Cystic fibrosis is a severe ion channel disease of autosomal recessive inheritance that is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Thanks to continuously improved symptomatic treatment during the last five decades this lethal paediatric disease has been transformed into a chronic disorder with a median life expectancy of nowadays more than 50 years.This 2nd edition provides the reader with the background and on-going preclinical and clinical research for the development of mutation-type specific therapy of cystic fibrosis. Starting with the…mehr
Cystic fibrosis is a severe ion channel disease of autosomal recessive inheritance that is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Thanks to continuously improved symptomatic treatment during the last five decades this lethal paediatric disease has been transformed into a chronic disorder with a median life expectancy of nowadays more than 50 years.This 2nd edition provides the reader with the background and on-going preclinical and clinical research for the development of mutation-type specific therapy of cystic fibrosis. Starting with the biology and biomarkers of CFTR in the context of cystic fibrosis, the reader gets insight into the basic and clinical research of CFTR modulators from bench to bedside. A large section of the book focuses on the clinical trials, post-approval observational studies and the real-world experience with the CFTR modulators.
1.CFTR and cystic fibrosis131.1.To set the stage: Cystic Fibrosis - etiology and significance131.2.The Molecular Structures of CFTR131.2.1.CFTR is an unusual ABC transporter and an unusual ion channel141.2.2.Structure of the non-phosphorylated CFTR151.2.3.Structure of phosphorylated CFTR in complex with ATP161.2.4.Conformational changes leading to channel opening161.2.5.The TM hinge as a hotspot for CFTR potentiation171.3.Features of CFTR: an epithelial anion channel with complex regulation191.3.1.The functional architecture of CFTR191.3.2.Phosphorylation-dependent regulation of CFTR: the RD191.3.3.Regulation of CFTR channel gating by ATP binding and hydrolysis: the NBDs201.3.4.Anion flow through the CFTR pore: the MSDs211.3.5.Structural rearrangements of CFTR domains during channel gating221.4.Basic defect in cystic fibrosis231.4.1.CF mutations cause molecular defects in the CFTR Cl- channel241.4.2.CF-associated mutations cause deficits of CFTR function251.4.3.Functional deficits of CFTR mutants lead to defects in epithelial function251.4.4.CFTR dysfunction causes defects in non-epithelial tissues261.5.Population genetics of CFTR mutations261.6.Molecular pathology of CFTR mutations331.6.1.Deletions, frame-shift mutations and stop mutations331.6.2.Splice mutations341.6.3.Missense mutations341.6.4.The major mutation p.Phe508del341.7.References352.Bioassays to assess CFTR function in humans432.1.Sweat chloride test and b-adrenergic sweat secretion432.2.Nasal transepithelial potential difference measurements452.2.1.Background452.2.2.Principle of the assay452.2.3.Applications462.3.Intestinal current measurements472.3.1.Principle of the assay472.3.2.Applications482.4.Primary cystic fibrosis intestinal organoids512.4.1.What are organoids?512.4.2.Organoid swelling as measure of transepithelial ion transport512.4.3.Exploring organoids as living biomarker542.5.Immunochemical CFTR protein analysis in patients' tissues552.6.References563.Endpoints of phase II and phase III trials with CFTR modulators653.1.Lung function653.2.Imaging663.3.Extra-pulmonary endpoints693.4.References714.Correctors of nonsense mutations: Molecular principles, preclinical and clinical trials774.1.Read-through of premature termination codons774.2.Novel drug developments784.3.The role of CFTR modulators as a therapeutic approach for CFTR nonsense mutations794.4.Variability in the response to read-through treatment804.5.NMD as a regulator of the response to read-through treatment804.6.UPR as a regulator of the response to read-through treatment814.7.References835.CFTR correctors