scholarly journals Inside Cover: Combating Cystic Fibrosis: In Search for CF Transmembrane Conductance Regulator (CFTR) Modulators / Second-Generation Iminoxylitol-Based Pharmacological Chaperones for the Treatment of Gaucher Disease (ChemMedChem 2/2011)

ChemMedChem ◽  
2011 ◽  
Vol 6 (2) ◽  
pp. 210-210
Author(s):  
Efrat Noy ◽  
Hanoch Senderowitz ◽  
Farah Oulaïdi ◽  
Sophie Front-Deschamps ◽  
Estelle Gallienne ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Gaucher Disease ◽  
Second Generation ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Pharmacological Chaperones ◽  
Cf Transmembrane Conductance Regulator ◽  
Cftr Modulators

scholarly journals Cystic Fibrosis Transmembrane Conductance Regulator Modulator Therapy: A Review for the Otolaryngologist

2020 ◽  
Vol 34 (4) ◽  
pp. 573-580
Author(s):  
Saangyoung E. Lee ◽  
Zainab Farzal ◽  
M.Leigh Anne Daniels ◽  
Brian D. Thorp ◽  
Adam M. Zanation ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Respiratory Compromise ◽  
Basic Understanding ◽  
Epithelial Cultures ◽  
Cf Transmembrane Conductance Regulator ◽  
Cystic Fibrosis Transmembrane ◽  
Cftr Modulators ◽  
Initial Results

Background Cystic fibrosis (CF) is a genetic disease that may result in multiple systemic disorders and potentially fatal severe respiratory compromise. However, the advent of CF transmembrane conductance regulator (CFTR) modulators has changed the management of CF for patients with select mutations. Although clinical trials have highlighted increased pulmonary function and decreased exacerbations as a result of these novel therapies, their effect on the sinuses has not been well-described. Objective Our objective is to review the CFTR modulators to provide otolaryngologists, physicians who frequently care for patients with CF, a basic understanding of these drugs and their effects on chronic rhinosinusitis (CRS) in patients with CF. Methods The clinically approved and available CFTR modulators and specific indications for their use are reviewed. Additionally, a systematic review of these therapies and effects on CRS in CF was performed. Results Four Food and Drug Administration approved CFTR modulators are available for patients with CF. Current drugs are approved for gating, residual function, or F508del mutations. Multiple reports describe CFTR modulators’ increase in transepithelial ion transport in nasal epithelial cultures; however, clinical studies regarding effects of these modulators on sinonasal health are limited to 5 studies that present new data of the effects of CFTR modulators in CRS. Conclusions CFTR modulators have changed management of CF. Initial studies of these medications demonstrate promising results in CF; however, there is a paucity of literature describing the effect of CFTR modulators on CF-associated CRS, although initial results are encouraging.

scholarly journals Progress in precision medicine in cystic fibrosis: a focus on CFTR modulator therapy

Breathe ◽  
2021 ◽  
Vol 17 (4) ◽  
pp. 210112
Author(s):  
Daniel H. Tewkesbury ◽  
Rebecca C. Robey ◽  
Peter J. Barry
Keyword(s):  
Cystic Fibrosis ◽  
Precision Medicine ◽  
Real World ◽  
Chloride Ion ◽  
Transmembrane Conductance Regulator ◽  
Therapeutic Approaches ◽  
Transmembrane Conductance ◽  
Cftr Protein ◽  
Cystic Fibrosis Transmembrane ◽  
Cftr Modulators

The genetic multisystem condition cystic fibrosis (CF) has seen a paradigm shift in therapeutic approaches within the past decade. Since the first clinical descriptions in the 1930s, treatment advances had focused on the downstream consequences of a dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) chloride ion channel. The discovery of the gene that codes for CFTR and an understanding of the way in which different genetic mutations lead to disruption of normal CFTR function have led to the creation and subsequent licensing of drugs that target this process. This marks an important move towards precision medicine in CF and results from clinical trials and real-world clinical practice have been impressive. In this review we outline how CFTR modulator drugs restore function to the CFTR protein and the progress that is being made in this field. We also describe the real-world impact of CFTR modulators on both pulmonary and multisystem complications of CF and what this will mean for the future of CF care.

