The focus of Dr Paola Vergani’s research is to gain an in-depth understanding of how the CF protein functions and how it goes wrong in cystic fibrosis. This knowledge can be used to gain a detailed understanding of how the current CFTR modifiers like Symkevi and Kaftrio work, and to design more effective drugs in the future.
Dr Vergani trained as a biophysicist, applying the discipline of physics to a biological system – in her case the CF protein. When she first moved to the UK in the early 2000s, it was difficult to get research funding to continue her basic science research, particularly while bringing up a young family at the same time.
“Some funding came from the Trust, as the clinical trials for CF modifiers were underway,” says Dr Vergani. “Getting the Trust funding was crucial, as it gave other funders the confidence to support my research, and it led to funding from elsewhere too.”
Dr Stella Prins and Dr Emily Cutting did their PhD studies in Dr Vergani’s lab, funded by the Trust. They worked together to develop a new method for studying the CF protein, using light-emitting tags. “We try to understand the changes the drugs are making to the CF protein, at a molecular level. This knowledge can be used to make better drugs in the future,” explains Dr Vergani.
What we know about the CF protein
To understand how their method works, here’s a reminder of what we know about the CF protein. Healthy copies of the CF protein are made inside the cell and then transported to the outside surface of the cell. Once they’re at the surface of the cell the CF protein acts as a channel: a special hole with a ‘gate’ that allows the controlled movement of chemicals to keep the lungs hydrated. In CF, different things go wrong with production of the protein or how it works, depending on which CF mutation (genotype) people have. This video by the Trust explains some of the things that can wrong.
The CF drugs currently available work in two ways: they either help the faulty CF protein get to the surface of the cell or they help it open the ‘gate’ when the protein is in position. Drugs like Kaftrio, Symkevi and Orkambi do both.
Glowing CF proteins
The new method that the Vergani lab has developed allows researchers to measure both how much of the protein has been transported to the surface of the cell, and how much of it is working correctly.
The scientists make the cells produce a tag that glows red under specific conditions under the microscope. Where the red glow ends, in microscopic images, marks the cell surface. At the same time, the location of the CF protein is tracked by a glow-in-the-dark yellow tag; yellow light at the boundaries of red areas corresponds to CFTR correctly positioned at the surface of cells. How well the gate of CFTR works can be assessed by monitoring changes in the intensity of the yellow light. So, in the lab, the scientists can measure the intensity of the red and yellow light to see how much CF protein is at the cell surface, and how well the protein is working.
What we don’t know about the CF protein
Although we know in general terms how Kaftrio, Symkevi and Kalydeco work, researchers don’t understand the fine detail of how these drugs alter the intricate folding of the CF protein, or how they help open its gate. Getting this deeper understanding will be crucial for designing the next generation of CF modifiers, that could work more effectively, for more mutations, or have fewer side effects.
The method that Drs Vergani, Cutting and Prins have developed could be used to increase knowledge of how the protein works. Using this method to measure how many different mutations within the CF protein respond to drugs in the laboratory can also give drug developers insight into how to treat people with rare mutations. The team at UCL have already begun using their method to investigate a range of rare CF mutations.
"It would be wonderful if a pharmaceutical company could use our method to do large scale screening of potential drugs, and modify them slightly, so that they could work for the rare mutations that don’t have drugs at the moment,” explains Dr Vergani.
Inspiring the next generation
Dr Stella Prins has only recently finished her PhD studies, passing the final ‘viva’ exam for her PhD at the beginning of October. She hopes to continue her CF research in the future.
In addition to running a research lab, Dr Vergani also has many teaching commitments at UCL. “Having an active research lab has meant that I often talk about CF and CF research in my teaching. So many medical students and science undergraduates come away with my enthusiasm and knowledge of cystic fibrosis.”
The research paper describing the method for measuring the location and function of the CF protein was published in the Journal of Biological Chemistry.