Can we cure cystic fibrosis? — Expectations heighten after two decades
Cystic fibrosis (CF) is the most common genetically inherited disease amongst Caucasian populations. It is said that 1 in 25 individuals carry one copy of the affected gene, and 1 in ~3000 newborns is affected by CF. The disease disrupts many organ functions, especially lungs, where chronic bacterial infections often lead to respiratory failure and death. CF patients may also suffer from the inability to properly digest food due to the lack of digestive enzymes, as well as experiencing intestinal blockages.
There was a breakthrough in the CF research back in 1989, when the gene responsible for the disease was finally identified. The gene encodes an ion channel named cystic fibrosis transmembrane conductance regulator (CFTR). A channel is a protein in the membrane of a cell that can pass select ions from one side of the membrane to the other. CFTR allows the passage of chloride ions from inside the epithelial cell to the surface of the cell that lines the ducts and tubes in the body, such as airways. This step is important in the production of mucus, digestive enzymes, and sweat. The presence of chloride ions makes the mucus that coats the surface of the ducts and tubes thin and fluid. Since its discovery, more than 1,800 mutations have been found in CFTR that cause CF.
The most common cause of CF is the F508del mutation in CFTR, which is the deletion of the 508th amino residue (or the building block of the protein). About 90% of CF patients have this mutation. F508del produces misshaped CFTR, resulting in the degradation of the protein, and only very few of CFTRs make it to the membrane of epithelial cells. Moreover, these few surviving CFTRs are defective and cannot pass enough chloride ions. Insufficient amount of chloride ions at the surfaces of ducts and tubes causes thickening of mucus and makes the area vulnerable to bacterial infections.
At the time of the discovery of CFTR, there was so much optimism for developing effective treatments for CF. The hope was to target the root cause of the disease rather than treating its symptoms. However, it proved to be a huge challenge. Usually, drugs work by blocking the function of proteins. In the case of CF, effective drugs must not only restore the function of CFTR (called “potentiators”), but also protect it from misshaping/degradation (called “correctors”). Such molecules are called CFTR corrector-potentiators.
Only very few molecules with the two activities have been identified so far, albeit intensive effort put into the search and development of CFTR corrector-potentiators. Also, mechanisms of actions of these molecules are not understood well because they were found by high-throughput screening (i.e. testing large numbers of molecules from chemical libraries). What is meant by large numbers? One pharmaceutical company has screened a total of about 514,000 compounds before identifying a couple of promising hits.
Last year, new excitement passed through CF communities as the first clinical trial of a CFTR potentiator was conducted. The drug is called Kalydeco (also formerly known as VX-770), developed by Vertex Pharmaceuticals. Kalydeco treats a rare G551D mutation (the 551st residue of CFTR is changed from glycine to aspartate) found in 4% of CF patients. The mutation makes CFTR unable to open properly. Kalydeco has proven effective during the clinical trial, and the drug was approved by the US Food and Drug Administration in January this year.
Another promising drug developed by Vertex may be making its way to the market as well. VX-809 is a CF corrector that seems to protect misshapen F508del CFTR from degradation. A clinical trial of combination of VX-809 and Kalydeco is currently conducted on CF patients with F508del CFTR. By combining the two drugs, investigators are hoping that VX-809 will increase the number of CFTRs in the membrane of epithelial cells, after which Kalydeco can get the CFTRs to function properly. Unfortunately, the initial combination clinical trial showed only small improvement in F508del patients in contrast to the effectiveness of Kalydeco on CF patients with G551D. Further test using a higher dosage is underway, with the result expected later in the year.
We may be able to keep our hopes high as more drugs developed by different biotech companies are also being tested in clinical trials. Meanwhile, investigators will be busy finding the modes of action of the CF drugs in hope of designing better drugs that can be applied to patients with other CFTR mutations. CFTR-targeted drugs have set out a new example in the treatment of genetic diseases, demonstrating that small molecules (which can be taken orally) can restore defective proteins. Researchers are excited that this example may be followed by many more for treating other diseases for which gene therapy and enzyme supplements are the only available options at the moment.
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