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Strategic Research Centre: Restoring airway function in CF using alternative chloride channels

Understanding more about alternative drug targets to CFTR to develop disease modifying treatments for cystic fibrosis.


Summary

The purpose of this programme of work is to understand whether proteins called ‘alternative chloride channels’ could do the job of CFTR when it is faulty in cystic fibrosis, and to look for drugs that can promote this. Drugs that act on the alternative chloride channels could work for everyone with CF, irrespective of their genotype.

Background

The most effective drugs to treat CF so far have been developed for common forms of cystic fibrosis. No drugs have been developed for people with CF who have rarer mutations (about 15% of people with the condition).

One of the functions of CFTR, the gene that is damaged in CF, is to allow the flow of chloride and bicarbonate from inside the cells to outside the cells, into the liquid that lines the surface of the lungs. In CF, chloride and bicarbonate cannot get through the CFTR channel, leading to thick, sticky, acidic mucus that bacteria thrive in and which is harder to clear. However, there are other channels that allow the passage of chloride and bicarbonate known as alternative chloride channels (ACCs).

Aims of the project

To compensate for the faulty CFTR gene, Dr Gray’s research is aiming to increase the activity of the ACCs by: ensuring more of the ACCs are present, understanding which cell types in the lining of the lungs have most ACCs and boosting the activity of the ACCs that are present.

The five main areas of this research will be:

  • To find and test drugs that increase how many alternative chloride channels are present on the surface of the cells. ACCs are proteins that sit on the boundary of the cell. Like all proteins they are made in specific compartments of the cell and then transported to where they need to be. One way to increase their activity is to make sure that more ACCs are correctly transported to the boundary of the cell where they work.
  • To develop lab methods to study the secretion and movement of mucus in CF, using samples from people with cystic fibrosis. Cell cultures known as ‘organoids’ will be created from cells donated from the nose or from the bronchioles of people with cystic fibrosis. The way that they’re grown will allow the researchers to study how mucus is secreted from the cells that line the lungs, and how it moves along their surface.
  • To generate a biorepository of airway epithelial material for future pre-clinical drug discovery. Different ways of collecting, storing or growing cells in the lab can all make a difference to the final results, particularly where they are donated from people with different CF genotypes. Creating a biorepository (collection) of cells will mean a greater consistency and reproducibility for studies within this SRC and in the future.
  • Ways to improve secretions by potential drugs. As soon as more is understood about how ACCs affect lung secretions in people with CF, the ways to improve them can be studied. The effects of drugs that act on each of two alternative chloride channels (TMEM16 and SLC269A) will be looked at. Researchers will also look to see the combined effects of ACC drugs with drugs that act on CFTR (precision medicines).
  • Looking at the ACC drugs in models that are more similar to the clinic. To understand more about whether any of the ACC drugs identified in this programme may be safe and beneficial in the clinic, the researchers will move from studying cells in lab dishes to using mouse models of CF generated in the previous SRC programme.

Who is involved?

Lead Principal investigator (PI): Dr Mike Gray (Newcastle University)

Co-PIs:

  • Dr Jeff Beekman, Utrecht, The Netherlands
  • Professor Karl Kunzelmann, Regensburg, Germany
  • Professor Margarida Amaral, Lisbon, Portugal
  • Dr Malcolm Brodlie, Newcastle University, UK
  • Dr Chris Ward, Newcastle University, UK
  • Professor Andre Falcao, Lisbon, Portugal

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