Neue Konzepte zur Pathophysiologie und Therapie der Mukoviszidose

Zusammenfassung

Inzwischen hat die Mehrheit der an Mukoviszidose (syn.: Cystische Fibrose, CF) leidenden Patienten in Deutschland die Volljährigkeit erreicht. Mit zunehmendem Lebensalter steigt jedoch die Morbidität und der Anteil pulmonaler Komplikationen überproportional an. Auch durch weitere Optimierung der bestehenden symptomatischen Maßnahmen kann diese Entwicklung nicht verhindert werden, so dass dringender Bedarf an neuen, kausal-orientierten Therapieregimen besteht. In den vergangenen Jahren wurden die molekularbiologischen Grundlagen der CF-Erkrankung intensiv erforscht und das erworbene Wissen steht heute als Basis für die Entwicklung innovativer Behandlungsstrategien zur Verfügung. Während die Struktur des CF-Gens und seines Genprodukts cystic fibrosis transmembrane conductance regulator (CFTR) inzwischen gut verstanden erscheinen, wird die Funktion von CFTR in den Atemwegen weiterhin kontrovers diskutiert. Insbesondere ist weiter unklar, wie aus dem CFTR Defekt eine klinisch manifeste Lungenerkrankung resultiert. Dieser Beitrag gibt einen Überblick über gegenwärtig postulierte Hypothesen normaler und veränderter CFTR-Funktion und deren Folgen für die Homöostase endobronchialer Sekrete. Daraus abzuleitende neue therapeutische Ansätze werden diskutiert. Durch pharmakologische Korrektur der Ionenkanalfunktion von CFTR, bzw. durch Rekrutierung alternativer Ionenkanäle in einem frühen Krankheitsstadium könnte die Entstehung von irreversiblen Lungenveränderungen bei CF in Zukunft verhindert werden.

Abstract

Today, the majority of cystic fibrosis (CF) patients treated in Germany have reached adulthood. However, with increasing age the morbidity and frequency of severe pulmonary complications continues to rise. Further optimization of conventional therapy alone will be insufficient to compensate for this development. In recent years, there has been impressive progress in our understanding of the molecular basis of the CF gene and its product, the cystic fibrosis transmembrane conductance regulator (CFTR). This knowledge can now be applied to develop new therapeutic strategies. However, important questions remain to be solved, i. e., little is known about the pathways that link the malfunctioning of the CFTR protein with the observed clinical phenotype. This review briefly touches on CF genetics as it applies to lung disease and will focus on the current hypotheses of CFTR (dys)function and its impact on pulmonary fluid homeostasis. New treatment options that target the molecular basis of the disease will be discussed.

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