Developing small molecules to target Duchenne muscular dystrophy

Prof Dame Kay Davies

This research aims to find drugs with the potential to increase levels of a protein called utrophin. Utrophin is similar to dystrophin and found in small amounts in adult muscle. Increasing its levels might compensate for the lack of dystrophin seen in boys with Duchenne muscular dystrophy. Professor Dame Kay Davies and her colleagues have already developed one drug, SMT C1100, which is currently in clinical trials. In this project, she aims to identify follow-on compounds that can increase utrophin levels more effectively. This approach is particularly advantageous because it is applicable to all people with Duchenne or Becker muscular dystrophy, whatever their mutation.

This project is funded by the Duchenne forum – a collaboration established to accelerate progress in the search for treatments and eventually cures.

What are the researchers aiming to do?

Duchenne muscular dystrophy is caused by mutations in the dystrophin gene. This gene contains the instructions for making dystrophin protein which acts as a shock absorber to prevent damage when the muscle contracts. The lack of dystrophin in Duchenne muscular dystrophy means that muscle is damaged when it contracts and this leads to wasting of the muscle, with the muscle fibres gradually being replaced by fat and scar tissue.

One way to counteract the effects of dystrophin loss may be to increase the levels of a protein called utrophin in the muscles. Utrophin is found in small amounts in adult muscle and is similar to dystrophin in structure and function. Evidence suggests that utrophin can compensate for the lack of dystrophin in a mouse model of Duchenne muscular dystrophy; with muscle function being nearly as good as in healthy mice.

Professor Davies has been working with Professor Angela Russell (also from Oxford University) and her team to identify potential drugs that could increase levels of utrophin in the muscle and may be of therapeutic benefit. The team has developed one potential drug – called SMT C1100 which has completed a Phase I trial that demonstrated that the drug was safe and successfully reached the blood stream. Further trials will now be performed to test whether SMT C1100 can increase the levels of utrophin in the muscles of boys with Duchenne muscular dystrophy and whether this could improve muscle function.

However, follow-on compounds now need to be developed which are more effective than SMT C1100. With funding from the Muscular Dystrophy Campaign, Professor Davies and her colleagues have generated a new, more sensitive drug screen to search for potential therapeutic compounds. Using this screen, new compounds have been identified that increase levels of utrophin more than SMT C1100 in muscle cells grown in the lab.

The aim of this project is to use the screen to identify more potential therapeutic compounds. The compounds will be tested in a mouse model of Duchenne muscular dystrophy and successful candidates will be developed for clinical trials. Professor Davies will work in collaboration with Summit Plc and other pharmaceutical or biotechnology companies as required to take potential new drug(s) into clinical trials, similar to the drug development process that SMT C1100 is currently undergoing.

How will the outcomes of the research benefit patients?

The main outcome of this research project will be the identification of new chemical compounds which increase the levels of utrophin and prevent pathology in the muscles of a mouse model of Duchenne muscular dystrophy. These compounds will be developed for clinical trials, as has been done with SMT C1100. A strong advantage of this approach to therapy is that it is applicable to all people with Duchenne muscular dystrophy or Becker muscular dystrophy, whatever their mutation.

Professor Davies said:

This grant makes a big difference to us as it allows the continued screening of the cell line we developed with previous funding from the Muscular Dystrophy Campaign. This approach, which is being carried out in collaboration with Dr Angela Russell in the Chemistry department of Oxford University, will allow us to identify novel hits which increase utrophin levels which we can develop as drug leads.

Grant information

Project leader: Professor Dame Kay Davies
Location: University of Oxford
Conditions: Duchenne muscular dystrophy; Becker muscular dystrophy
Duration: Two years, starting 2013
Total project cost: £128,064
Official title: Development of Small Molecule Upregulators of Utrophin for the Treatment of Duchenne Muscular Dystrophy

Further information and links

Dowload a summary of this research project

Learn more about Duchenne muscular dystrophy and Becker muscular dystrophy

Read about other Duchenne muscular dystrophy research projects we are funding

Read the latest research news for Duchenne muscular dystrophy

 

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