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Cystic Fibrosis Trust

Novel nonsense mediated decay inhibitor for restoration of CFTR function

Investigation of the efficacy of a novel nonsense-mediated decay inhibitor in combination with a translational bypass therapeutic, for restoration of CFTR function.
Senior scientific officer Dr Richard Beniston using the University of Sheffield's state of the art OrbiTrap mass spectrometer.
  • New treatment approach to correct underlying defect in Class I mutations
  • New compound targeting the cell's in-built quality control system
  • Potential to boost the effect of Ataluren when given in combination

Our research strategy includes a commitment to backing transformational science to correct the basic defect in cystic fibrosis. This grant has been awarded to Professor Carl Smythe of the University of Sheffield to fund early stage work to address the underlying genetic defect in Class I mutations.

Also known as 'stop' or ‘nonsense' mutations, Class I mutations account for approximately 10% of the world's cystic fibrosis population.

To make a protein like CFTR (which is faulty in people with cystic fibrosis) the cell makes copies of the gene from the DNA. It sends these to a special 'cellular factory' called the ribosome, where it is read like a set of instructions to produce the protein. In the nonsense mutation a 'full stop' appears in the middle of the DNA instructions and it is reproduced in the copy, which prevents the instructions being read all the way through.
A quality control system called Nonsense Mediated Decay (NMD) detects this full stop and destroys most of the defective copies.

As a result, very few sets of instructions for the protein ever make it to the 'factory', and those which do make it through can't be used because the full stop means the 'factory' stops following the instructions at that point.
Professor Smythe is working on a new compound to partially block the quality control system from catching and destroying the defective copies, so that more reach the 'factory'.

An oral drug called Ataluren is currently being developed by PTC Therapeutics to treat people who have nonsense mutations. The drug works at the 'factory' level, ignoring the full stop so that the full set of instructions is followed and the complete CFTR protein is made. However, it is thought the drug is not as effective as it could be because so much of the defective ‘copy’ with the instructions has already been destroyed earlier in the process by the quality control system.

This grant aims to demonstrate that the new compound allows more of the defective copy to escape the quality control system, so that more sets of instructions for the CFTR protein can be read when Ataluren helps the process in the 'factory'.

Professor Carl Smythe said: "We are delighted the Cystic Fibrosis Trust has provided this opportunity for us to investigate the efficacy of our novel compound targeting cells' in-built quality control systems to facilitate the action of Ataluren. We are extremely grateful to the many donors who have made this opportunity possible."

Professor Smythe is a leading expert in cell biology with a particular focus on intra-cellular surveillance and quality control systems. He normally works in areas related to cancer and this is the first time he has applied his expertise and pioneering techniques to cystic fibrosis.

The Trust is pleased to support this world-class project because it pioneers a new approach to restoring working CFTR in cells with this kind of mutation and, if successful, it will set a clear path for developing a new treatment. The grant reflects our ambition to attract top-class scientists from other disciplines into cystic fibrosis research to facilitate a broader range of novel and creative approaches.

* Image above shows senior scientific officer Dr Richard Beniston using the University of Sheffield's state of the art OrbiTrap mass spectrometer. The team aims to use their mass spectrometer to investigate their compound's effect on the production of complete CFTR protein.

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