‘Noisy whispers’ – how rare, brief openings of the CF protein could improve the design of new medicines

Cystic fibrosis is caused by the absence of, or faults in, the CF transmembrane conductance regulator (CFTR) protein (shortened here to the ‘CF protein’). James Charlick, based at the University of Bristol, will use his Early Career Research Development Award to explore the implications of new insights into how the CF protein works at a microscopic level. Understanding tiny details about faults in this protein can help researchers design more effective medicines for CF and make them available to a wider group of people.

Measuring CF protein activity and why it is important

The CF protein forms a gated pathway, like a ticket-barrier, that allows chloride and bicarbonate to flow in many organs. Inherited defects in the CF gene cause faults in the CF protein, which can vary between different people with CF. 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 is measured as microscopic electric currents. In earlier research on the most common cause of CF, caused by the F508del variant in the CF protein, 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.

James Charlick and his colleagues will carry out four workstreams to achieve this goal as outlined below.

  • 1. To improve the quality of measurement of the partial openings of the CF protein

    James will make improvements to how the studies are conducted using state-of-the-art equipment. This will increase the amount of information gained about these microscopic electric currents.

  • 2. Understanding more about why partial openings occur

    To understand more about why partial openings of the CF protein occur, James will study the electrical activity of the CF protein in different ways. He will study different CF defects on their own and in the presence of CF modulator medicines. For example, different combinations of the individual medicines that make up Kaftrio and Alyftrek. These studies will be performed with cells that can be easily grown in the lab.

  • 3. Studying the changing shape of the CF protein

    To develop medicines that target partial openings of the CF protein, it is important to understand the shapes and movements of the protein that cause the gated pathway to only open partially. With collaborators at the University of Bristol, James will use cutting-edge computational techniques to develop models of the CF protein, which will help address this aim of the project.

    All proteins are made up of small building blocks called amino acids, that are folded into a specific three-dimensional shape to allow them to work. When stimulated, the CF protein changes its shape so that its gated pathway opens and closes. Defects in the CF gene can harm this process in ways that cause the gated pathway to only open or close part way. 

    To address this issue, James will make computer models of modulator medicines docked with the CF protein. This information will help James and colleagues understand more about the specific faults caused by CF defects, and how these faults might be targeted with new medicines.

  • 4. Studying the CF protein activity in cells from people with CF

    The studies undertaken in the previous aims of this project will use lab-grown cells. In this aim, James will perform similar experiments in cells generously donated by people with CF.  These experiments will be challenging, but any results have the potential to help bridge the gap between precisely controlled lab-based experiments and complex clinical observations.  

    The improved understanding of rare and hard to treat CF protein variants, produced by this work, will help develop more effective therapies for people with CF who can’t benefit from current medicines.

Who is involved?

Principal investigator: James Charlick, University of Bristol

Co-investigators

Professor David Sheppard, University of Bristol
Dr Sofia Oliveira, University of Bristol