DMD research

Helping muscle regeneration with repurposed medicines


  • Duchenne UK is awarding a grant of £199,245 to the University of Geneva to investigate the potential of repurposed compounds to regenerate muscle and prevent fibrosis.
  • We are testing a range of compounds including anti-fibrotics, anti-oxidants and repurposed medicines such as montelukast and tamoxifen.

This project will test whether a combination of approved medicines can reduce fibrosis, improve muscle function and regenerate muscle in people with Duchenne Muscular Dystrophy (DMD).

When you have DMD, your muscles weaken because you cannot produce dystrophin to protect them. Muscle fibres then become inflamed and die and are replaced with fat and scar tissue – this is called fibrosis.

If fibrosis can be prevented, it might be possible to encourage muscles to regenerate.

The scientists will be working on repurposed medicines which have already been approved for use and tested on humans. Using them, rather than creating new compounds, drastically reduces the time it takes to get medicines into the clinic and patients.

The project will start by looking at the drug Pirfenidone. This is an antifibrotic and anti-inflammatory medication used as a treatment for idiopathic pulmonary fibrosis.

Then researchers will investigate a selection of dietary supplements and drugs that have either been approved for human use or are in the clinical trial stage for DMD. These include anti-oxidants, such as green tea polyphenol. They will look at the drug Montelukast, which is currently used to treat asthma patients who do not respond to steroids. They will also investigate the anti-fibrotic properties of the breast cancer drug Tamoxifen (Tamoxifen is currently in the clinical trial stage in the UK to establish its efficacy in the protection of muscle fibres).

The final stage of the project will build on the results of the previous stages – looking further at the best two anti-fibrotic drugs which have been identified. It will involve AAVs – a harmless viral vector used to deliver drugs in gene therapy. The project will consider whether the drugs identified can improve how to direct AAVs to muscle cells in the limbs, diaphragm and heart. For more information on AAVs and gene therapy, click here. This final stage will depend on the results of the first stages.

Duchenne UK is very excited to be working with the University of Geneva once again. Its researchers have extensive experience in assessing potential drugs in DMD mouse models. Recently, the findings from their studies have resulted in clinical trials for green tea polyphenols, Rimeporide and Tamoxifen. They have chosen to follow a ‘drug repurposing’ approach, to ensure a quick translation of their findings into effective treatments. We are very excited to be working with them again.

Emily Crossley & Alex Johnson, co-founders of Duchenne UK, said:

“The work that the University of Geneva did on the potential benefits of Tamoxifen as a treatment for DMD has resulted in a clinical trial which is now ongoing. Duchenne UK is co-funding this trial and has committed £1.6million. We are very pleased to be partnering with them again on this important project to accelerate potential treatments for patients with DMD.”

Leonardo Scapozza, Professor, Department of Pharmaceutical Biochemistry, University of Geneva said:

“I have a team of 22 scientists committed to develop new therapeutic strategies. This collaboration with Duchenne UK is a great opportunity for us to push the boundary of research in the field of pharmacotherapy of DMD and to strength our commitment towards bringing drugs to patients suffering from diseases with unmet medical needs.”

We would like to thank our partner charities and family funds for supporting this project: Joining Jack, Chasing Connor’s Cure, Help Harry, Hope for Harry, Smile with Shiv, Action for Arvin and Archie's March.

Q&A with Dr Olivier Dorchies at the University of Geneva 

What is fibrosis?

In most tissues of our body, such as the liver, the kidney, and muscles, the cells are held together via sheets of connective tissue that shape the organs and help ensuring normal functions. The connective tissue is made of fibroblasts and the extracellular matrix that the fibroblasts produce.

Fibrosis is a pathological accumulation of connective tissue resulting from activation of fibroblast, which under certain conditions, proliferate and produce excessive amounts of extracellular matrix, of which collagen is a major component.

Why is this a problem for boys with DMD?

In boys with DMD, chronic oxidative stress and inflammation cause muscle fibrosis, which progressively replaces myofibres. Fibrosis also increases muscles stiffness, which makes contraction of the remaining fibres less efficient. Some DMD boys have inherited from their parents a modified version of the LTBP4 gene, a genetic modifier associated with enhanced fibrosis and a more rapid disease progression. In conclusion, fibrosis is a major complication for all DMD boys and in particular for those bearing a defective LTBP4 gene.

Fibrosis is a major complication in Duchenne Muscular Dystrophy (DMD), because of its effect on different types of muscle cells all over the body. In the limbs, it reduces the ability for the muscle to contract, whilst in the heart, it disturbs the electrical conduction, which allows it to beat regularly and pump blood through the body. Further to this, it also can restrict the diffusion of drugs and viruses, reducing their uptake by the cells, which is particularly problematic for the administering of AAV in some gene therapy. As such, it can greatly reduce the effectiveness of a wide range of treatments for DMD

What drugs have you selected to test and why?

We will determine the anti-fibrotic efficacy of a number of drugs in dystrophic mice presenting with enhanced fibrosis due to a mutation similar to the one in LTBP4 in DMD boys. We have selected pirfenidone and halofuginone, two drugs that are known to be anti-fibrotic via targeting fibroblast growth and function directly. Preliminary experiments by others suggested that pirfenidone is beneficial to dystrophic mice. We will give pirfenidone a second chance using state-of-the-art methods in strictly controlled preclinical settings.

