synergistically with ivacaftor during acute and chronic treatment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ciaran A. Shaughnessy ◽  
Pamela L. Zeitlin ◽  
Preston E. Bratcher
Keyword(s):  
Cystic Fibrosis ◽  
Early Death ◽  
New Combination ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Acute And Chronic Treatment ◽  
Cftr Mutations ◽  
Small Molecule Modulators ◽  
Cystic Fibrosis Transmembrane

AbstractCystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), which lead to early death due to progressive lung disease. The development of small-molecule modulators that directly interact with CFTR to aid in protein folding (“correctors”) and/or increase channel function (“potentiators”) have proven to be highly effective in the therapeutic treatment of CF. Notably, incorporation of the next-generation CFTR corrector, elexacaftor, into a triple combination therapeutic (marketed as Trikafta) has shown tremendous clinical promise in treating CF caused by F508del-CFTR. Here, we report on a newly-described role of elexacaftor as a CFTR potentiator. We explore the acute and chronic actions, pharmacology, and efficacy of elexacaftor as a CFTR potentiator in restoring function to multiple classes of CFTR mutations. We demonstrate that the potentiating action of elexacaftor exhibits multiplicative synergy with the established CFTR potentiator ivacaftor in rescuing multiple CFTR class defects, indicating that a new combination therapeutic of ivacaftor and elexacaftor could have broad impact on CF therapies.

scholarly journals Nanomolar-potency ‘co-potentiator’ therapy for cystic fibrosis caused by a defined subset of minimal function CFTR mutants

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Puay-Wah Phuan ◽  
Joseph-Anthony Tan ◽  
Amber A. Rivera ◽  
Lorna Zlock ◽  
Dennis W. Nielson ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Class Ii ◽  
Bronchial Epithelial Cell ◽  
Therapeutic Benefit ◽  
Initial Structure ◽  
Transmembrane Conductance Regulator ◽  
Loss Of Function ◽  
Nonsense Mutations ◽  
Minimal Function ◽  
Cftr Mutations

AbstractAvailable CFTR modulators provide no therapeutic benefit for cystic fibrosis (CF) caused by many loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, including N1303K. We previously introduced the concept of ‘co-potentiators’ (combination-potentiators) to rescue CFTR function in some minimal function CFTR mutants. Herein, a screen of ~120,000 drug-like synthetic small molecules identified active co-potentiators of pyrazoloquinoline, piperidine-pyridoindole, tetrahydroquinoline and phenylazepine classes, with EC50 down to ~300 nM following initial structure-activity studies. Increased CFTR chloride conductance by up to 8-fold was observed when a co-potentiator (termed ‘Class II potentiator’) was used with a classical potentiator (‘Class I potentiator’) such as VX-770 or GLPG1837. To investigate the range of CFTR mutations benefitted by co-potentiators, 14 CF-associated CFTR mutations were studied in transfected cell models. Co-potentiator efficacy was found for CFTR missense, deletion and nonsense mutations in nucleotide binding domain-2 (NBD2), including W1282X, N1303K, c.3700A > G and Q1313X (with corrector for some mutations). In contrast, CFTR mutations G85E, R334W, R347P, V520F, R560T, A561E, M1101K and R1162X showed no co-potentiator activity, even with corrector. Co-potentiator efficacy was confirmed in primary human bronchial epithelial cell cultures generated from a N1303K homozygous CF subject. The Class II potentiators identified here may have clinical benefit for CF caused by mutations in the NBD2 domain of CFTR.

Diagnosis of cystic fibrosis in adulthood and eligibility for novel CFTR modulator therapy

2021 ◽  
pp. postgradmedj-2020-139278
Author(s):  
Hannah Farley ◽  
Sarah Poole ◽  
Stephen Chapman ◽  
William Flight
Keyword(s):  
Cystic Fibrosis ◽  
Chronic Respiratory Disease ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Radiological Data ◽  
Patient Database ◽  
Cftr Mutations ◽  
History Of ◽  
Autosomal Recessive Condition ◽  
Cystic Fibrosis Transmembrane

BackgroundCystic fibrosis (CF) is an autosomal recessive condition that primarily manifests as a chronic respiratory disease. CF is usually diagnosed in early childhood or through newborn screening although in a small but important group, diagnosis is not made until adulthood. Highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies are now available for most genetic causes of CF highlighting the importance of identifying people with late presentations of CF.AimWe aimed to identify the clinical characteristics of people diagnosed with CF in adulthood and their resulting eligibility for novel CFTR modulator therapies.DesignRetrospective single-centre cohort study.MethodsPatients diagnosed with CF at age 18 years or older were identified from a patient database. Paper and electronic medical records were reviewed and clinical, microbiological and radiological data at diagnosis were recorded.ResultsNineteen patients were identified. Median age at diagnosis was 38 years (range: 19–71) and 9 (47%) were female. All patients had a history of chronic respiratory symptoms and 18/19 (94%) had radiological evidence of bronchiectasis. All patients had two pathogenic CFTR mutations identified with 16/19 (84%) compound heterozygotes for the F508del mutation. The majority of patients had a CFTR genotype considered eligible for CFTR modulator therapy (84% and 89% according to European and US licences, respectively).ConclusionsAdult patients with unexplained chronic bronchiectasis should be thoroughly investigated for CF. A low index of suspicion will help to identify adults with undiagnosed CF who are likely to benefit from CFTR modulator therapy.

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