Mutation-specific therapies in cystic fibrosis

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 fibrosis13 1.1.To set the stage: Cystic Fibrosis – etiology and significance13 1.2.The Molecular Structures of CFTR13 1.2.1.CFTR is an unusual ABC transporter and an unusual ion channel14 1.2.2.Structure of the non-phosphorylated CFTR15 1.2.3.Structure of phosphorylated CFTR in complex with ATP16 1.2.4.Conformational changes leading to channel opening16 1.2.5.The TM hinge as a hotspot for CFTR potentiation17 1.3.Features of CFTR: an epithelial anion channel with complex regulation19 1.3.1.The functional architecture of CFTR19 1.3.2.Phosphorylation-dependent regulation of CFTR: the RD19 1.3.3.Regulation of CFTR channel gating by ATP binding and hydrolysis: the NBDs20 1.3.4.Anion flow through the CFTR pore: the MSDs21 1.3.5.Structural rearrangements of CFTR domains during channel gating22 1.4.Basic defect in cystic fibrosis23 1.4.1.CF mutations cause molecular defects in the CFTR Cl– channel24 1.4.2.CF-associated mutations cause deficits of CFTR function25 1.4.3.Functional deficits of CFTR mutants lead to defects in epithelial function25 1.4.4.CFTR dysfunction causes defects in non-epithelial tissues26 1.5.Population genetics of CFTR mutations26 1.6.Molecular pathology of CFTR mutations33 1.6.1.Deletions, frame-shift mutations and stop mutations33 1.6.2.Splice mutations34 1.6.3.Missense mutations34 1.6.4.The major mutation p.Phe508del34 1.7.References35 2.Bioassays to assess CFTR function in humans43 2.1.Sweat chloride test and b-adrenergic sweat secretion43 2.2.Nasal transepithelial potential difference measurements45 2.2.1.Background45 2.2.2.Principle of the assay45 2.2.3.Applications46 2.3.Intestinal current measurements47 2.3.1.Principle of the assay47 2.3.2.Applications48 2.4.Primary cystic fibrosis intestinal organoids51 2.4.1.What are organoids?51 2.4.2.Organoid swelling as measure of transepithelial ion transport51 2.4.3.Exploring organoids as living biomarker54 2.5.Immunochemical CFTR protein analysis in patients’ tissues55 2.6.References56 3.Endpoints of phase II and phase III trials with CFTR modulators65 3.1.Lung function65 3.2.Imaging66 3.3.Extra-pulmonary endpoints69 3.4.References71 4.Correctors of nonsense mutations: Molecular principles, preclinical and clinical trials77 4.1.Read-through of premature termination codons77 4.2.Novel drug developments78 4.3.The role of CFTR modulators as a therapeutic approach for CFTR nonsense mutations79 4.4.Variability in the response to read-through treatment80 4.5.NMD as a regulator of the response to read-through treatment80 4.6.UPR as a regulator of the response to read-through treatment81 4.7.References83 5.CFTR correctors and CFTR potentiators89 5.1.Preclinical studies89 5.2.Clinical pharmacology: Pharmacokinetics, metabolism and drug-drug interactions92 5.2.1.Polypharmacy and Cystic Fibrosis92 5.2.2.Comparison of the CFTR modulators93 5.2.3.Pharmacokinetics of the CFTR modulators93 5.2.3.1.Distribution93 5.2.3.2.Metabolism94 5.2.4.Impact of Cyp-inhibitors on ivacaftor serum levels94 5.2.5.Impact of liver function94 5.2.6.Inducers of the Cyp-System95 5.2.7.Tezacaftor and elexacaftor – novel agents with lower risk for interactions95 5.3.Clinical trials96 5.4.Post-approval studies104 5.5.References107 6.Perspectives on mutation-specific drug therapies for cystic fibrosis121 6.1.References124 7.Abbreviations127 Index128