Article
Medicine, Research & Experimental
Michael D. Kim, Charles D. Bengtson, Makoto Yoshida, Asef J. Niloy, John S. Dennis, Nathalie Baumlin, Matthias Salathe
Summary: Highly effective modulator therapies greatly improve prognosis for cystic fibrosis patients. However, not all patients with the most common F508del mutation in CFTR benefit from ETI therapy. The study found that elevated levels of active TGF-??1 in the upper airway were associated with poor response to ETI, as evidenced by low sweat chloride concentrations and lack of lung function improvements. TGF-??1 impaired the function of corrected F508del-CFTR and led to increased absorption rates of airway surface liquid and mucus hyperconcentration in vitro. Losartan reversed the negative effects of TGF-??1 and improved ASL hydration in CF airway epithelium.
JOURNAL OF CLINICAL INVESTIGATION
(2022)
Article
Chemistry, Medicinal
Irene Brusa, Elvira Sondo, Emanuela Pesce, Valeria Tomati, Dario Gioia, Federico Falchi, Beatrice Balboni, Jose Antonio Ortega Martinez, Marina Veronesi, Elisa Romeo, Natasha Margaroli, Maurizio Recanatini, Stefania Girotto, Nicoletta Pedemonte, Marinella Roberti, Andrea Cavalli
Summary: A new RNF5 inhibitor, called 1,2,4-thiadiazol-5-ylidene, has been discovered in this study. It selectively corrects the folding defect of CFTR protein in CF patients and has no toxic side effects. This finding provides evidence for the pursuit of novel treatment strategies for CF.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Biochemistry & Molecular Biology
Evelina Moliteo, Monica Sciacca, Antonino Palmeri, Maria Papale, Sara Manti, Giuseppe Fabio Parisi, Salvatore Leonardi
Summary: There is substantial evidence that patients with cystic fibrosis (CF) have higher oxidative stress levels, which contribute to the progression of chronic lung damage. CF patients exhibit an abnormal proinflammatory environment in their airways even before infection, possibly due to elevated oxidative stress and abnormal lipid metabolism. CFTR deficiency appears to cause a redox imbalance in epithelial cells and extracellular fluids.
Article
Biochemistry & Molecular Biology
Andrew G. McKee, Eli F. McDonald, Wesley D. Penn, Charles P. Kuntz, Karen Noguera, Laura M. Chamness, Francis J. Roushar, Jens Meiler, Kathryn E. Oliver, Lars Plate, Jonathan P. Schlebach
Summary: Cystic fibrosis (CF) is a genetic disorder caused by mutations in the CFTR chloride channel. While most CF variants can be partially rescued by therapeutic correctors, some are insensitive to them. By studying CF variants and the effects of correctors, researchers have discovered that the response to correctors depends on the level of expression and proximity to corrector binding pockets. Combining correctors can rescue more variants by stabilizing different folding transitions. These findings provide insights into CF variant expression and offer new approaches for precision pharmacology.
CELL CHEMICAL BIOLOGY
(2023)
Article
Pharmacology & Pharmacy
Matthew D. Strub, Shyam Ramachandran, Dmitri Y. Boudko, Ella A. Meleshkevitch, Alejandro A. Pezzulo, Aravind Subramanian, Arthur Liberzon, Robert J. Bridges, Paul B. McCray
Summary: Cystic fibrosis is a lethal genetic disease caused by mutations in the CFTR gene, leading to misfolded proteins and degradation. Several strategies have been developed to partially correct CFTR function in vitro, but translating these interventions into therapies remains a challenge.
CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY
(2022)
Article
Pediatrics
Qiyu Li, Siyuan Liu, Xuemei Ma, Jiaping Yu
Summary: This meta-analysis evaluated the effectiveness and safety of small molecule therapy in children diagnosed with cystic fibrosis (CF). The results showed that CFTR modulators can improve respiratory function, lung clearance index, sweat chloride concentration, and other aspects of function in children with CF, with comparable adverse events compared to the placebo group.
