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treatment should also be directed against the multiple manifestations in the GI tract.

Repairing defective CFTR Most CF patients carry a mutation that leads to early degradation of the premature protein that would otherwise be functional if inserted into the plasma membrane. The most prevailing causative mutation, F508del, leads to an improper folding of the protein. The quality control mechanisms located in the trans-Golgi network detect the misfolded protein and submit it to the ubiquitin-proteasome pathway.13

Tampering with the quality

control system would eventually rescue enough protein to restore its activity. Currently it is estimated that reaching 10% of the wild-type CFTR activity would be sufficient to yield a normal phenotype in patients. It is unsurprising that most pharmacological attempts were aimed to bypass the quality control system. None of these approaches was nearly as successful as trying to activate dysfunctional CFTR that was already inserted into the membrane. The glycine-to-aspartate mutation, G551D, is the most promising candidate for such an approach. G551D is the third most common mutation, with a higher prevalence among people of Celtic origin. The mutation leads to a defect in the gating of the CFTR, which means that the channel is in a closed state most of the time and therefore unable to conduct anions correctly. A drug targeted to alter the conductive state of such a protein would show that it is the lack of anion transport that is responsible for the pathophysiology in CF.


Cystic fibrosis is the most frequent inherited disease among Caucasians. The genetic defect underlying CF results from mutations in the gene encoding CFTR. Most mutations in the CFTR gene result in a lack of functional CFTR expression in the membrane. It therefore seemed prudent to assume that impaired epithelial electrolyte transport is the primary cause for the pathophysiology of CF; however, patients suffering from this disease are affected by numerous other symptoms that cannot always be related to dysfunctional Cl–

transport. CF is still

a lethal disease, but the lifespan of CF patients has increased markedly over the past years. This can certainly be attributed to an improved knowledge about the disease, resulting in new and

intensified therapeutic schemes. Novel drugs, however, are still rare and in high demand. Current strategies are aimed either to correct the genetic defect or to influence the pathophysiological consequences of the CFTR mutations. Because of the impact defective CFTR has on the disease, most developments are directed to rescue the defective protein and restore its activity in the cell membrane. For the first time, a drug designed to target a specific mutation in

Physiol Sci 2003;18:38–42.

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13. Ward CL, Omura S, Kopito RR. Degradation of CFTR by the ubiquitin-proteasome pathway. Cell

"For the first time, a drug designed to target a specific mutation in the CFTR gene, thereby correcting the transport defect, has shown clinical benefit for a subset of patients"

has meanwhile been launched in a number of EU countries during the second half of 2012. Ivacaftor is most effective on a mutation present only in a small proportion of CF patients, and other compounds are currently under investigation in clinical trials. At this stage a real cure for all CF patients is still wishful thinking, but the combined use of novel drugs opens up the hope of greatly increased quality of life for CF patients. l

the CFTR gene, thereby correcting the transport defect, has shown clinical benefit for a subset of patients. In a series of clinical trials, the small molecule, ivacaftor (VX-770), demonstrated safety and effectiveness in a panel of outcome parameters. The drug, already marketed in the USA as Kalydeco™

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