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Preventing Bacteria from Communicating Could Make CF Therapies Like Kalydeco More Effective, Study R

Preventing bacteria from communicating with each other may be a way to bolster the effectiveness of current cystic fibrosis (CF) therapies, a study reports.

According to researchers at the University of Montreal Hospital Research Centre (CRCHUM), the use of quorum-sensing inhibitors can help to prevent the harmful effects of bacteria like Pseudomonas aeruginosa, a common source of infection in CF patients, while preserving and enhancing the effects of CFTR corrector drugs (a defective CFTR gene is the cause of CF).

In the past decade, advances were made to improve CF treatment and two new therapies — Kalydeco (ivacaftor) and Orkambi (ivacaftor/lumacaftor), developed by Vertex Pharmaceuticals — were introduced. However, these therapies are only available to patients with specific genetic mutations, and clinical data have demonstrated that they can be of limited efficacy.

It is still unclear why, in some patients, these therapies are less effective. Besides the natural treatment response variability among patients, however, some studies suggest that lack of patient response may, in part, be due to the deleterious effects of bacterial infections.

Emmanuelle Brochiero, a CRCHUM researcher and professor at Université de Montréal, and colleagues tested the impact of P. aeruginosa infection on the activity of the CFTR protein — the protein that is dysfunctional in CF — and on CFTR modulator therapies.

First, the team exposed cells with a normal CFTR protein and to different strains of P. aeruginosa. This experiment revealed that the bacteria released specific substances that they often use to communicate with each other; interestingly, these substances could impair CFTR activity.

Next, the team blocked the production of these substances by either genetic manipulation or chemical inhibition, and found that normal CFTR activity was not changed, or was rescued, by doing so. This finding, the researchers said, demonstrated that compounds in the bacterial communication system, or quorum sensing, are responsible for some of the abnormal CFTR activity seen in CF patients.

Researchers then repeated these experiments, but this time in cells with a mutated CFTR (F508del mutation), and in cells and lung tissue samples collected from CF patients. A similar CFTR inhibitory effect was observed when the cells were in the presence of bacteria, an effect that not seen in the presence of quorum sensing inhibitors.

In addition, the team found that Kalydeco’s efficacy was reduced by the bacteria-produced substances. When they treated the cells with lumacaftor (VX-809) or Kalydeco in addition to the quorum sensing inhibitors, they saw this combination could improve treatment efficacy, and rescue CFTR activity.

“In a sterile in vitro environment, Kalydeco and Orkambi treatments work well. But in real life, the lungs of sick patients are colonized by bacteria, Pseudomonas aeruginosain particular. Much evidence has indicated that the bacteria could interfere with the treatment,” Brochiero said in a news release. “Thanks to this study, we have been able to determine which substances released by the bacteria could reduce the efficacy of the treatments.

“Adding molecules called quorum-sensing inhibitors to current drugs not only reduces bacterial production of certain harmful residues but also restores the efficacy of existing treatments on the cells of cystic fibrosis patients,” Brochiero added.

The researchers believe that quorum-sensing inhibitors may represent a therapeutic option to supplement and enhance currently available CF therapies. But additional studies are required to evaluate their safety and efficacy in patients.

“Our work confirms that different bacterial strains, depending on whether they come from acute infections — especially in young patients — or chronic infections — especially in older patients — affect treatment efficacy in different ways,” said Émilie Maillé, a research assistant at Brochiero’s lab and lead author of the study.

The team also believes that these findings open new opportunities for personalized medicine in CF.

“By using cells collected from patients, we think that it will be possible to test and predict the efficacy of treatments such as Kalydeco and Orkambi, on cells collected from the patient, in the presence of the bacteria taken from the same patient,” Brochiero said.

The team is planning to continue its work by identifying the most effective bacterial quorum-sensing inhibitors and evaluate their potential in helping to repair lung tissue.

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