Tackling the underlying cause of cystic fibrosis

Cystic fibrosis is a genetic condition caused by having two mutated copies of the CF gene known as ‘CFTR’. The specific mutations present in each copy of the gene is known as a ‘genotype’. The most effective way of treating CF is to restore the function of the protein produced by the mutated gene, known as the CFTR protein.

Research is underway to treat the underlying cause of CF in a number of ways. These include increasing the amount of working CFTR protein in the cell, understanding more about lung clearance and inflammation to improve treatments, developing genetic therapies to produce healthy copies of CFTR and boosting the function of proteins that work in a similar way to CFTR.

Research into keeping the CF lungs healthier

Two biological processes contribute to the lung symptoms that people with CF experience. One is the presence of thick, sticky mucus that is difficult to clear, and the other is the presence of excessive lung inflammation. Better ways to treat these symptoms are needed. In order to do this, more needs to be understood about how and why they happen.

Thick, sticky mucus makes it more difficult for people with CF to breathe and harder for them to clear infections. Professor Pietro Cicuta at the University of Cambridge is leading a Strategic Research Centre to develop state-of-the-art methods to measure and understand the biophysics of mucus clearance and to investigate whether the variations that everyone has in how mucus is cleared from their lungs could explain why individuals with CF, even with the same genotype, have a different experience of cystic fibrosis. In a complementary study we are co-funding a PhD studentship at UCL to apply computer modelling analysis to understand more about mucus clearance and how to improve it in cystic fibrosis.

Within the GI tract there are hundreds of species of bacteria that help the body to digest food. To stay healthy there needs to be a range of bacteria across these species. As soon as the balance of bacteria within the GI tract changes, the chemicals produced can trigger inflammation in the lungs. This balance of bacteria is altered in CF, and we’re funding a Strategic Research Centre led by Professor Daniel Peckham at the University of Leeds to understand more about why it is happening and whether changing things in the gut can lead to reduced inflammation in the lungs.Read more about research we’re funding on this topic, through our strategic research centre (SRC) and Venture and Innovation Award (VIA) funding schemes:

Understanding and correcting the CFTR protein

Drugs that modulate the function of the CF protein are known as CFTR modulators or precision medicines. To date, these have been developed to treat the genetic mutations found in around 90% of people with CF in the UK.

However, some people with the mutations treatable by CFTR modulators do not respond to the drugs, or they are not able to tolerate them. For the remaining 10% of people there are no treatments that address the underlying cause of cystic fibrosis.

Careful study of the shape, properties and function of the CFTR protein and how these are affected by CF mutations is underway in our F508del Strategic Research Centre led by Professor David Sheppard at the University of Bristol. This research may pave the way for more effective CFTR modulators, that work for a larger number of different CFTR mutations.

Investigating genetic treatments

The discovery of the CF gene over 30 years ago led to interest in the development of genetic therapies for cystic fibrosis. Initially the focus was on ‘gene therapy’ and more recently, with improvements in technology and knowledge, a related approach of ‘gene editing’ is being explored. The aim of a gene editing therapy is to get into the cell to fix the faulty CF gene permanently. Gene therapy, on the other hand, aims to deliver new copies of the healthy gene, leaving the existing faulty gene in place. Good progress is being made towards genetic-based treatments. While these are unlikely to be available as standard to people with CF for many years, when they become available, they could make a significant difference to everyone.

Methods of treating CF on a genetic level include gene therapy and gene editing. Gene editing is a relatively new technique that has become more feasible since the discovery of the gene editing tool ‘CRISPR/Cas9’. There are many things to be worked out before gene editing therapy will be feasible as a treatment for cystic fibrosis. Researchers in our gene editing methods Strategic Research Centre are studying the effects of gene editing in the lab, the best ways to edit the gene and how a gene editing treatment would be delivered to the body. Building on these foundations we've recently announced funding for a Strategic Research Centre on therapeutic gene editing. This SRC is co-funded by the Trust and the CF Foundation in the United States.

Rather than developing a method to correct each specific CF mutation (there are over 1,700 of them!), Professor Patrick Harrison and colleagues are working on a method of gene editing that could work for people with a number of different genotypes, a project we are co-funding through a Venture and Innovation Award.

Gene-based therapies work by manipulating the process that makes proteins from genes. Gene editing changes the DNA itself. To make the logistics of delivering a therapy easier, Professor Stephen Hart is looking to correct the CF gene at a later stage in the protein-making process, by altering a chemical called mRNA. We are co-funding this research through a Venture and Innovation Award with Action Medical Research.

Read more about research we’re funding on this topic, through our strategic research centre (SRC) and Venture and Innovation Award (VIA) funding schemes:

Developing treatments for everyone

Dr Mike Gray and colleagues have taken a different approach to developing treatments suitable for everyone with cystic fibrosis. Rather than repairing the CFTR gene or protein itself, research is underway to see if alternative proteins can be either activated or blocked to compensate for the lack of working CFTR. In a Trust-funded Strategic Research Centre they are looking for drugs that act on ‘alternative chloride channels’ and are investigating how these channels might work.

CFTR modulators and drugs that act on alternative proteins in people with CF work by correcting or compensating for the function of the CFTR protein throughout the body. Unfortunately, these drugs are not able to repair any damage that has already been caused in the lungs. In light of this, researchers at the UK CF Innovation Hub based at Cambridge University are in the early laboratory stages of developing therapies that may be able to repair this lung damage. We are also co-funding Dr Robert Gray and colleagues at the University of Edinburgh , who are investigating whether cells in the lungs can be activated to repair this damage.

Read more about research we’re funding on this topic, through our Innovation Hub and strategic research centre (SRC) and Venture and Innovation Award (VIA) funding schemes.

Research we fund

We fund research to tackle some of the most pressing issues in CF today. Find out how your donations are making a difference.

What is CF?

Cystic fibrosis, or CF, affects the lungs, digestive system and other organs, and there are over 10,600 people living with it in the UK.

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