and CFTR potentiators895.1.Preclinical studies895.2.Clinical pharmacology: Pharmacokinetics, metabolism and drug-drug interactions925.2.1.Polypharmacy and Cystic Fibrosis925.2.2.Comparison of the CFTR modulators935.2.3.Pharmacokinetics of the CFTR modulators935.2.3.1.Distribution935.2.3.2.Metabolism945.2.4.Impact of Cyp-inhibitors on ivacaftor serum levels945.2.5.Impact of liver function945.2.6.Inducers of the Cyp-System955.2.7.Tezacaftor and elexacaftor - novel agents with lower risk for interactions955.3.Clinical trials965.4.Post-approval studies1045.5.References1076.Perspectives on mutation-specific drug therapies for cystic fibrosis1216.1.References1247.Abbreviations127Index128
1.CFTR and cystic fibrosis131.1.To set the stage: Cystic Fibrosis - etiology and significance131.2.The Molecular Structures of CFTR131.2.1.CFTR is an unusual ABC transporter and an unusual ion channel141.2.2.Structure of the non-phosphorylated CFTR151.2.3.Structure of phosphorylated CFTR in complex with ATP161.2.4.Conformational changes leading to channel opening161.2.5.The TM hinge as a hotspot for CFTR potentiation171.3.Features of CFTR: an epithelial anion channel with complex regulation191.3.1.The functional architecture of CFTR191.3.2.Phosphorylation-dependent regulation of CFTR: the RD191.3.3.Regulation of CFTR channel gating by ATP binding and hydrolysis: the NBDs201.3.4.Anion flow through the CFTR pore: the MSDs211.3.5.Structural rearrangements of CFTR domains during channel gating221.4.Basic defect in cystic fibrosis231.4.1.CF mutations cause molecular defects in the CFTR Cl- channel241.4.2.CF-associated mutations cause deficits of CFTR function251.4.3.Functional deficits of CFTR mutants lead to defects in epithelial function251.4.4.CFTR dysfunction causes defects in non-epithelial tissues261.5.Population genetics of CFTR mutations261.6.Molecular pathology of CFTR mutations331.6.1.Deletions, frame-shift mutations and stop mutations331.6.2.Splice mutations341.6.3.Missense mutations341.6.4.The major mutation p.Phe508del341.7.References352.Bioassays to assess CFTR function in humans432.1.Sweat chloride test and b-adrenergic sweat secretion432.2.Nasal transepithelial potential difference measurements452.2.1.Background452.2.2.Principle of the assay452.2.3.Applications462.3.Intestinal current measurements472.3.1.Principle of the assay472.3.2.Applications482.4.Primary cystic fibrosis intestinal organoids512.4.1.What are organoids?512.4.2.Organoid swelling as measure of transepithelial ion transport512.4.3.Exploring organoids as living biomarker542.5.Immunochemical CFTR protein analysis in patients' tissues552.6.References563.Endpoints of phase II and phase III trials with CFTR modulators653.1.Lung function653.2.Imaging663.3.Extra-pulmonary endpoints693.4.References714.Correctors of nonsense mutations: Molecular principles, preclinical and clinical trials774.1.Read-through of premature termination codons774.2.Novel drug developments784.3.The role of CFTR modulators as a therapeutic approach for CFTR nonsense mutations794.4.Variability in the response to read-through treatment804.5.NMD as a regulator of the response to read-through treatment804.6.UPR as a regulator of the response to read-through treatment814.7.References835.CFTR correctors and CFTR potentiators895.1.Preclinical studies895.2.Clinical pharmacology: Pharmacokinetics, metabolism and drug-drug interactions925.2.1.Polypharmacy and Cystic Fibrosis925.2.2.Comparison of the CFTR modulators935.2.3.Pharmacokinetics of the CFTR modulators935.2.3.1.Distribution935.2.3.2.Metabolism945.2.4.Impact of Cyp-inhibitors on ivacaftor serum levels945.2.5.Impact of liver function945.2.6.Inducers of the Cyp-System955.2.7.Tezacaftor and elexacaftor - novel agents with lower risk for interactions955.3.Clinical trials965.4.Post-approval studies1045.5.References1076.Perspectives on mutation-specific drug therapies for cystic fibrosis1216.1.References1247.Abbreviations127Index128
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