scholarly journals Correction of CFTR function in intestinal organoids to guide treatment of cystic fibrosis

2020 ◽  
Vol 57 (1) ◽  
pp. 1902426 ◽  
Author(s):  
Anabela S. Ramalho ◽  
Eva Fürstová ◽  
Annelotte M. Vonk ◽  
Marc Ferrante ◽  
Catherine Verfaillie ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Clinical Data ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Vast Number ◽  
Sweat Chloride ◽  
Intestinal Organoids ◽  
Rectal Biopsies ◽  
Cftr Modulators

RationaleGiven the vast number of cystic fibrosis transmembrane conductance regulator (CFTR) mutations, biomarkers predicting benefit from CFTR modulator therapies are needed for subjects with cystic fibrosis (CF).ObjectivesTo study CFTR function in organoids of subjects with common and rare CFTR mutations and evaluate correlations between CFTR function and clinical data.MethodsIntestinal organoids were grown from rectal biopsies in a cohort of 97 subjects with CF. Residual CFTR function was measured by quantifying organoid swelling induced by forskolin and response to modulators by quantifying organoid swelling induced by CFTR correctors, potentiator and their combination. Organoid data were correlated with clinical data from the literature.ResultsAcross 28 genotypes, residual CFTR function correlated (r2=0.87) with sweat chloride values. When studying the same genotypes, CFTR function rescue by CFTR modulators in organoids correlated tightly with mean improvement in lung function (r2=0.90) and sweat chloride (r2=0.95) reported in clinical trials. We identified candidate genotypes for modulator therapy, such as E92K, Q237E, R334W and L159S. Based on organoid results, two subjects started modulator treatment: one homozygous for complex allele Q359K_T360K, and the second with mutation E60K. Both subjects had major clinical benefit.ConclusionsMeasurements of residual CFTR function and rescue of function by CFTR modulators in intestinal organoids correlate closely with clinical data. Our results for reference genotypes concur with previous results. CFTR function measured in organoids can be used to guide precision medicine in patients with CF, positioning organoids as a potential in vitro model to bring treatment to patients carrying rare CFTR mutations.

scholarly journals VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1

2013 ◽  
Vol 24 (19) ◽  
pp. 3016-3024 ◽  
Author(s):  
Hong Yu Ren ◽  
Diane E. Grove ◽  
Oxana De La Rosa ◽  
Scott A. Houck ◽  
Pattarawut Sopha ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Chloride Transport ◽  
Genetic Disorder ◽  
Missense Mutations ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Regulator Protein ◽  
Folding Defect ◽  
Membrane Spanning ◽  
Cf Transmembrane Conductance Regulator

Cystic fibrosis (CF) is a fatal genetic disorder associated with defective hydration of lung airways due to the loss of chloride transport through the CF transmembrane conductance regulator protein (CFTR). CFTR contains two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory domain, and its channel assembly requires multiple interdomain contacts. The most common CF-causing mutation, F508del, occurs in NBD1 and results in misfolding and premature degradation of F508del-CFTR. VX-809 is an investigational CFTR corrector that partially restores CFTR function in people who are homozygous for F508del-CFTR. To identify the folding defect(s) in F508del-CFTR that must be repaired to treat CF, we explored the mechanism of VX-809 action. VX-809 stabilized an N-terminal domain in CFTR that contains only MSD1 and efficaciously restored function to CFTR forms that have missense mutations in MSD1. The action of VX-809 on MSD1 appears to suppress folding defects in F508del-CFTR by enhancing interactions among the NBD1, MSD1, and MSD2 domains. The ability of VX-809 to correct F508del-CFTR is enhanced when combined with mutations that improve F508del-NBD1 interaction with MSD2. These data suggest that the use of VX-809 in combination with an additional CFTR corrector that suppresses folding defects downstream of MSD1 may further enhance CFTR function in people with F508del-CFTR.

scholarly journals Maturation and function of cystic fibrosis transmembrane conductance regulator variants bearing mutations in putative nucleotide-binding domains 1 and 2.