FRONTIERS IN PEDIATRICS
(2022)
Article
Biochemistry & Molecular Biology
Roberta Bongiorno, Alessandra Ludovico, Oscar Moran, Debora Baroni
Summary: Cystic fibrosis (CF) is a lethal autosomal recessive disease caused by loss of function variants of CFTR. Small-molecule modulators, potentiators and correctors, have been developed to rescue defective F508del CFTR. Kaftrio, a next-generation triple-combination drug, has shown to be a life-changing therapeutic for CF patients worldwide. The study investigated the activity of VX445 on mutant F508del CFTR to reveal its mechanism of action.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Chiara Brandas, Alessandra Ludovico, Alice Parodi, Oscar Moran, Enrico Millo, Elena Cichero, Debora Baroni
Summary: Cystic fibrosis is caused by loss-of-function mutations in the CFTR protein, with F508del being the most common mutation. Small molecules called correctors have been developed to rescue defective F508del CFTR, showing better results when used in combinations. Targeting different structural and functional defects of mutant CFTR with corrector combinations appears to be the most promising therapeutic approach for a larger cohort of CF patients.
Review
Pharmacology & Pharmacy
Yizi Wang, Bin Ma, Wenya Li, Peiwen Li
Summary: Triple combination therapy for cystic fibrosis patients achieves better clinical results and comparable adverse events compared to the control group.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Genetics & Heredity
Morgan Sanders, James M. J. Lawlor, Xiaopeng Li, John N. Schuen, Susan L. Millard, Xi Zhang, Leah Buck, Bethany Grysko, Katie L. Uhl, David Hinds, Cynthia L. Stenger, Michele Morris, Neil Lamb, Hara Levy, Caleb Bupp, Jeremy W. Prokop
Summary: Studying CFTR variants across diverse populations reveals potential heritable causes of CF and identifies a genomic region that can influence CF pathology through modulation of noncoding RNA expression. This highlights the need for further insights into CF genetics.
Article
Pharmacology & Pharmacy
Jia Liu, Allison P. Berg, Yiting Wang, Walailak Jantarajit, Katy J. Sutcliffe, Edward B. Stevens, Lishuang Cao, Marko J. Pregel, David N. Sheppard
Summary: This study investigates the action of a new CFTR potentiator, CP-628006, and compares it with the marketed CFTR potentiator ivacaftor. CP-628006 has distinct effects compared to ivacaftor, suggesting a different mechanism of CFTR potentiation. The emergence of CFTR potentiators with diverse modes of action makes therapy with combinations of potentiators a possibility.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Medicine, General & Internal
Lotte Vanherle, Darcy Lidington, Franziska E. Uhl, Saskia Steiner, Stefania Vassallo, Cecilia Skoug, Joao M. N. Duarte, Sangeetha Ramu, Lena Uller, Jean-Francois Desjardins, Kim A. Connelly, Steffen-Sebastian Bolz, Anja Meissner
Summary: Our study investigated the mechanisms that alter hippocampal neurons following myocardial infarction (MI) and explored the therapeutic potential of correcting cystic fibrosis transmembrane regulator (CFTR) as an intervention. We found that MI leads to reduced hippocampal dendrite length and spine density, which is associated with decreased neuronal CFTR expression and inflammatory responses. Blocking CFTR activity down-regulates synaptic regulator PSD-95 expression in neurons, while pharmacologically correcting CFTR expression rescues the down-regulation. Increasing hippocampal neuron CFTR expression improves MI-associated alterations in neuronal structure and memory function. These findings suggest that CFTR therapeutics can attenuate cognitive impairment in heart failure patients.
Review
Biochemistry & Molecular Biology
Laura Carrasco-Hernandez, Esther Quintana-Gallego, Carmen Calero, Rocio Reinoso-Arija, Borja Ruiz-Duque, Jose Luis Lopez-Campos
Summary: The role of CFTR in the pathophysiology of COPD is becoming increasingly important, with its dysfunction leading to thicker and more viscous secretions in the airway, reduced mucociliary clearance, and promotion of airway inflammation. Studying CFTR in the context of COPD pathogenesis is crucial for a comprehensive understanding of COPD's complex pathophysiology and exploring potential therapeutic approaches to address this dysfunction.
Article
Multidisciplinary Sciences
Sara Bitam, Ahmad Elbahnsi, Geordie Creste, Iwona Pranke, Benoit Chevalier, Farouk Berhal, Brice Hoffmann, Nathalie Servel, Danielle Tondelier, Aurelie Hatton, Christelle Moquereau, Melanie Faria Da Cunha, Alexandra Pastor, Agathe Lepissier, Alexandre Hinzpeter, Jean-Paul Mornon, Guillaume Prestat, Aleksander Edelman, Isabelle Callebaut, Christine Gravier-Pelletier, Isabelle Sermet-Gaudelus
Summary: The compound C407 and its derivatives correct the F508del-CFTR protein by stabilizing specific positions on the protein molecule. An analog of C407, G1, significantly improves CFTR activity by interacting more effectively with ICL4. These findings suggest new strategies for optimizing the ICL4-NBD1 interface.
