2103 is the number of mutations identified to date in patients with cystic fibrosis, the most common fatal genetic disease in Canada. Behind this figure lie huge challenges for patients and research. Emmanuelle Brochiero and Damien Adam, two scientists at the CHUM Research Centre (CRCHUM), intend to tackle them.

Today, nearly 4,400 Canadians are living with cystic fibrosis, caused by mutations in the Cftr gene. Although this 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 is responsible for the production of a protein called CFTR, which plays a crucial role in the airway surface hydration and secondarily, in the mucus removal. This phenomenon is the first line of defence against infection. When the Cftr gene is defective, the channel no longer plays its role, which favours chronic infection. Severe pulmonary damage then develops over time, leading to a gradual decline in pulmonary function, until requiring lung transplant or ultimately causing the death of the patient.

In this month of cystic fibrosis awareness, researcher Emmanuelle Brochiero, the director of the CRCHUM’s pulmonary physiopathology laboratory and a professor at the Université de Montréal, and researcher Damien Adam give us an overview of their cystic fibrosis projects. In their laboratory, they are studying pulmonary damage and ways of improving the ability of injured lungs to repair and regenerate.

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 ten years, new treatments, directly targeting the defects caused by some of the mutations affecting the Cftr gene, have been developed.

In this regard, a first drug, Kalydeco, was approved. The problem is that it targets mutations found in fewer than 10% 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% of patients. This precision medicine drug is not yet available in the 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, 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,” explained Emmanuelle Brochiero. “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, her team showed 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.

Today, Emmanuelle and Damien are 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, they 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.

Are we moving towards personalized treatments in cystic fibrosis?

“In our laboratory, we can count on a cell and tissue biobank, directed by Emmanuelle, 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,” explained Damien Adam.

In short, the 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,” added Emmanuelle Brochiero.

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 both patients eligible for current treatments as well as those carrying rare mutations.

Our two researchers are united by a single goal: promoting the repair and regeneration of lung tissue in ALL patients with cystic fibrosis, regardless of their mutation.

About the research

This research work was carried out in collaboration with the CHUM’s clinical teams in thoracic surgery, from the transplant program and the cystic fibrosis clinic, as well as national and international collaborators with expertise in bacterial infection.

Funding for this project, carried out in the laboratory of Emmanuelle Brochiero and her colleague Damien Adam, was provided by the Canadian Institutes of Health Research. The biobank receives funding from the Quebec Respiratory Health Research Network (Fonds de recherche du Québec – Santé). The biobank also contributes to the advancement of respiratory health research by sharing valuable samples from patients with various lung diseases with the scientific community.