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Novel therapeutic approaches

Figure 2: Classes of CF mutation that facilitate correction of the basic defect by CFTR modulators through a "mutation-specific" approach. Class I mutations, which abrogate protein production, often include mutations that generate premature stop codons, class Ia (e.g. G542X) that lead to mRNA degradation by nonsense-mediated decay or those affecting canonical splice sites class Ib (e.g. 1717-1G>A). Class II mutations (including the most prevalent, F508del) cause retention of a misfolded protein at the ER, and subsequent degradation in the proteasome. Class III mutants affect channel regulation, impairing channel opening (e.g. G551D). Class IV mutants exhibit reduced conduction: that is, decreased flow of ions (e.g. R334W). Class V mutants cause significant reduction in mRNA and/or protein levels – albeit with normal function – often through causing alternative splicing (e.g. 3272-26A>G). Class VI mutants cause significant plasma membrane instability and includes F508del when rescued by most correctors (rF508del). Abbreviations: MSD, membrane-spanning domain; NBD, nucleotide-binding domain; P phosphorylation of the R domain; PKA, protein kinase A; PPase, protein phosphatase; RD, regulatory domain

that is, the channel is only able to conduct a reduced flow of Cl-

ions. These

mutations are mostly located in the transmembrane domains, thus affecting the channel pore properties. – Class V – These mutations lead to a drastic reduction in the amount of normal CFTR protein. In general, mutations in this class lead to alternative splicing (the 'cutting and pasting' of the coding portions of the gene), thus resulting in only a small amount of normally processed CFTR mRNA and consequently also very low amounts of normal CFTR protein. – Class VI – These mutations lead to a reduced stability of CFTR protein at the cell membrane, due to decreased anchoring. The clinical phenotype associated with mutations is diverse but, in general, classes I, II and III are typically associated with more severe

manifestations of CF, whereas classes IV, V and VI correspond usually to milder forms of the disease.


Therapeutic strategies aimed at correcting the basic defect Most of the current therapeutic strategies used to tackle CF are directed to the various clinical symptoms of the disease. Although improvements in these symptomatic therapies have increased

significantly the life expectancy of CF patients, the disease will only be adequately tackled upon correction of the basic defect. This will avoid the development of the so-called 'CF pathogenesis cascade'1

that starts with

two mutations in the CFTR gene, leading to a defective protein and abnormalities in ion transport. Such alterations ultimately result in obstruction of the airways, multiple cycles of inflammation and infection, usually leading to disseminated bronchiectasis, complete impairment of lung function and death. To treat the basic defect in CF, great efforts have been made in the past decade to identify small molecule compounds that are able to correct the specific basic defect of each mutation/ class. The major achievements in this regard are described below.

Read-through agents As in class I mutations, there is no production of complete CFTR protein due to the presence of a premature termination codon (PTC), the search for compounds that promote the read- through of stop codons has been the aim of drug discovery to correct these mutants. Some of the compounds that achieve this goal are antibiotics in the

family of aminoglycosides (such as G418 or gentamicin).

Another compound, Ataluren (called PTC124: 3-[5-(2-fluorophenyl)-[1,2,4] oxadiazol-3-yl]-benzoic acid) has been shown to mimic, at lower concentrations, the read-through activity of gentamicin. Ataluren has undergone clinical trials and preliminary results from Phase III studies showed that CF patients who received the drug had a lower decline in lung function and a lower rate of pulmonary exacerbations, compared with those who took a placebo (


Mutations in class II lead to intracellular retention of CFTR protein, thus a therapeutic strategy should promote folding of mutant CFTR so as to relocate to the cell surface.2

Although several compounds, known as chemical chaperones (such as glycerol or trimethylamine-N-oxide (TMAO)) have for long been shown to promote folding of F508del-CFTR,3

most of these

compounds are unsuitable for clinical trials, because either (1) their inherent toxicity is high, or (2) the mechanism by which they act is poorly characterised at the cellular level, or (3) they act at very general mechanisms in the cell, being

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