Generating a model of FSHD and testing a potential therapeutic approach

Peter Zammit

Professor Zammit and his team at King’s College London will generate a mouse model that will enable them to study the molecular mechanisms underlying facioscapulohumeral muscular dystrophy (FSHD). The team will also investigate whether small pieces of genetic material, called molecular patches, could be used to prevent production of the toxic DUX4 protein; a potential therapeutic approach. 

Professor Zammit and Dr Panamarova have generated a mouse model of FSHD that allows them to investigate the genetic switch that controls production of the toxic DUX4 protein. They found that the gene generating DUX4 is switched on in very few muscle fibres at any one time. This is similar to what has been observed in the muscle fibres of people with FSHD. Unfortunately this low gene activity limits the use of the mouse model in testing potential treatments. This is because it will be difficult to sensitively measure whether a potential treatment is having an effect on DUX4. Nevertheless, the mouse model is still helpful in giving researchers a better understanding of FSHD.

One way to potentially treat FSHD is to prevent the production of DUX4 protein by using molecular patches. The researchers tested different molecular patches in a human cell model and found that they varied in effectiveness. This indicates that the human cell model is a useful method to quickly and easily test new designs of synthetic molecular patches for FSHD.

Dr Panamarova has presented this work at two conferences. She won a Young Investigator prize at the 45th European Muscle Conference and a prize for her poster presentation at the UK Neuromuscular Translational Research Conference. Some of the work was also published in a scientific journal.

What are the researchers aiming to do in this project?

FSHD is most often caused by the deletion of a segment of DNA in a region called D4Z4. D4Z4 consists of a number of repeated units of DNA and in people with FSHD, the number of repeats in the D4Z4 region is less than in unaffected individuals. The deletion leads to the abnormal production of a protein called DUX4 from the last D4Z4 unit, that is toxic to muscle cells. However, the biological pathways that lead to the production of DUX4 and the molecular effects that cause the muscle cell death are not well understood.

Professor Zammit aims to address some of these questions by generating a mouse model that will allow an analysis of the genetic switch that turns DUX4 protein production on and off. Initially, the researchers will use the mouse model to investigate how, when, and in which cells DUX4 protein production is turned on. A better understanding of the biological pathways that lead to DUX4 production could help to identify targets for future therapeutics.

The mouse model will also be used to test a potential therapeutic approach that could prevent DUX4 protein being produced by the last D4Z4 unit. The researchers will test whether short pieces of genetic material called molecular patches are able to prevent protein production and explore the feasibility of developing this into a future therapeutic approach for people with FSHD.

How will the outcomes of the research benefit patients?

This project will generate a mouse model that will enable the molecular mechanisms underlying FSHD to be studied; this is an important step in better understanding the condition and providing researchers with a valuable tool for testing potential therapeutic strategies.

The work will also reveal whether molecular patches could be used as a potential therapy for FSHD. Useful information about their function will be acquired, such as their ability to prevent production of the toxic DUX4 protein and target different muscle groups in different states of repair. If the technique shows potential as a therapeutic approach, this information will be essential for further development of the molecular patches for FSHD. Indeed, molecular patches are currently being tested on patients with Duchenne muscular dystrophy, showing the feasibility of this approach for muscle-wasting conditions.

Grant information

Project leader: Professor Peter Zammit
Location: King’s College, London
Conditions: Facioscapulohumeral muscular dystrophy (FSHD)
Duration: three years, starting 2015
Total project cost: £174,271
Official title: Modeling FSHD as a platform for testing therapeutics

Further information and links

Download a summary of this research project

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