Developing effective treatments for all

Genetic therapies are a type of treatment that are being developed for cystic fibrosis. They work in a completely different way to CFTR modulator medicines. There are currently no CF genetic therapies approved as treatments. However, in the last few years, many are starting to be tested in clinical trials. 

You can read and listen to videos explaining more about genetic therapies in our genetic therapies resources section of the website, and by searching for ‘genetic therapies’ on our Trials Tracker.

Researchers around the world are investigating treatment approaches for a group of rarer CF variants known as ‘Class 1’, ‘stop’ or ‘nonsense’ variants (these are all names used for one group of CF variants). People with class 1 CF variants do not make full length copies of CF protein.

We’re funding a Strategic Research Centre to support this area of research, led by Dr Mike Gray at Newcastle University. A team of researchers from across Europe are investigating potential medicines that work in two different ways to allow a full-length protein to be made. It is hoped that these new medicines would work in combination with CFTR modulator medicines. To find out about this exciting approach, read the summary of the Karen Menzies PTSuppress SRC.

Find out more

Sometimes it is very difficult to tell if someone has cystic fibrosis, especially when they have rarer CF variants. This can be difficult both during newborn screening and as symptoms of CF are explored in older children or adults. We are funding research to address these challenges.

More information on CF diagnosis can be found in the ‘How is CF diagnosed’ section of our website.

Newborn screening for CF background

The newborn screening test for CF, also known as the ‘heel prick test’, has been very successful at quickly finding out if babies have CF, but sometimes the tests can lead to uncertainty about whether or not someone definitely has CF. For some babies, a positive newborn screening result suggests that they might have CF, but follow-up tests do not confirm a diagnosis of CF. Where there is uncertainty, children may be given a designation of CFSPID (‘CF-screen positive, inconclusive diagnosis’).

 A small number of children with CFSPID may develop CF as they grow older, meaning that the majority of children with CFSPID remain well. However, it is difficult to predict whether an individual child with CFSPID will develop CF or not.

Could new lung tests help monitor children with CFSPID?

For CF teams and children with a CFSPID designation and their families, there is a difficult balancing act of monitoring the child’s health in case they go on develop symptoms that can be treated, but not checking them too much, to allow them to live with as little disruption as possible to day-to-day life. 

We’re co-funding research with the charity Action Medical Research to understand more about which children with CFSPID might be more likely to develop CF or CF-related disorders in the future. The researchers, led by Dr Rebecca Dobra, will follow the health of 25 children with a CFSPID designation over two years. They will study if the results from a new, more sensitive test of lung function and radiation-free imaging can detect those that are more likely to develop CF.

Improving diagnosis and treatment options for people with hard-to-diagnose CF

Some people may have symptoms of CF but a diagnosis hasn’t been confirmed, as the test results don’t give definite answers. They can live with worsening health for many years, without treatments that could help their symptoms. Many of these people are likely to have rarer CF variants. For some of these people, it is not known whether they may benefit from taking CFTR modulator medicines. 

A Trust-funded Development Award led by Prof Nick Simmonds is investigating whether gut organoids, a test method used in research studies, could be used to in the clinic to provide more certainty for people whose CF is difficult to diagnose. They are also investigating whether the same technology could be used to find out if individuals may benefit from CFTR modulator medicines. Prof Simmonds from the Heart and Lung Institute at Imperial College London is leading a research team including lab and hospital-based researchers in London and Utrecht in The Netherlands. Read more about their ‘ADVANCE-CFTR’ research programme. 

The CFTR protein acts as a gated channel, like a ticket barrier, allowing the movement or transport of two chemicals - chloride and bicarbonate ions - out of cells. When chloride and bicarbonate move through the gate, they draw water with them. Without this ion and water movement, the liquid outside cells becomes very thick and sticky, for example on the surface of the lungs and in the GI tract. 

By increasing our understanding of how the CF protein works and how chemicals move through its gated channel, there is potential to design new and innovative medicines for cystic fibrosis. Future medicines could make a bigger difference for more people with cystic fibrosis.