1991 ◽  
Vol 11 (8) ◽  
pp. 3886-3893 ◽  
Author(s):  
R J Gregory ◽  
D P Rich ◽  
S H Cheng ◽  
D W Souza ◽  
S Paul ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Amino Acid ◽  
Functional Activity ◽  
Nucleotide Binding ◽  
Missense Mutations ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Fluorescence Measurements ◽  
Cf Transmembrane Conductance Regulator ◽  
Altered Proteins

One feature of the mutations thus far found to be associated with the disease cystic fibrosis (CF) is that many of them are clustered within the first nucleotide-binding domain (NBD) of the CF transmembrane conductance regulator (CFTR). We sought to discover the molecular basis for this clustering by introducing into the two NBDs of CFTR mutations either mimicking amino acid changes associated with CF or altering residues within highly conserved motifs. Synthesis and maturation of the mutant CFTR were studied by transient expression in COS cells. The ability of the altered proteins to generate cyclic AMP-stimulated anion efflux was assessed by using 6-methoxy-N-(sulfopropyl) quinolinium (SPQ) fluorescence measurements in HeLa cells expressing mutated plasmids. The results show that (i) all CF-associated mutants, with one exception, lack functional activity as measured in the SPQ assay, (ii) mutations in NBD1 are more sensitive to the effects of the same amino acid change than are the corresponding mutations in NBD2, (iii) cells transfected with plasmids bearing CF-associated mutations commonly but not exclusively lack mature CFTR, (iv) NBD mutants lacking mature CFTR fail to activate Cl- channels, and (v) the glycosylation of CFTR, per se, is not required for CFTR function. We reason that the structure of NBD1 itself or of the surrounding domains renders it particularly sensitive to mutational changes. As a result, most NBD1 mutants, but only a few NBD2 mutants, fail to mature or lack functional activity. These findings are consistent with the observed uneven distribution of CFTR missense mutations between NBD1 and NBD2 of CF patients.

scholarly journals Dysfunctional cystic fibrosis transmembrane conductance regulator inhibits phagocytosis of apoptotic cells with proinflammatory consequences

2009 ◽  
Vol 297 (4) ◽  
pp. L677-L686 ◽  
Author(s):  
R. William Vandivier ◽  
Tiffany R. Richens ◽  
Sarah A. Horstmann ◽  
Aimee M. deCathelineau ◽  
Moumita Ghosh ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Rho Kinase ◽  
Negative Regulator ◽  
Apoptotic Cells ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Altered Expression ◽  
Proinflammatory Mediators ◽  
Downstream Effector ◽  
Cf Transmembrane Conductance Regulator

Cystic fibrosis (CF) is caused by mutated CF transmembrane conductance regulator (CFTR) and is characterized by robust airway inflammation and accumulation of apoptotic cells. Phagocytosis of apoptotic cells (efferocytosis) is a pivotal regulator of inflammation, because it prevents postapoptotic necrosis and actively suppresses release of a variety of proinflammatory mediators, including IL-8. Because CF is associated with accumulation of apoptotic cells, inappropriate levels of IL-8, and robust inflammation, we sought to determine whether CFTR deficiency specifically impairs efferocytosis and its regulation of inflammatory mediator release. Here we show that CFTR deficiency directly interferes with efferocytosis by airway epithelium, an effect that is not due to altered binding of apoptotic cells to epithelial cells or altered expression of efferocytosis receptors. In contrast, expression of RhoA, a known negative regulator of efferocytosis, is substantially increased in CFTR-deficient cells, and inhibitors of RhoA or its downstream effector Rho kinase normalize efferocytosis in these cells. Impaired efferocytosis appears to be mediated through an amiloride-sensitive ion channel, because amiloride restores phagocytic competency in CFTR-deficient cells. Finally, ineffective efferocytosis in CFTR-deficient cells appears to have proinflammatory consequences, because apoptotic cells enhance IL-8 release by these cells, but not by wild-type controls. Therefore, in CF, dysregulated efferocytosis may lead to accumulation of apoptotic cells and impaired regulation of the inflammatory response and, ultimately, may suggest a new therapeutic target.

Sign in / Sign up

Export Citation Format

Share Document