SCIENTIFIC REPORTS
(2021)
Article
Biology
Margarida C. Quaresma, Hugo M. Botelho, Ines Pankonien, Claudia S. Rodrigues, Madalena C. Pinto, Pau R. Costa, Aires Duarte, Margarida D. Amaral
Summary: In this study, systems biology was applied to investigate the pathways connecting dysfunctional CFTR to epithelial-mesenchymal transition (EMT). The results showed that YAP1 is abnormally active in the presence of mutant CFTR and interacts with F508del-CFTR, and YAP1 knockdown can rescue the processing and function of F508del-CFTR. Moreover, YAP1 was identified as an important mediator of the fibrotic/EMT processes in cystic fibrosis (CF). Additionally, several key pathways, including the Hippo pathway, the Wnt pathway, the TGF beta pathway, the p53 pathway, and MYC signaling, were found to be involved in linking mutant CFTR to EMT. The identification of potential hub proteins in these pathways may serve as therapeutic targets for both CF and cancer.
LIFE SCIENCE ALLIANCE
(2022)
Article
Physiology
Mark J. Turner, Yishan Luo, David Y. Thomas, John W. Hanrahan
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
(2020)
Article
Pharmacology & Pharmacy
Miqueias Lopes-Pacheco, Iris A. L. Silva, Mark J. Turner, Graeme W. Carlile, Elvira Sondo, David Y. Thomas, Nicoletta Pedemonte, John W. Hanrahan, Margarida D. Amaral
BIOCHEMICAL PHARMACOLOGY
(2020)
Article
Pharmacology & Pharmacy
Mark J. Turner, Nurlan Dauletbaev, Larry C. Lands, John W. Hanrahan
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
(2020)
Article
Immunology
Dusik Kim, Jie Liao, Nathan B. Scales, Carolina Martini, Xiaojie Luan, Asmahan Abu-Arish, Renaud Robert, Yishan Luo, Geoffrey A. McKay, Dao Nguyen, Marc A. Tewfik, Charles D. Poirier, Elias Matouk, Juan P. Ianowski, Saul Frenkiel, John W. Hanrahan
Summary: The airway surface undergoes large pH excursions during breathing, reaching pH 9.0 during inhalation. Reduced luminal bicarbonate and CA12 expression in cystic fibrosis lead to impaired bacterial-killing efficacy. Defective pH oscillations may compromise airway host defense in other respiratory diseases.
JOURNAL OF EXPERIMENTAL MEDICINE
(2021)
Article
Physiology
Mieke Veltman, Juan B. De Sanctis, Marta Stolarczyk, Nikolai Klymiuk, Andrea Baehr, Rutger W. Brouwer, Edwin Oole, Juhi Shah, Tomas Ozdian, Jie Liao, Carolina Martini, Danuta Radzioch, John W. Hanrahan, Bob J. Scholte
Summary: In cystic fibrosis, a deficiency in CFTR function leads to chronic lung disease. Abnormalities in lipid metabolism and oxidative stress were observed in CF airway epithelium, indicating potential roles in CF lung pathology progression. Treatment with antioxidants or CFTR modulators may require a combination approach for correction of the CF phenotype.
FRONTIERS IN PHYSIOLOGY
(2021)
Review
Pharmacology & Pharmacy
Mark J. Turner, Kathy Abbott-Banner, David Y. Thomas, John W. Hanrahan
Summary: Cystic Fibrosis (CF) lung disease is caused by mutations in the CFTR gene that affect anion and fluid secretion. Studying members of the PDE family regulating CFTR-dependent secretion and the effects of PDE inhibitors on cyclic nucleotide-regulated functions.
