Understanding heart failure in Duchenne and Becker and developing an improved gene therapy

Heart failure is a serious and common complication of Duchenne and Becker muscular dystrophy. In this project, Dr Federica Montanaro and her team at University College London (UCL) will gain a better understanding of how dystrophin is involved in heart function. This knowledge will inform the design of improved microdystrophins that can be used for gene therapy.

What are the aims of this research project?

The overall aim is to develop an improved gene therapy product that fully addresses the heart problems experienced by people with Duchenne and Becker muscular dystrophies. This research builds on results from an MDUK-funded PhD studentship supervised by Professor Jenny Morgan and Dr Federica Montanaro.

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 from heart disease. No one really knows which parts of the gene are essential to include in these microdystrophins for them to be able to function optimally in the heart.

Dr Montanaro and her team are aiming to address this knowledge gap by studying the bit of dystrophin that binds to a protein called cavin-1. Cavin-1 is important in controlling the contraction of heart muscle and disruption of its function is known to cause heart disease in mice and humans.

Why is this research important?

Preclinical studies suggest that current microdystrophin gene therapies are unable to preserve heart function although they do protect skeletal muscle function. Generating a microdystrophin that is functional in both of these tissues will be crucial for developing a fully effective gene therapy for Duchenne and Becker muscular dystrophy.

What will the researchers do?

The researchers will first identify the precise location in the dystrophin protein that facilitates binding to cavin-1. They will do this by testing several dystrophin genes containing different binding regions in heart cells grown in the laboratory.

A new microdystrophin containing this cavin-binding region will then be generated. This will be packaged into a virus and tested in cells grown in the laboratory and in a mouse model of Duchenne muscular dystrophy. The researchers will assess whether this microdystrophin binds to cavin-1 and whether this improves heart and limb function in the treated mice.

The researchers will also investigate whether binding of dystrophin to cavin-1 plays a role in regulating the contraction and relaxation of the heart. The researchers will test this hypothesis by measuring contraction in heart muscle cells and mice that have different forms of dystrophin (some that bind cavin-1 and some that do not).

How will the outcomes of this research benefit people with Duchenne or Becker muscular dystrophy?

This research will give us a better understanding of the essential elements of the dystrophin gene. This could lead to the development of new microdystrophin gene therapies that protect the heart in people with Duchenne muscular dystrophy and Becker muscular dystrophy.

In addition, the findings from this project will be useful for understanding the causes of severe heart disease in people with Becker muscular dystrophy. More knowledge of the cell signalling that underlies heart muscle contraction will also be useful for identifying potential heart drugs.

Grant information

Project leader: Dr Federica Montanaro
Institute: UCL Institute of Child Health
Condition(s): Duchenne and Becker muscular dystrophies
Duration: three years
Total cost: £225,000
Official title: Characterisation and disease relevance of a novel interaction between cardiac dystrophin and cavins

Further information

If you would like further details about this research project, please contact the MDUK Research Line on 02078034813 or email research@musculardystrophyuk.org

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