Getting the CF protein into shape

The CF protein is a large protein carefully folded into shape to do its job. The CFTR modulator medicines work by subtly altering the shape of a specific section of the faulty CF protein. The medicines make faulty CF protein closer to the shape of healthy, undamaged protein. Research has shown that altering the shape of a different part of faulty CF proteins could make bigger improvements to how they work.

The aim of the Goodchild SRC on CFTR folding and function led by Professor David Sheppard at the University of Bristol is to investigate these new findings in more detail. Their results will provide important information for the development of new CFTR medicines in the future, that could benefit people with a wider range of errors in the CFTR gene..

Read more about Professor Sheppard’s Goodchild SRC on CFTR folding and function

How the CF protein transports bicarbonate

Researchers have conducted many studies to understand how chloride transport through the CF protein is affected in cystic fibrosis, but they know less about how bicarbonate transport defects lead to the symptoms of CF. A greater understanding of bicarbonate transport could lead to improved treatments for CF tailored to individuals. The Trust is funding an SRC programme on bicarbonate transport.

The ‘Restoring the Fizz: Pharmacological repair of bicarbonate transport in cystic fibrosis’ SRC is led by Dr Paola Vergani based at UCL in London. It aims to better understand the flow of bicarbonate in different organs affected by CF. They hope that the results of their lab-based studies will generate ideas on how to treat CF in the future, with medicines more suited to individuals based on the form of CF they have and the severity of different symptoms.

Read more about Restoring the FIZZ SRC on repair of bicarbonate transport

How rare, brief openings of the CF protein could improve the design of new medicines

One of the ways CF modulator medicines work is by keeping the gated pathway of the CF protein open. While modulators are very effective medicines for many people, they do not completely restore function to the CF protein. 

In the lab, flow of chloride and bicarbonate through individual CF proteins can be measured as microscopic electric currents. For the F508del variant in the CF protein, early career researcher James Charlick observed that these currents were sometimes smaller than expected, indicating that the gated pathway only opened part way. James also found that these partial openings are influenced by CFTR modulator medicines. 

Learning more about how and why these partial openings occur, could lead to the development of improved CF modulator medicines in the future, and possibly increase the number of CF variants treated by future modulators, this is the topic of his Early Career Research Development Award.

Learn more about this research

Ensuring chemicals move through the CF protein gate in one direction 

Just like the opening of an ordinary gate, when the CFTR gate is open, chemicals can move in either direction – in or out of the cell. To keep the lungs healthy, chemicals need to move through the CFTR ‘gate’ from the inside of cells to the outside. 

One way to keep chemicals moving in the right direction is to increase the levels of potassium inside the cell. The potassium enters the cell through a separate potassium ‘gate’ or channel.

Treatments currently available for CF are focussed on ensuring that the CFTR gate is working well. In a research study co-funded by the Trust and Action Medical Research, Dr Guy Moss is leading studies in the lab to test whether medicines that act to boost the activity of potassium channels could be effective treatments for CF. 

Dr Moss and UK-based colleagues will investigate whether potassium channel activators can improve the effectiveness of CFTR modulators. They will also investigate whether new combinations of potassium channel activators and other medicines might be an effective way to treat people who are not able to benefit from CFTR modulators.

How does the natural chemical succinate affect lung health in people with CF?

Scientists have recently shown that a natural chemical called succinate is linked to increasing the activity of the CF protein in the lungs. Succinate acts as a first line of defence against infections in the lungs. The CF protein is a key part of this process and when the CF protein is faulty mucus clearance is reduced, which leads to infections.

However, there seems to be a tipping point where the actions of succinate shift from being protective to harmful, possibly when succinate is present in the lungs for a long time. 

In a Trust-funded Established Investigator Development Award, Dr Mike Gray from Newcastle University and Dr Carlos Flores from Valdivia, Chile are investigating the role of succinate in more detail. Understanding more about the activity of succinate in the lungs of people with CF could lead to new treatments for CF in the future, to improve lung health and reduce lung damage.

Read about the studies on succinate in more detail