Cystic Fibrosis: a Shift Toward Causative Treatment?

Abstract

Cistična fibroza (CF) najčešća je nasljedna smrtonosna bolest u ljudi bijele rase. Uzrokovana je odsutnošću ili poremećajem funkcije multifunkcionalnog proteina CFTR-a (engl. Cystic Fibrosis Transmembrane Conductance Regulator). Do sada je otkriveno više od 1000 mutacija CFTR-gena podijeljenih u šest klasa. Terapijski pristup u CF-u temelji se na liječenju komplikacija i simptoma, a ne na liječenju uzroka bolesti. Međutim, istražuje se više oralno aktivnih supstancija – modifikatora CFTR-a – koje modificiraju funkciju CFTR-proteina. Time se pokušava korigirati podliježući genski defekt koji uzrokuje CF. S obzirom na to da terapijski učinak modi(katora CFTR-a ovisi o individualnom defektu proteina, za odabir prikladnih bolesnika nužno je poznavanje genotipa na oba alela CFTR-gena. Trenutačno je samo nekoliko modi(katora CFTR-a završilo treću fazu kliničkih ispitivanja i registrirano je za upotrebu. Nažalost, njihova je klinička učinkovitost skromna. Zbog izrazito nepovoljnog omjera troška i koristi kombinacija lumakaftor-ivakaftor za sada se ne može preporučiti pri liječenju bolesnika homozigota za mutaciju F508del CFTR-a. Potrebno je uložiti daljnje napore u razvoj učinkovitijih modifikatora CFTR-a.Cystic fibrosis (CF) is the most common lethal inherited disease in the white population. It is caused by the absence or dysfunction of the multifunctional CF transmembrane conductance regulator (CFTR) protein. More than 1,000 mutations of the CFTR gene divided into six classes have been described. Current treatments for CF manage complications and symptoms, rather than the cause of the disease. However, there are several orally active compounds under development – CFTR modulators – that aim to correct the underlying gene defect that leads to CF by modifying the function of the CFTR protein. Since the therapeutic effects of CFTR modulators are based on individual protein defects, knowledge of the genotype of both alleles of the CFTR gene is necessary for appropriate patient selection. At present there are only a few CFTR modulators which have completed the third phase of clinical trials and have been approved for use. Unfortunately, their clinical effectiveness seems to be modest. At present, due to extremely unfavourable cost-benefit ratio, the lumacaftor-ivacaftor combination can not be recommended for CF patients who are homozygous for F508del CFTR mutation. Further efforts are needed to develop the next generation of CFTR modulators with more effective modifying potential