The latest research developments

Cystic fibrosis is a genetic condition caused by the deficiency of a protein known as the Cystic Fibrosis Transmembrane Conductance Regulator or CFTR. CFTR is a protein inserted into the apical part of cells at the junction between tissue and mucus. Organs affected by CFTR deficiency include the sinuses, bronchi, bronchi, pancreas, pancreas, liver, intestines, and sperm-carrying ducts known as Vas deferens. CFTR is also deficient in sweat absorption channels, which helps limit salt loss in hot weather. Measuring the concentration of chloride (salt) in sweat is used as a diagnostic test for this condition. The function of CFTR is to allow small, negatively charged molecules called anions to pass through. The exchange of anions can take place from the cell to the mucus or from the outside liquid to the inside of the cell. By facilitating the passage of anions, and particularly chloride, CFTR ensures adequate hydration of the mucus lining respiratory and digestive secretions. Hydration is ensured by the salt concentration (NaCl) which is determined by the efficiency of chloride transport through the CFTR. A deficiency in the function or abundance of CFTR leads to a significant thickening of the mucus and an obstruction of the channels containing mucus in the respiratory, digestive and reproductive systems.

There are over 2,000 different CFTR gene mutations that may be associated with a diagnosis of cystic fibrosis. However, all of these mutations can be classified into five categories, of which only three are associated with a severe form of cystic fibrosis. Class I includes gene defects that cause deformed DNA to evoke a signal to stop the transcription of the genetic message. This stopping of transcription prevents the cell from producing the protein. The premature stopping of protein production can be reversed and corrected in Petri dishes by adding certain antibiotics from the aminoglycoside class (e.g. gentamicin, tobramycin). These are antibiotics that patients with infections with Pseudomonas aeruginosa are already being taken by inhalation. On the other hand, the concentrations needed to correct the class I defect would be toxic and another drug is under development to correct the class I defect. This is PTC124 or Ataluren. Clinical studies in Israel seem to show positive results. On the other hand, clinical studies with patients from North America demonstrate less favorable results, which could be explained by variations in the genetics of these two populations. However, we now know that it will be possible to correct the genetic defect in CFTR type I, which represents a defect found in approximately one in 15 people with cystic fibrosis.

Considerable progress has been made for people with cystic fibrosis whose mutation is a class III mutation. This is a defect in the regulation of the opening of the CFTR. The CFTR protein is present in normal quantities, but due to a defect in its regulation, the passage of chlorides does not take place. A new drug, Kalydeco® (ivacaftor) has been on the market for less than a year. Kalydeco® allows the opening of the chloride channel and the normalization of the function of CFTR, the mutation of which is part of class III. In Quebec, there is approximately one person out of a hundred people with cystic fibrosis who could benefit from this treatment. Although they are a tiny minority of people with cystic fibrosis, this research advance offers a lot of hope, as clinical experience confirms that even in people with very significant digestive and respiratory impairment, there are significant improvements associated with correcting CFTR function. It is therefore hoped that people with cystic fibrosis associated with the other mutation classes could also benefit from a possible correction of their CFTR. Kalydeco® improved respiratory function by approximately 10% and taking this medication is also associated with a decrease in the number of respiratory exacerbations and a weight gain of more than 3 kg. In addition, people with cystic fibrosis with a class III genetic defect reported a marked improvement in their quality of life when taking Kalydeco®. For the time being, Kalydeco® remains a difficult drug to obtain because of its high price, but each patient file with a class III mutation can be studied in the context of the exceptional patient program at the Régie de l'Assurance-Maladie du Québec.

Nine out of ten people with cystic fibrosis have a class II mutation on at least one of their two CFTR genes. Half of people with cystic fibrosis in Quebec have two copies of the CFTR gene with a class II defect. It is therefore obvious that a therapy that can correct a class II defect will include a major breakthrough in cystic fibrosis therapy. The CFTR class II defect causes the protein to be malformed and because of its deformation, it is recognized by the protein quality control system as defective. Defective proteins are rapidly destroyed by enzymes in an organelle called a proteosome. Researchers have discovered new small molecules that can stabilize the shape of CFTR sufficiently to allow part of this protein to pass to the cell membrane. Although CFTR class II has a reduced function, the passage of this malformed protein to the membrane allows some of the function of salt and water transport to be restored. On the other hand, the correction is not sufficient to observe clinical benefits and it is therefore necessary to combine these new small molecules with Kalydeco®. The molecule that allows the deformed CFTR to migrate to the membrane is called lumacaftor. The combination of lumacaftor with Kalydeco® has been studied in a small number of patients with cystic fibrosis and class II mutation. This small study demonstrated a significant, though modest, improvement in respiratory function. There was also a slight improvement in the sweat test confirming that this therapy really works on the basic defect of cystic fibrosis. These encouraging results have therefore prompted Vertex to undertake two major clinical research studies aimed at people with cystic fibrosis and carriers of the CFTR class II genetic defect in whom a combination therapy will be used for a period of one year. The two studies include 500 patients each, some of whom will receive the placebo. Enrollment for these two studies is now complete and we look forward to receiving the results of this clinical research aimed at helping the vast majority of patients with cystic fibrosis.

Even though these new molecules are in clinical trials, there are also several advances in fundamental research that allow us to believe that there will be new molecules that are even more effective than those currently under study and that will be able to correct CFTR defects regardless of the class of these defects. It is therefore a particularly encouraging period for cystic fibrosis researchers and especially for patients and their families. It is all the more important that people with cystic fibrosis work effectively with the professionals in their clinics in order to do everything possible to preserve their health as much as possible while waiting for the arrival of these new therapies. Researchers strongly believe that it will be possible to correct the basic defect of cystic fibrosis for all people with this condition. On the other hand, the marketing of these new products will probably take two to five years, which is why it is important to continue to perform all prescribed treatments in order to benefit as much as possible from these advances in research.

Finally, it is interesting to note that Cystic Fibrosis Quebec and Cystic Fibrosis Canada contribute significantly to the funding of many of the research that has allowed these advances and that these successes are the result of the efforts of volunteers from the various sections of Cystic Fibrosis Quebec. As a researcher, I want to thank all these volunteers and assure them that the researchers and health professionals associated with cystic fibrosis clinics in Quebec are more motivated than ever to convert their efforts into tangible results.

Dr Andre Cantin Pulmonologist Full Professor

Department of Pulmonology Sherbrooke University Hospital Center

Sherbrooke (Quebec)

Canada

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