Cystic Fibrosis Research 2016

More than 4,000 doctors, nurses, researchers, and other health professionals gathered from October 27 to 29, 2016 in Orlando for the 30th Annual Cystic Fibrosis Conference. It is the most important conference on research and care for people with cystic fibrosis. This conference, known as the North-American Cystic Fibrosis Conference (NACFC), allowed participants to mark the thirtieth anniversary of the modern era of cystic fibrosis research. Thirty years ago, in 1986, the gene responsible for cystic fibrosis was not known and the number of adult patients followed at the Sherbrooke Cystic Fibrosis Clinic was only 6 when there were nearly 40 children. Thirty years later, not only has the gene responsible for cystic fibrosis been identified, but we have begun to prescribe drugs whose therapeutic aim is to correct the fundamental defect caused by the mutations in the fundamental defect, namely the CFTR protein (Cystic Fibrosis transmembrane conductance regulator). In addition, we now have ten times as many adults at our cystic fibrosis clinic while the number of children has remained the same. The identification of the gene responsible for cystic fibrosis, the development of drugs aimed at correcting the fundamental defect of this disease and the dramatic increase in the number of adults monitored in our clinics represent spectacular advances both in research and in the management of patients with cystic fibrosis.

The gene responsible for cystic fibrosis was identified by a Canadian and American team whose director was a young professor at the University of Toronto supported by grants from Cystic Fibrosis Canada, Dr. Lap-Chee Tsui. Dr. Tsui was one of the first researchers to use an innovative and modern technology that is now the standard in medical genetics, which is the identification of a gene using a reverse genetic approach. Previously, discoveries of genes associated with hereditary diseases required knowledge of the defective protein before the genetic code responsible for this defect could be identified. Dr. Tsui innovated by using an approach in which he did not have to know the faulty protein to identify the gene. This approach was based on epidemiological studies of populations of families and individuals with cystic fibrosis. Several families in Quebec participated in this research in the 1980s by giving personal medical information and by providing blood samples for DNA analysis. This extraordinary involvement of patients and families living with cystic fibrosis is a great example of the benefits that participation in clinical research can bring to an entire population. Dr. Tsui used the information obtained to identify genetic traits that were transmitted simultaneously with the disease to children. Some of these genetic traits had already been mapped and the location of each genetic trait in the human genome allowed Dr. Tsui's team to get closer and closer to the site where the faulty gene was located. In 1989, these researchers realized that they had just identified the exact site of expression of the defective gene and they were thus able to clone this gene, produce the protein and begin a major sequence of fundamental research focused on the knowledge offered by this exceptional discovery. These discoveries include the development of several models of cystic fibrosis in animals, which did not exist before. There are also several new tools such as antibodies and
cells specific to the CFTR defect that have been developed and made available to other researchers. Following a series of discoveries resulting from the identification of the cystic fibrosis gene, new molecules that could correct the defect were identified and clinical research has made it possible to market two new drugs for part of the fibrocystic population. These new drugs, produced by the company Vertex, are known under the name ivacaftor (Kalydeco) and the combination ivacaftor/lumacaftor (Orkambi).

At the NACFC conference, several works involving clinical studies were presented and it was noted that patients with class III mutations treated with ivacaftor not only have a significant correction in their sweat test, which reflects a correction of the fundamental defect, but also a significant and sustained improvement in their respiratory functions, weight gain and respiratory symptoms. In addition, it has been reported that the inflammatory load in the bronchi in patients treated with ivacaftor decreases and clinicians even observe in some individuals a disappearance of certain bacterial microorganisms that were previously chronically observed in the respiratory secretions of these patients. So there is evidence that it is possible not only to improve the symptoms and signs of cystic fibrosis, but to reverse some of the manifestations of cystic fibrosis that we previously thought were irreversible. Unfortunately, ivacaftor is only useful in a minority of people with cystic fibrosis because this medication does not work for mutations in other classes.

The most common mutation in Canada in people with cystic fibrosis is F508d, a class II mutation. Class II mutations cause the CFTR protein to be abnormally structured and this malformed protein is degraded inside the cell before it can reach the membrane to do its job of producing salt and bicarbonate in mucus. The absence of salt and bicarbonate in the mucus promotes thickened mucus and impairs the antibacterial defenses of the airway surface. During the conference, several researchers demonstrated that excessive acidification of mucus in cystic fibrosis can contribute to the promotion of bacterial growth. There are therefore several works in progress to try to discover ways to counter the excessive acidification of mucus.

The most effective therapy for correcting the defect in the secretion of salt chloride and bicarbonate in mucus would be a therapy that allows the defective CFTR molecule of the F508d type to reach the membrane and function. Lumacaftor is a new molecule that allows the class II CFTR protein to not be degraded and to reach the membrane. Once at the membrane, CFTR F508d still has two other defects to correct, namely its slowness in opening and its tendency to disappear quickly from the membrane. Adding ivacaftor to lumacaftor (Orkambi) not only allows the CFTR F508d to travel to the membrane, but also to remain in an open and functional position for an extended period of time. Clinical studies have shown that there is a 20 to 25% decrease in the amount of salt in sweat when people who are homozygous (F508d/F508d) for this class II mutation are treated with ivacaftor/lumacaftor. New clinical data have confirmed the partial effectiveness of this medication for this segment of the population affected by cystic fibrosis. This is a partial correction, but it is associated with a statistically significant improvement in respiratory function and especially a decrease of approximately 40% in the number of infectious exacerbations. Unfortunately, this medication is not for all of our individuals with cystic fibrosis. This new drug does not work when there is only one copy of the faulty F508d gene. There are therefore other clinical studies in progress with a new generation of similar molecules with a greater capacity to correct the fundamental defect observed in individuals carrying the mutation.
F508d class II. Finally, several other researchers presented preliminary data on different molecular approaches that also make it possible to correct the function of CFTR in cell models and in animal models. This research is still in the preclinical stage, but should soon be the subject of clinical studies in which individuals with cystic fibrosis will be called upon to participate.

There is other research work with molecules that have an impact on pulmonary and systemic inflammation as well as on diabetes and liver disease (cirrhosis). These various works will also require the participation of several patients with cystic fibrosis.

In this context, it is very important to be aware of the opportunities for participation in various clinical research studies. Information concerning the various clinical research programs is available at Cystic Fibrosis Quebec and at Cystic Fibrosis Canada. In addition, directors of cystic fibrosis clinics across Canada are well aware of ongoing studies and will be able to share this information upon request.

We are living in very promising years in cystic fibrosis and we are already seeing very important advances in the survival and quality of life of some people treated with or without the new drugs aimed at correcting the CFTR defect. It is essential that we do even more and we will reach the goal only by working together. It is essential that researchers and clinicians continue their efforts in medical research and that charitable organizations (e.g. Cystic Fibrosis Canada) support these researchers. It is even more important than ever that people living with cystic fibrosis get informed and also participate in this joint effort to defeat cystic fibrosis. Together, we will get there!

Dr Andre Cantin

Pulmonologist — Full Professor
Department of Pulmonology Sherbrooke University Hospital Center
Sherbrooke (Quebec) Canada

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