Duchenne UK is granting £82,405 to Dr Lee Borthwick and Professor Derek Mann at Newcastle University to develop a new test of potential medicines to treat fibrosis in DMD.

Fibrosis research in DMD is most commonly focused on skeletal muscle, but this study will focus on cardiac tissue. As DMD progresses and fibrosis of the heart develops, cardiomyopathy, conduction-defects (heart rhythm disturbance) and tachyarrhythmias (faster heart rate) may develop.

At the moment there are no anti-fibrotic therapies approved for the treatment of DMD. There is an urgent unmet need to better understand cardiac fibrosis in DMD, to enable the development of new therapeutic targets and compounds. 

The study will specifically look at the possibility of developing Precision Cut Slices (PCS) of human cardiac tissue. Such slices would be structurally and physiologically representative of normal human tissue. Current models have only been developed for ‘soft’ tissues such as liver and lung.

Duchenne UK’s Research Director Dr David Bull said: “Drug development is traditionally a long and expensive process. Currently, the probability of a drug progressing from Phase I to approval is less than 10%, despite large investments in drug development. The more effort we put in to improving the quality and depth of pre-clinical research, the greater the chance of accurately predicting the safety and efficacy of new treatments in the clinic. Many such pre-clinical studies are, necessarily, still carried out in animal models or in human cell cultures. The more representative the test system is of the human disease/condition the greater the probability of a drug progressing successfully through early clinical trials.“ 

Emily Crossley, Co-CEO of Duchenne UK said: “Duchenne UK is funding this study because we need better and more reliable tissue to give more accurate results from preclinical research. We want to support the development of more reliable and reflective tissue test systems. Such systems may improve the quality of data coming from preclinical research. Data on compounds tested in test systems comprised of functional, disease-mimicking tissues are more likely to be effective in early clinic trials.”

Professor Derek Mann, Professor of Hepatology and Dean of Research in the Faculty of Medical Sciences at Newcastle University said: “I am honoured and delighted that Duchenne UK have chosen to partner with the Newcastle Fibrosis Research Group to develop pre-clinical models of cardiac fibrosis. I am confident that our expertise with modelling fibrosis in precision cut tissue slices and their application for anti-fibrosis drug discovery will help advance the mission of Duchenne UK towards improving the lives of boys affected by Duchenne muscular dystrophy”.

  • This study aims to develop a technique using human cardiac tissue which, if successful, could provide us with a better way to test new (or repurposed) drugs which could treat fibrosis in DMD.
  • If development of such a system in cardiac tissue is successful it could potentially offer us a new, more representative, test bed for new drugs aimed at combatting fibrosis in DMD. Current in-vitro cell cultures, or in-vivo rodent models, are less reflective of the human disease state meaning it is less likely the same results in humans.
  • This could really enhance our understanding of the processes associated with fibrosis in DMD and improving research capacity nationally and beyond.

We are extremely pleased to be working with world leaders in the fibrosis field. Professor Derek Mann is Professor of Hepatology and Dean of Research in the Faculty of Medical Sciences at Newcastle University and founder of the Newcastle Fibrosis Research Group (NFRG). Dr Lee Borthwick is a lecturer at Newcastle University with expertise in inflammatory-fibrogenic signaling and has driven the development of the lung and liver PCS test systems.

The aims in this pilot study are to explore the feasibility of developing a human cardiac PCS platform for target identification and validation in Duchenne Muscular Dystrophy. The proposed study has four chronological aims:

  1. Determine the best practical aspects of acquiring tissues such that we can produce functional, viable precision cut slices.
  2. Establish the optimal extended culture conditions for human cardiac precision cut slices.
  3. Investigate human cardiac precision cut slices as a model of inflammation and fibrosis
  4. Test a range of known anti-inflammatory and anti-fibrotic compounds in the model

 

We would like to thank Joining Jack for contributing £10,000 to this project.

We have put together a short Q&A to explain why this project is so important and what it could bring to the Duchenne community. 

Q: Why is this project so important? 

A: There are currently no anti-fibrotic therapies approved specifically for the treatment of DMD. We need to understand better the fibrosis that occurs in the heart and skeletal muscle in people with DMD to allow us to discover therapeutic targets and develop therapies.  

Drug development is a long and expensive process. Many potential treatments fail at the clinical phase because they do not work in the same way in early clinical trials as predicted by pre-clinical research. Part of the reason for this is that most pre-clinical work is currently carried out using animal models of human disease. By investing in, and improving the relevance of, pre-clinical research we hope to increase the chance of accurately predicting how treatments will work in patients. By using test systems more representative of the human disease, for example using human tissue, we may reduce the likelihood of failure at the clinical stages.  

This project aims to investigate the possibility of creating slices of human cardiac tissue and maintaining their viability in vitro. Systems such as this have been developed for some tissues, such as the liver and lung, but not in heart tissue.  

Q: What will the outcomes of this project be? 

A: This pilot study aims to see if it is possible to develop a human cardiac precision cut slice (PCS) test system for target identification and validation in DMD. Put simply, we aim to see if it is possible to create thin slices of human cardiac tissue to use as a model system to test anti-fibrotic and anti-inflammatory drugs for DMD. The project has 3 main aims: 

  • Determine the optimal conditions to maintain the viability of the slices.  
  • Investigate how we can use the cardiac slices to model the inflammation and fibrosis seen in DMD. 
  • Finally, test a range of known anti-inflammatory and anti-fibrotic drugs to determine the potential value of the model as a test system. 

Q: How will this project benefit the Duchenne community? 

A: The overall aim of this project is to create a model which mimics the cardiac tissues in people with DMD with the specific aim of testing anti-fibrotics in futureUsing this system to test potential new treatments in pre-clinical research should provide us with more relevant results than using animal models of the disease. Compounds tested in functional disease-mimicking tissues is more likely to be effective in early clinical trials.  This should improve the landscape of anti-fibrotic drug discovery and help improve the lives of boys affect by Duchenne muscular dystrophy

Please GET IN TOUCH with any questions.

 

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NOTES FOR EDITORS

 

What is Duchenne Muscular Dystrophy? 

Duchenne Muscular Dystrophy 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. The charity has been formed by the coming together of Joining Jack and Duchenne Children's Trust, the two biggest funders of research in the UK in the last three years. Its president is HRH The Duchess of Cornwall. Its patrons include the broadcasters Krishnan Guru-Murthy and Mary Nightingale, and the sports stars Owen Farrell, Kris Radlinski and Andy Farrell. 

 

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 DUCH10 £10 to 70070

 

For more information and interview requests: 

Visit www.duchenneuk.org

Molly Hunt – Communications Manager, Duchenne UK

E: [email protected]