Looking at microdystrophin in the heart

Dr Federica Montanaro, at the UCL Great Ormond Street Institute of Child Health, is leading an important piece of research into heart disease in Duchenne and Becker muscular dystrophy.

Muscular Dystrophy UK is funding this research, looking into how dystrophin works in the heart and how it works differently in Becker and Duchenne muscular dystrophies.

Dystrophin is a protein that normally sits in the membrane that surrounds muscle fibres – like a skin – and protects the membrane from damage during muscle contraction. Without dystrophin, the muscle fibre membranes become damaged and eventually the muscle fibres die. Dystrophin is missing in people who have Duchenne muscular dystrophy and reduced in those who have Becker muscular dystrophy.

Replacing dystrophin is the goal of gene therapies for Duchenne. However, the dystrophin gene is extremely large and cannot fit into the delivery viruses currently used in gene therapy. For this reason, researchers have created shortened versions of the dystrophin gene, called microdystrophins, which seem to work well in skeletal muscle but may not fully protect the heart. No-one really knows which parts of the gene are essential to include in these microdystrophins so they can function optimally in the heart.

Ultimately, thanks to the work of researchers like Dr Montanaro, there could be improved gene therapy products that fully address the heart problems experienced by people with Duchenne and Becker muscular dystrophies.

Dr Montanaro’s team is using microdystrophin as a tool to understand the triggers of heart disease in Duchenne and Becker muscular dystrophies.

In their work this year, they have characterised a heart cell line that we can grow in the lab. A cell line is developed from a single cell – in this case from the heart – that can divide to make more cells that are copies of one another. This great tool can be modified to look at many different features of cell biology.

Dr Montanaro’s team has started modifying their heart cell line to identify new microdystrophins that work better in the heart. Specifically, they are looking for microdystrophins that can join with two proteins important for heart function, called cavin-1 and cavin-4.

The team has also improved methods to measure the behaviour of molecules that might be linked to the disrupted connection between dystrophin and cavin-4 in the heart.

With these two tools now optimised, Dr Montanaro and her team are proceeding to screen microdystrophins and test their ability to correct the problems associated with heart disease in the laboratory.

Once Dr Montanaro has identified microdystrophins that could protect the heart, she and her team will work with animal models to see if the microdystrophins really do protect the heart.

This research is still a long way from studies in patients, but it is an important part of the pathway in developing optimised treatments for people with Duchenne and Becker muscular dystrophies.

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