| Abstract | Cistična fibroza multisistemska je autosomno recesivna genetska bolest. Unutar zadnjih nekoliko godina napravljeni su veliki koraci u razumijevanju patofiziologije cistične fibroze, što je omogućilo pretpostavku mehanizma koji uzrokuje kliničku sliku pacijenata. Otkriće CFTR (engl. cystic fibrosis transmembrane conductance regulator) gena 1989. godine, omogućilo je pretpostavku strukture i funkcije CFTR proteina. Nakon toga otkrića opisano je više od 2000 varijanti CFTR gena te njihov utjecaj na količinu i funkciju CFTR proteina. Uloga CFTR proteina kao ionskog kanala za transport klorida i bikarbonata te utjecaj na različite epitelne stanice organa i mukusa, sada su bolje shvaćene. Mehanizmi u pozadini osjetljivosti na infekciju također su pretpostavljeni, a uključuju nepravilnosti u sastavu, volumenu i kiselosti površinske tekućine dišnih putova (engl. airway surface liquid, ASL); promjene u anatomiji i funkciji submukoznih žlijezda te deficijencije u sustavu mukocilijarnog klirensa. Dotaknute su brojne hipoteze koje bi objasnile prekomjerni upalni odgovor, a uključuju oslabljen mukocilijarni klirens, perzistentnu hipoksiju, lipidne abnormalnosti, disproporcije proteaza i antiproteaza te neravnotežu oksidansa i antioksidansa. Osim patofiziologije cistične fibroze, ovaj rad osvrće se i na terapijske pristupe ovoj bolesti. Osim aktualnih terapija, ovaj rad donosi pregled
nekih od terapijskih pristupa, koji su još uvijek u razvoju, odnosno u pretkliničkim i kliničkim fazama ispitivanja. Neki od tih terapijskih pristupa uključuju aktivatore, potencijatore i efektore, gensku terapiju, mRNA terapiju, terapiju antimikrobnim lijekovima (terapije na simptomatskoj razini), terapiju inhibitorima, oligonukleotidima, gensku terapiju, editiranje gena te različite kombinirane terapije. |
| Abstract (english) | Cystic fibrosis is a multisystem autosomal recessive genetic disease. In the last few years, huge steps have been made in understanding cystic fibrosis pathophysiology, which allowed hypothesis of mechanism causing mainfestation of the disease. Discovery of CFTR gene in 1989. allowed assumption of the structure and function of CFTR protein. Since the
discovery, more than 2000 variants of the CFTR gene have been described, as well as their influence on the amount and function of the CFTR protein. Now, role of the CFTR protein as an ionic channel for chloride and bicarbonate transport, and their influence on different epithelial cells of various organ and mucus, are better understood. Mechanisms behind infection susceptibility have also been hypothesized, and they include abnormalities in composition, volume and acidity of airway surface liquid (ASL); changes in anatomy and function of submucosal glands and the deficiency in mucociliary clearance. A lot of hypothesis have been observed, that would explain excessive inflammatory response, and they include impaired mucociliary clearance, persistent hypoxia, lipid abnormalities, protease/antiprotease disproportion and oxidant/antioxidant imbalance. Except the pathophysiology of cystic fibrosis, this paper also focuses on therapeutic approaches for the disease. In addition to current therapies, this paper brings a review of some therapeutic approaches, still in the development phase or preclinical and clinical trials phase. Some of those approaches include activator, potentiator and effector therapy, mRNA
therapy, antimicrobial therapy (on symptomatic level), inhibitor therapy, oligonucleotides, gene therapy, gene editing and various combined therapies. |