In order to test the effectiveness of pirfidenone, we will use another anti-fibrotic drug Halofuginone, developed by Akashi Therapeutics, to be the control arm. Halofuginone was in clinical trial for DMD. It was stopped after the unexpected death of one patient. We are using it in this study solely to be the control arm so that we can have something to compare Pirfidenone with. We are not testing Halofuginone to develop it as a treatment for DMD.

Are there any other drugs you are investigating?

In DMD, fibrosis is thought to be primarily the consequence of chronic oxidative stress and inflammation. Thus, we have selected promising antioxidants and anti-inflammatory drugs among which EGCG, a powerful antioxidant polyphenol from green tea; tamoxifen, a modulator of estrogen receptor that recently reached clinical trials for DMD; Montelukast, an anti-inflammatory drug used to treat asthma; and statins, a class of lipid-lowering drugs that also reduce oxidative stress. These drugs will be compared to prednisolone, a steroid that is the gold standard for DMD treatment.

If this project is successful, what will the next steps be? 

The project will allow us to determine whether the drugs prevent or even reverse fibrosis in mice. The next steps, in mice, will address (i) the anti-fibrotic efficacy of combination of the most promising drugs, and (ii) whether anti-fibrotic treatments enhance targeting of therapeutic AAVs to muscles as a step towards optimizing AAV-driven restoration of microdystrophin.

All the drugs that we have selected are available at low cost. Moreover, they are already approved for Human use or are in clinical trial for DMD with focus on readouts other than fibrosis. Recently, pirfenidone has been approved for treating pulmonary fibrosis. Should these drugs be efficacious in dystrophic mice, they may benefit to DMD patients swiftly.

Why are you looking at these compounds in mice when one (tamoxifen) is already being looked at in a clinical trial?

When muscle fibres die in DMD they cause inflammation in the muscle, and this in turn can cause fibrosis – the buildup of tough fibrous material which hinders good muscle function. Tamoxifen is an anti-inflammatory drug and we are testing it in boys to see if it can help reduce inflammation - and therefore reduce fibrosis and improve muscle function - without some of the damaging side effects we see with the use of steroids. We will test tamoxifen plus one similar drug and a dietary supplement in this study.

But there are other mechanisms which may lead to buildup of fibrosis. One of these is called ‘oxidative stress’ – it’s caused by unused oxygen breaking down into single oxygen atoms (you may have heard them called ‘free radicals’). These are very reactive and can damage muscle fibres leading to fibrosis. If we could reduce the number of free radicals, then we could reduce fibrosis, improve muscle function and perhaps allow muscle to regenerate if caught early enough. In this study we will also test three known drugs which reduce free radicals to see if they improve muscle function. 

In addition, some drugs can fight fibrosis directly, for example by attacking the cells (called fibroblasts) that initiate the process of producing the fibrosis. One such drug is pirfenidone(marketed by Roche as Esbriet®). This is currently used in Europe to treat fibrosis in the lung. As a positive control (i.e. just to demonstrate that the model is working properly) we will use Halofuginone. You may well have heard of the sad death of a boy on a trial with Halofuginone and we wish to assure you that this is only being used to allow us to compare accurately with our ‘test’ drug, pirfenidone.

All of the above will be compared to the well-known and much-used prednisolone, and we will do all this in a new mouse model which is better at mimicking the human disease.

If you have any further questions, do email [email protected]

This project is part of our DMD INSPIRE Major Grant Call. Find out more here:Duchenne UK invests £1,25 million into new research of treatments for DMD


What is Duchenne Muscular Dystrophy?

Duchenne muscular dystrophy (DMD) is the most common fatal genetic disease diagnosed in childhood. Children born with DMD cannot produce the protein dystrophin which is vital for muscle strength and function. Muscle weakness starts in early childhood. Many use a wheelchair by around the age of 12. As deterioration continues it leads to paralysis and early death, often in their 20s. It almost exclusively affects boys. There is no treatment or cure. In the UK there are around 2,500 boys affected and around 300, 000 worldwide. It is classified as a rare disease.

Who are Duchenne UK?

Duchenne UK is a lean, ambitious and highly focused charity with a clear vision: to fund and accelerate treatments and a cure for Duchenne muscular dystrophy.

We are investing millions of pounds in research right now to bring treatments and a cure to help this generation. Duchenne UK is the largest funder of DMD research in the UK. We are also committed to accelerating the pace of research. 90p in every £1 raised is committed to research.

Our president is HRH The Duchess of Cornwall. Our patrons include the broadcasters Krishnan Guru-Murthy and Mary Nightingale, and the sports stars Owen Farrell, Kris Radlinski and Andy Farrell. 

We need your help, because we need to keep funding promising new research.

How to donate?

Duchenne UK is entirely reliant on donations to fund research for treatments and a cure to DMD. This can be done via:

  • Direct Debit – Duchenne Direct
  • Individual Donation – Donate
  • If you are a family or friend affected by DMD you can set up your own fund with Duchenne UK – Family and Friend Funds
  • Take part in one of our fundraising events – Events
  • Text DUCHENNE to 70085 to donate £5. This costs £5 plus a std rate msg.

For more information and interview requests:

Visit www.duchenneuk.org

Molly Hunt – Head of Communications, Duchenne UK E: [email protected]

Published on 8 September 2019

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