Karen Menzies PTSuppress SRC – Novel lead compounds as potential suppressor drugs for CFTR Premature Termination Codon (PTC) variants

The combination therapy for stop variants would work by designing new medicines to act on two parts of the process for making new proteins, and then use CFTR modulator medicines to do the rest. To go into more detail, we need to explain how a protein is made.

To make a protein a number of steps are involved. Very briefly, our DNA is read to make a protein-making template (known as messenger RNA or mRNA). The template is then used to assemble the protein. A number of quality control checks are in place, to prevent faulty proteins being assembled. As a final step, the protein is folded and secured into its correct 3D shape.

For people with stop variants, a fault is introduced into the protein-making template that stops the assembly of CF protein mid-way through the process. This means that a shorter than normal CF protein is made, that doesn’t work. However, a quality control check destroys most copies of the protein-making template with ‘stop’ errors, preventing lots of shorter than normal proteins from being made.

Researchers in the lab are investigating a complex combined therapy approach to treat people with CF with stop variants. They hope to find:

• A new medicine to block the activity of the quality control checks, so more protein-making templates are made.
• A new medicine to ‘overrule’ the stop signal in the protein-making template, allowing full length copies of the CF protein to be made.
• A further benefit by adding existing CFTR modulator medicines such as Kaftrio to make this approach more effective as a possible new treatment approach.

(Researchers will also look for one potential medicine that could both block the quality control and overrule/read through the stop signal).

The research programme is organised into five work packages (WP). 

Work packages 1 and 2 are to find the new medicines to block the quality control of CF protein production, and to overrule the stop signal that causes a short version of the protein to be made. 

Work packages 3-5 are to do early tests on combination therapies, by putting together not only novel chemicals from WP1 and 2, but also by combining these with currently approved CFTR modulator medicines.

WP1. Designing and testing new medicines from scratch

The researchers in Lisbon will improve the chemistry of 10 potential medicines they have designed previously. After each adjustment to the chemical design, new versions of the medicines will be tested for effectiveness using novel methods that have been developed.

WP2. Testing if existing medicines work in new ways (known as re-purposing)

To find more options for the combination therapy, researchers in Utrecht will do initial tests (known as screening) on over 1,400 approved medicines held in storage in a chemical library. (It is possible that existing medicines designed for other conditions could have properties that are helpful for treating CF too). 

Any promising medicines from this screening will be tested in mini-guts or mini-lung ‘organoids’ in the lab, created from biopsy samples donated from people with CF who have stop variants.

WP3. Working out the best combination of medicines to try

From the results of WP1 and WP2, the most effective chemicals for blocking the quality control and/or overruling the stop signals will be tested alongside current CFTR modulator medicines to see which combination of medicines works the best. Several different ways of testing the effects of each combination will be used. 

WP4. Would a combination therapy work for all CF stop variants?

There are over 200 different types of stop variants in the CFTR gene known so far, depending on where the stop signal is found in the gene. Some stop variants are found in hundreds of people with CF in the UK, and some are found in less than five people. Researchers in Newcastle will study the effects of combinations therapies on different stop variants. 

WP5. Testing the effects of combination therapy on lung cells in the lab 

If the combination therapy for the rescue of CF stop variants works, then they should improve lung cell health. Researchers will test the effects of combination therapy on the health of respiratory cells from people with CF grown in the lab. They will check that the rescued CF protein works correctly in these cells, and that the liquid on the surface of the lungs is properly hydrated and has a correct acid-alkali balance (important for reducing infections).

Principal investigator

Dr Mike Gray, Newcastle University

Co-investigators

Prof Margarida Amaral, University of Lisbon

Prof Jeffrey Beekman, Utrecht University

Dr Nicoletta Pedemonte, IRCCS Instituto G Gaslini

Dr Luka Clarke, University of Lisbon

Dr Cristina Moiteiro, University of Lisbon

Dr Malcolm Brodlie, Newcastle University

Dr Iram Haq, Newcastle University

Dr Valeria Capurro, IRCCS Instituto G Gaslini

Dr Valeria Tomati, IRCCS Instituto G Gaslini 

Dr Gimano Amatngalim, Utrecht University

Dr Vasco Cachatra, University of Lisbon