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

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. Utrophin is produced in small amounts in adult muscle cells and is similar to dystrophin in structure and function. Evidence suggests that utrophin can compensate for the lack of dystrophin in amouse model of Duchenne muscular dystrophy; with muscle function being nearly as good as in healthy mice.

Professor Russell has been working with Professor Kay Davies (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; this 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.

Although SMT C1100 has been tested in clinical trials, the precise mechanism by which it increases levels of utrophin are not fully understood. The aim of this project is to investigate the molecular mechanism of action of the most promising new lead compounds. This will be done by:

1. Studying the relationship between the structure and activity of promising new molecules that have been identified in the new, more sensitive drug screens
2. Identifying the targets of the new molecules in cells; the molecular mechanisms and pathways in cells that are affected by the new molecules will be investigated using biological and chemical methods.

Findings from the study will help the researchers develop drugs that increase levels of utrophin protein in muscle, which could halt or improve the muscle wasting in boys and men with Duchenne and/or Becker muscular dystrophies.

How will the outcomes of the research benefit patients?

This research will show how drugs that increase utrophin protein levels in muscles are working at a biological level. Understanding the mechanisms of action of these potentially therapeutic molecules will be immensely useful for the development of more drugs that act in a similar way. It may also help with the identification of molecules that can be used to monitor the progression of Duchenne muscular dystrophy (biomarkers). Importantly, this therapeutic approach is applicable to all boys with Duchenne muscular dystrophy, regardless of mutation. The approach could also treat people with Becker muscular dystrophy.

Speaking about being awarded the grant, Professor Russell said:

“This funding will allow us to unravel the mechanism of action of a promising series of compounds we have discovered that increase levels of a protein called utrophin which can stabilise the degeneration of muscle fibres in Duchenne muscular dystrophy. This is an immensely important step in our overall goal of finding a drug that increases levels of utrophin, which has a potential benefit for all people with Duchenne muscular dystrophy regardless of the type of mutation they have.”

Second year report (February 2016):

We have continued to develop new compounds with an improved ability to increase levels of utrophin protein in cells. These new compounds are structurally-related to the utrophin-modulating hits identified from our recent drug screen and have been optimised to improve their drug-like properties, such as solubility. The biological activity of the compounds is assessed in cell-based experiments designed to measure how much they activate utrophin gene expression. Throughout this project so far, over 150 different compounds have now been synthesised and tested, 25 of which were prepared by the student over the past 11 months.

We have also conducted structure activity relationship studies around the most promising hit compound, OX01914. These studies explored the key structural features that are essential or non-essential for modulating utrophin levels in cells from the mdx mouse model and from people withDuchenne muscular dystrophy. Additionally we have prepared ‘probe’ molecules, based on OX1914, which we will use to identify the specific proteins the molecule interacts with, therefore telling us the identity of the molecular target of the compounds. This will help us understand the mechanism through which it acts to increase utrophin levels, and will also allow us to make more potent molecules using computer based design methods.

Finally, we have continued to progress the UtroDMD Alliance (the partnership between Muscular Dystrophy UK, Muscular Dystrophy Association, Medical Research Council, University of Oxford and Summit Therapeutics) which represents a joint enterprise to bring focus, discipline and unparalleled domain expertise to the discovery and development of novel utrophin modulator therapies for the potential benefit of people with Duchenne muscular dystrophy.

Grant information