PHARMACOLOGY & THERAPEUTICS
(2021)
Article
Multidisciplinary Sciences
Yukiko Sato, Kamila R. Mustafina, Yishan Luo, Carolina Martini, David Y. Thomas, Paul W. Wiseman, John W. Hanrahan
Summary: Evidence suggests that CFTR anion channel is highly expressed in ciliated cells of human bronchial epithelium (HBE), despite low levels of CFTR mRNA detected in these cells. Immunostaining and imaging techniques revealed apical immunofluorescence patterns in ciliated cells, with a correlation between CFTR antibodies and ciliary protein rootletin X1 expression levels. This may explain anomalous apical immunofluorescence in well-differentiated cells expressing F508del-CFTR.
SCIENTIFIC REPORTS
(2021)
Article
Cell Biology
Miqueias Lopes-Pacheco, Mafalda Bacalhau, Sofia S. Ramalho, Iris A. L. Silva, Filipa C. Ferreira, Graeme W. Carlile, David Y. Thomas, Carlos M. Farinha, John W. Hanrahan, Margarida D. Amaral
Summary: The study investigated the effects and mechanism of action of a newly developed F508del-CFTR corrector, MCG1516A, and found that it has additive effects to the FDA-approved corrector VX-661 in rescuing F508del-CFTR. Additionally, MCG1516A showed additive effects to genetic revertant R1070W, suggesting a potential binding site for this compound. This suggests that a combination of MCG1516A with other compounds could enhance correction of F508del-CFTR defects.
Review
Cell Biology
John W. Hanrahan, Asmahan Abu-Arish, Francis H. Wong, Mark J. Turner, Graeme W. Carlile, David Y. Thomas, Andre M. Cantin
Summary: Chronic obstructive pulmonary disease (COPD) is a leading cause of death, with cigarette smoke being the main risk factor. COPD shares similarities with cystic fibrosis (CF), particularly in terms of inflammation, mucus obstruction, and infection. Understanding the effects of cigarette smoke on CFTR function may lead to the development of novel therapeutics for reducing the progression and severity of COPD.
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Yukiko Sato, Dusik Kim, Mark J. Turner, Yishan Luo, Syeda Sadaf Zehra Zaidi, David Y. Thomas, John W. Hanrahan
Summary: CFTR is a tightly regulated anion channel that mediates chloride and bicarbonate conductance. This study found that the regulation of CFTR depends on the cell type, and identified FOXI1 as a regulator of ionocyte markers and CFTR expression. The study also revealed that PDE1C can suppress CFTR activity. These findings have implications for the development of therapeutics for cystic fibrosis.
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
(2023)
Article
Biology
Martin Ondra, Lukas Lenart, Amanda Centorame, Daciana C. Dumut, Alexander He, Syeda Sadaf Zehra Zaidi, John W. Hanrahan, Juan Bautista De Sanctis, Danuta Radzioch, Marian Hajduch
Summary: This article describes the preparation and validation of a novel in vitro model system using CRISPR/Cas9 genome editing, which can tag the endogenously expressed WT-CFTR and detect CFTR in the plasma membrane of live cells. By inserting the HiBiT tag in WT-CFTR, a reporter luciferase with bright luminescence can be generated. Nine homozygous clones with the HiBiT knock-in were identified from the screened clones, and two clones were genetically and functionally validated. This work lays the foundation for developing unique cellular CF models by CRISPR-mediated insertion of CF-causing mutations.
LIFE SCIENCE ALLIANCE
(2023)
Article
Cell Biology
Sonya Kouthouridis, Julie Goepp, Carolina Martini, Elizabeth Matthes, John W. Hanrahan, Christopher Moraes
Summary: Culture at the air-liquid interface is considered necessary for differentiation of epithelial cells, but can be expensive and challenging. Hyperoxygenated submerged culture can significantly improve epithelial differentiation, offering an important strategy for respiratory toxicology and therapeutic development.
INTEGRATIVE BIOLOGY
(2021)
Meeting Abstract
Pediatrics
M. Veltman, J. B. De Sanctis, T. Ozdian, M. Stolarczyk, N. Klymiuk, A. Baehr, R. Brouwer, J. Shah, C. Martini, J. Liao, D. Radzioch, J. W. Hanrahan, B. J. Scholte
PEDIATRIC PULMONOLOGY
(2020)
Meeting Abstract
Biophysics
Kamila R. Mustafina, Yukiko Sato, John W. Hanrahan, Paul W. Wiseman
BIOPHYSICAL JOURNAL
(2020)
Article
Biochemistry & Molecular Biology
Diogo R. Poroca, Noha Amer, Audrey Li, John W. Hanrahan, Valerie M. Chappe