The CFTR protein that causes CF when it goes wrong, is involved in many processes that keep the body healthy, including inflammation. The process of inflammation is part of the body’s natural defence system to clear away infections and respond to tissue damage. When the CFTR protein is faulty, then inflammation goes wrong too, by becoming overactive and leading to permanent lung damage.
As part of our inflammation and joint disease Strategic Research Centre (SRC), researchers based at the University of Leeds are exploring why inflammation becomes overactive in CF and ways to treat or manage its effects. Professors Michael McDermott and Daniel Peckham and Dr Sinisa Savic, who are researchers leading this SRC, have recently completed a research study identifying a new link between CFTR protein and inflammation. They have applied this knowledge to broaden our understanding about how the CF drugs, Orkambi and Symkevi work.
Learning more about Orkambi and Symkevi
Orkambi and Symkevi are the latest CFTR modulators available to treat cystic fibrosis in the UK. They work by partially correcting the faulty CFTR protein, making sure it gets to the right place in the cell and that it functions properly. Like all new drugs, Orkambi and Symkevi were thoroughly tested, both in the lab and in clinical trials, to ensure their safety and effectiveness. However, despite many years of testing, there’s still more to find out about exactly how they work. Up until this point, no-one had investigated whether these drugs could correct overactive inflammation in cystic fibrosis.
Untangling how inflammation goes wrong
Depending on the type of infection or damage, different processes in our cells become active to help keep the body healthy, and inflammation is the end result of these processes. To understand what’s happening in CF, it is necessary to understand the role of all of these individual processes that can trigger inflammation.
In a previous study, the researchers at the University of Leeds focussed on one of these processes known as the ‘inflammasome’. They discovered that the blood levels of chemicals involved in triggering the inflammasome were raised in people with CF, compared to the levels in people without the condition. This work suggested that the inflammasome is being triggered too often in people with CF, which in turn could explain why inflammation is overactive.
What did the researchers do?
In this Trust-funded research study, the researchers wanted to test whether Orkambi and Symkevi were able to correct the faulty inflammasome process. To start with, they took blood from patients who were not taking CFTR modulators and treated their cells with Orkambi or Symkevi in the lab, and then artificially triggered the inflammasome. The drugs were able to reduce inflammasome-causing inflammation. Next, they measured the levels of inflammation in blood samples from people with CF who had recently started taking Orkambi and Symkevi. They found that inflammation was also reduced, with Symkevi showing a stronger anti-inflammatory effect, confirming what they had found in their lab studies.
They measured the levels of inflammation in blood samples taken from 21 people with CF who were taking either Orkambi or Symkevi on compassionate grounds (who had lung function of less than 40% of their predicted FEV1 )(the study was conducted before October 2019 when wider access to these drugs was approved).
What does this mean for people with cystic fibrosis?
This research study reported by lead authors Drs Heledd Jarosz-Griffiths and Thomas Scambler and their colleagues provides new information about how inflammation goes wrong in CF and shows for the first time that Orkambi and Symkevi may have a beneficial anti-inflammatory effect.
Future research studies are needed to confirm that the same effects of Orkambi and Symkevi are seen in people with CF with better lung function. The methods for measuring the levels of inflammation in the blood developed in this study could potentially be used to measure inflammation in future CF clinical trials.
The research study was published in the journal eLife, where you can read the full research paper.
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