What are the researchers aiming to do?
Duchenne muscular dystrophy is caused by a mutation in the dystrophin gene, which leads to a lack of the essential muscle protein, dystrophin. Dystrophin acts as a shock absorber in skeletal muscles and prevents muscles from getting damaged during contractions. Dystrophin is also normally found in heart muscle and its absence leads to cardiomyopathy, or chronic heart muscle disease.
Molecular patches are currently in clinical trial for Duchenne muscular dystrophy. They effectively ‘mask’ the mutation in the dystrophin gene, allowing the cell to ‘read’ the gene properly and produce a shorter but still functional version of the dystrophin protein. However there have been problems associated with the delivery of molecular patches to the body, especially to the heart and diaphragm.
Professor Wood and his team have developed molecular patches that are linked to a short protein fragment called a peptide. These peptides help the molecular patches to penetrate cells and so improve delivery of the molecular patches to target organs. Professor Wood and his team have recently shown that the peptide-linked molecular patches they have developed are very effective at restoring dystrophin levels in the heart of mouse models of Duchenne muscular dystrophy and are also capable of stabilising heart function. One of the aims of this new project is to gain a better understanding of the peptide-linked molecular patches and learn what other improvements they have on the heart. For example, the researchers will assess whether peptide-linked molecular patches are able to restore normal metabolism, which is very important to the health of the heart.
It is not known whether these peptide-linked molecular patches will be efficient in the hearts of people with Duchenne muscular dystrophy as they have only been tested in mouse models. Therefore, another aim of this project is to study the effectiveness of peptide-linked molecular patches in human heart muscle cells that have been grown in the laboratory from induced pluripotent stem (iPS) cells originating from people with Duchenne muscular dystrophy.
Finally, the heart has a very limited ability to repair itself. As Duchenne muscular dystrophy progresses, the heart deteriorates but no one knows how well it can repair itself. Therefore this project aims to understand more about the repair capacity of dystrophic hearts. The researchers will do this by studying hearts from mouse models of Duchenne muscular dystrophy and comparing them with the hearts of healthy mice. Once the researchers understand more about the process of repair in dystrophic hearts, they can then investigate ways to help improve this. For example, they will test whether restoring dystrophin levels using the peptide-linked molecular patches can help to increase the repair capacity of dystrophic mouse hearts.
How will the outcomes of the research benefit patients?
Following the evaluation of peptide-linked molecular patches on heart cells grown in the laboratory, the team is planning a clinical trial in 2017/18 to test them in people with Duchenne muscular dystrophy. If the peptide-linked molecular patches prove to be effective, they could prevent deterioration of the heart or even restore heart function in people with Duchenne muscular dystrophy. With cardiomyopathy being a major contributor to death in people with Duchenne muscular dystrophy, tackling this aspect of the condition will offer invaluable benefits.
Project leader: Professor Matthew Wood
Location: University of Oxford
Conditions: Duchenne muscular dystrophy
Duration: three years, starting 2016
Total project cost: £180,000
Official title: Peptide-PMO treatment to prevent cardiomyopathy in Duchenne muscular dystrophy (DMD): efficacy in DMD patients and effects on cardiac metabolism and regeneration.
Find out more about other Duchenne muscular dystrophy research we are funding
Find out more about the MDUK Oxford Neuromuscular Centre
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