Therapie der Mukoviszidose mit CFTR-Modulatoren

Zusammenfassung

Die Mukoviszidose ist das erste Beispiel für die erfolgreiche Entwicklung einer Mutationstyp-spezifischen Therapie. Diese autosomal rezessiv vererbte Störung des epithelialen Transports von Chlorid und Bikarbonat wird durch Mutationen im CFTR-Gen ausgelöst. Zur Behandlung der ursächlichen Störungen werden zwei Klassen von CFTR-Modulatoren unterschieden. Potentiatoren erhöhen die Aktivität des mutanten Ionenkanals. Korrektoren überlesen irreguläre Stopp-Codons oder erleichtern die ko- und posttranslationale Prozessierung der CFTR-Mutante. In Deutschland sind zurzeit der Potentiator Ivacaftor zur Behandlung von Kanalöffnungsstörungen und der Korrektor Lumacaftor in Kombination mit Ivacaftor zur Therapie der häufigsten Mutante Phe508del CFTR zugelassen. Dieser Artikel gibt praktische Hinweise für die Anwendung der zugelassenen Modulatoren und informiert über die Populationsgenetik der CFTR-Mutationen in Deutschland, CFTR-Biomarker zur Erfolgskontrolle der Modulatortherapie und über die bisherige und aktuelle präklinische und klinische Forschung zur Entwicklung von CFTR-Modulatoren.

Abstract

Personalized medicine promises that medical decisions, practices and products are tailored to the individual patient. Cystic fibrosis, an inherited disorder of chloride and bicarbonate transport in exocrine glands, is the first successful example of customized drug development for mutation-specific therapy. There are two classes of CFTR modulators: potentiators that increase the activity of CFTR at the cell surface, and correctors that either promote the read-through of nonsense mutations or facilitate the translation, folding, maturation and trafficking of mutant CFTR to the cell surface. The potentiator ivacaftor and the corrector lumacaftor are approved in Germany for the treatment of people with cystic fibrosis who carry a gating mutation such as p.Gly551Asp or who are homozygous for the most common mutation p.Phe508del, respectively. This report provides an overview of the basic defect in cystic fibrosis, the population genetics of CFTR mutations in Germany and the bioassays to assess CFTR function in humans together with the major achievements of preclinical research and clinical trials to bring CFTR modulators to the clinic. Some practical information on the use of ivacaftor and lumacaftor in daily practice and an update on pitfalls, challenges and novel strategies of bench-to-bedside development of CFTR modulators are also provided.

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