Cystic fibrosis: towards better treatment and stronger lungs

Some 2,103 mutations have been identified in patients with cystic fibrosis (CF), the most common fatal genetic disease in Canada, and together they pose huge challenges for patients and researchers, including those affiliated with Université de Montreal and its teaching hospital, the Centre hospitalier de l’Université de Montréal (CHUM).

Nearly 4,400 Canadians are today living with CF, which is caused by mutations in a gene called CFTR (cystic fibrosis transmembrane conductance regulator). Although the disease affects several organs, the main cause of death is related to the gradual deterioration of the lungs and their loss of function.

In the lungs of a person in good health, the CFTR gene produces a crucial protein for hydration of the airway surface and removal of mucus, the first line of defence against infection. When the gene is defective, it no longer plays its role; chronic infection ensues, leading to severe pulmonary damage and a gradual decline in pulmonary function. A lung transplant becomes necessary, or ultimately the patient dies.

Two scientists leading the way to better outcomes are Emmanuelle Brochiero and Damien Adam of the CHUM Research Centre (CRCHUM). An UdeM medical professor, Brochiero is director of the CRCHUM’s pulmonary physiopathology laboratory; Adam is a researcher there. In their laboratory, they are studying pulmonary damage and ways of improving the ability of injured lungs to repair and regenerate.

With May being the U.S. Cystic Fibrosis Foundation’s CF Awareness Month, the two scientists are keen to give an overview of their various research projects related to this debilitating disease.

What treatments are currently offered for cystic fibrosis?

For a long time, most treatments were aimed at reducing symptoms, particularly by fighting infection. In the last 10 years, new treatments have been developed that directly target the defects caused by some of the mutations affecting the CFTR gene.

In this regard, a first drug, Kalydeco, was approved. The problem is that it targets mutations found in fewer than 10 per cent of patients. Other CFTR modulators, Orkambi and Symdeko, were developed for patients carrying the most common mutation, F508del.

Today, Trikafta, a triple combination therapy which is potentially more effective, could be used to treat up to 80 per cent of patients. This precision medicine drug is not yet available in this country, but has been accepted by Health Canada for a priority review.

What obstacles still have to be overcome?

Unfortunately, the efficacy of these drugs is limited and variable among patients, and a non-negligible proportion of patients are not eligible for these treatments.

In people with cystic fibrosis, the lungs are damaged and their ability to self-repair is hampered by the basic defect in the CFTR channel and the presence of bacterial infections, particularly by Pseudomonas aeruginosa and Staphylococcus aureus. Moreover, our laboratory showed that these bacteria reduce the efficacy of treatments targeting CFTR.

Therefore, the goals of our team are to identify ways of counteracting the negative effect of the bacteria, improving treatment efficacy and promoting lung repair, regardless of the type of mutation. In recent years, we’ve shown in vitro that molecules interfering with the production of harmful virulence factors by bacteria would help maintain the effectiveness of treatments on CFTR and the repair of airway tissue.

We’re now pursuing this line of research to counteract the effects of infection, limit its impact on therapies and promote the restoration of lung tissue integrity.

From a personalized medicine perspective, we also want to predict treatment efficacy based on the types of bacteria present in the lungs of people with the disease. Indeed, bacteria change as the disease progresses and, logically, treatments should adapt. Easier said than done!

Can we look forward to personalized treatments for cystic fibrosis?

In our laboratory, we can count on a biobank of cells and tissue that contains rare samples from patients with different lung diseases, including cystic fibrosis. Thanks to our expertise in tissue engineering, we are able to recreate respiratory epithelial tissues using cells from the respiratory and pulmonary tracts of patients. This allows us to study the disease and test our therapeutic approaches aimed at repairing the lungs.

In short, our research team is able to map and predict therapeutic response to CFTR modulators, in the presence of different bacterial strains taken from patients at various stages of the disease. We recently established protocols to assess our personalized treatment strategies promoting epithelial repair on living lung tissues, in the presence of mucus from patients, collected during lung transplantation.

Thanks to the wealth of this biobank, tissue samples from healthy subjects and cystic fibrosis patients with a range of mutations are available. This allows them to consider the possibility of personalizing and testing therapeutic cocktails combining treatments targeting the CFTR channel and other ionic channels, as well as molecules attenuating bacterial virulence. These strategies will be tested on cells and tissues from patients eligible for current treatments as well as those carrying rare mutations.

We’re united by a single goal: promoting the repair and regeneration of lung tissue in all patients with cystic fibrosis, regardless of their mutation.

About this research

In their research, Emmanuelle Brochiero and Damien Adam collaborate with the CHUM’s clinical teams in thoracic surgery, as well as its transplant program and cystic fibrosis clinic, along with national and international partners with expertise in bacterial infection. Funding is provided by the Canadian Institutes of Health Research. Tthe team’s biobank receives funding from the Quebec Respiratory Health Research Network (Fonds de recherche du Québec – Santé) and contributes to the advancement of respiratory health research by sharing valuable samples from patients with various lung diseases with the scientific community.

About the CRCHUM

The University of Montreal Hospital Research Centre (CRCHUM) is one of North America’s leading hospital research centres. It strives to improve adult health through a research continuum covering such disciplines as the fundamental sciences, clinical research and public health. Over 1,850 people work at the CRCHUM, including more than 550 researchers and more than 460 graduate students

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