Moving closer to a gene therapy for Duchenne muscular dystrophy

Gene therapy offers the hope of delivering a fully functional dystrophin gene to muscles for people with Duchenne muscular dystrophy. In this project Professor George Dickson and his team will develop improved gene therapy techniques that have an enhanced ability to increase dystrophin protein in muscles. The researchers will do this by making changes to the micro-dystrophin gene and to the harmless virus that delivers it to muscles. This is a continuation of Professor Dickson’s previous work that could result in improved, second-generation gene therapies to test in future clinical trials, and better treatment options for people with Duchenne muscular dystrophy in the long term.

Harmless DNA carriers, known as adeno-associated viruses (AAV) can be used to deliver the dystrophin gene to muscles. However there is a limit to the size of DNA that AAV can carry and so shortened versions of the dystrophin gene have had to be developed. These so-called micro-dystrophin proteins may only be present at low levels have limited functionality.

Professor Dickson and his team have added a number of elements, which act as control switches, to the AAV carrier to try and increase the production of this shortened dystrophin in areas targeted for gene therapy, such as the heart. The researchers are also testing the effect of adding back in parts of the dystrophin gene to see if this improves the levels and functionality of the micro-dystrophin.  Different combinations of these elements are being tested in a Duchenne muscular dystrophy mouse model to see which arrangement gives the greatest amount of dystrophin in treated muscles.

What are the researchers aiming to do?

Duchenne muscular dystrophy is caused by mutations in the dystrophin gene that contains the information for making dystrophin protein. The dystrophin protein acts as a shock absorber to prevent damage when the muscles contract. In people with Duchenne muscular dystrophy the mutation leads to the complete absence of dystrophin protein.

Gene therapy offers the possibility of delivering a functional copy of the dystrophin gene to muscle cells where it could restore production of the dystrophin protein. The most promising approach is based on the use of a harmless virus called adeno-associated virus (AAV) as a carrier; this has been shown to effectively deliver genes to a range of different types of cells and tissues including muscle.

One of the challenges is the dystrophin gene being too big for the virus to carry – just like an envelope only holds so many pieces of paper, a virus can only carry a certain amount of DNA. To get around this challenge, researchers have made mini- and micro-dystrophin genes that are shorter than the full-length gene and which make shorter but still functional proteins. Professor Dickson and his team have developed one such micro-dystrophin, which has been successfully tested in animal models of Duchenne muscular dystrophy and is planned to be tested in a European phase I/IIa clinical trial.

Clinical trials of other, first-generation gene therapies have been completed, but these have only had limited success in increasing dystrophin levels. Therefore developing more effective versions of the gene therapy is necessary to ensure more and better potential treatment options for people with Duchenne muscular dystrophy in the future.

To improve the design of the gene therapy, Professor Dickson and his team have developed a slightly longer micro-dystrophin gene. They have also identified two changes that they plan to make to the virus to increase its ability to drive protein production, especially in heart muscles. Treating heart muscle will be crucial for a successful treatment as heart function declines in people with Duchenne muscular dystrophy.

The changes will be made to the virus to see which is most efficient at increasing dystrophin protein in muscles. To identify the best combination of gene and virus for a gene therapy, different micro-dystrophin genes will be tested with different viruses in an animal model of Duchenne muscular dystrophy, the mdx mouse, and the researchers will measure dystrophin expression in skeletal, heart and respiratory (diaphragm) muscles.

How will the outcomes of the research benefit patients?

The promise of this gene therapy is demonstrated by the fact that some potential gene therapies have already being tested in clinical trials. However, this project offers new and improved (second-generation) options for the delivery of a functional dystrophin gene to muscles, giving more potential treatment options for people with Duchenne muscular dystrophy.

Grant information

Project leader: Professor George Dickson
Location: Royal Holloway University of London
Condition: Duchenne muscular dystrophy
Duration: three years, starting 2015
Total project cost: £174,100
Official title: Second-generation hyper-active micro-dystrophin AAV vectors for Duchenne muscular dystrophy gene therapy

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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