Developing genetic therapies for Duchenne muscular dystrophy

Dr Linda Popplewell has been awarded a prestigious five year Lectureship to build capacity in research for Duchenne muscular dystrophy. In this research programme which will include two PhD studentships, she aims to develop a unique and comprehensive genetic therapy for Duchenne muscular dystrophy that will address the mutation in the dystrophin gene, reduce fibrosis and encourage muscle growth. Her approach will be applicable to the majority of boys with the condition.

In the first year of this project Dr Popplewell and her team have made important progress towards the development of a combination treatment for Duchenne muscular dystrophy.

The four main achievements have been:

  • The development of novel molecular patches to block expression of a protein that prevents muscle growth. The aim is to allow dystrophic muscle to grow bigger and stronger.
  • The design of molecular patches to specifically block the expression of a protein that causes the scarring of skeletal muscle in Duchenne muscular dystrophy.
  • The design of molecular scissors to remove a region of the dystrophin gene where mutations commonly occur. This could allow the development of a therapy that could potentially benefit 85% of people with Duchenne muscular dystrophy.
  • The researchers have started to work with a major pharmaceutical partner to design and produce a type of protein, called an antibody. This antibody will block the activity of a specific protein involved in scarring of skeletal muscle in Duchenne muscular dystrophy

The PhD student has been trained in a number of laboratory techniques, writing of reports, presenting of results and has supervised undergraduate students. This work has been presented as two posters at the Ninth UK Translational Research Conference in Oxford (March 2016).

What is the researcher aiming to do?

This grant will allow Dr Popplewell to begin to establish her own research group by recruiting two PhD students for an ambitious research project. It is widely accepted in the scientific community that the most effective treatment for Duchenne muscular dystrophy will be a combination of different approaches. In this project, Dr Popplewell and her team will develop new techniques for tackling fibrosis, muscle-wasting and the underlying genetic cause of Duchenne muscular dystrophy.

To address the mutation in the dystrophin gene, Dr Popplewell will develop a cutting edge genome surgery technique to permanently remove the mutation from a person’s own DNA. This will involve using enzymes called nucleases that act like molecular scissors to cut the DNA and remove the part of the dystrophin gene where most mutations occur. By doing this, the genome editing approach would be beneficial for at least 85% of boys with Duchenne muscular dystrophy. After removal of this part of the gene, the cell will re-join the remaining ends to give a shorter gene and a shorter, but still functional dystrophin protein.

Dr Popplewell will also use molecular scissors and other techniques that involve turning genes on and off, to modulate fibrosis. She will also develop a similar way of promoting muscle growth by switching off a gene called myostatin. This gene contains the instructions for a protein that inhibits muscle growth; inhibiting the protein will allow more muscle growth.

The overarching goal and challenge of the project is to combine the therapies into one single treatment. This will be tested in a mouse model of Duchenne muscular dystrophy which has particularly high levels of fibrosis.

How will the outcomes of the research benefit patients?

This approach offers the benefit of targeting several aspects of muscle degeneration and dysfunction as well as permanently addressing the underlying genetic cause of Duchenne muscular dystrophy. It is expected to benefit at least 85% of boys with the condition as it would address many of the mutations that cause it. The genome editing procedure will permanently change the person’s DNA, meaning there would be no need for repeated gene editing treatments.

By targeting fibrosis, muscle wasting and the underlying genetic cause of Duchenne muscular dystrophy, this combined approach has great potential as a successful treatment.

Background

Boys with Duchenne muscular dystrophy lack a protein called dystrophin. This is due to the dystrophin gene, which contains instructions about how to make dystrophin protein, having a mutation, or a mistake in it. Dystrophin protein acts like a shock absorber in skeletal muscle, protecting it when the muscle contracts; without it muscle becomes damaged and breaks down. Over time, the muscle is replaced with fatty tissue and scar tissue, a process called fibrosis, and this prevents muscles from functioning properly.

Grant information

Project leader: Dr Linda Popplewell
Location: Royal Holloway University of London
Condition: Duchenne muscular dystrophy
Duration: five years, starting 2015
Total project cost: £551,573 (inclusive of Royal Holloway University of London’s contribution of £301,573 )
Official title: Development of broadly applicable combinatorial genome editing and antisense therapies for Duchenne muscular dystrophy addressing dystrophin deficiency, muscle wasting and muscle fibrosis

For further information

Download a summary of this research project

Learn more about Duchenne muscular dystrophy

Read about other Duchenne muscular dystrophy research we are funding

Read the latest research news for Duchenne muscular dystrophy

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