Using exon skipping to boost muscle growth
Prof George Dickson plans to build on the current exon skipping work to develop molecular patches that can block the activity of a protein called myostatin. Researchers have shown that blocking myostatin activity can have a positive effect on muscle growth, allowing the muscles to grow bigger and potentially stronger - an approach that may be applicable to a wide range of muscle wasting conditions. In this project, Prof Dickson aims to test molecular patches to block myostatin in combination with exon skipping to restore dystrophin, the protein that is missing in Duchenne muscular dystrophy. This combination therapy may prove to be more effective than each treatment on its own.
- What are the researchers aiming to do?
- How will the outcomes of the research benefit patients?
- Grant information
- Further information and links
Duchenne muscular dystrophy is caused by mutations in the dystrophin gene. This gene contains the instructions for making dystrophin protein which acts as a shock absorber to prevent damage when the muscle contracts. The loss of dystrophin in Duchenne muscular dystrophy leads to wasting of the muscle, with the muscle fibres gradually being replaced by fat and scar tissue.
Myostatin is a protein naturally produced by the body. It is an inhibitor of muscle growth and, together with other proteins that promote muscle growth, it works to keep the size and strength of muscle within the normal range. Researchers have shown in animals that blocking the activity of myostatin causes the muscles to increase in strength and size while having less fat and scar tissue. This approach is attractive avenue for developing a therapy because it may be a useful way to "bulk up" muscles in people with muscle disease, helping to increase their muscle strength.
This project focuses on the use of technology called exon skipping that is currently in clinical trial for Duchenne muscular dystrophy. It involves using small pieces of DNA called molecular patches or 'antisense oligonucleotides' to change the way the instructions contained within a gene are read. The therapy currently in clinical trial for Duchenne muscular dystrophy uses molecular patches to specifically mask the area of the dystrophin gene where there is a mutation. This has the effect of restoring the production of dystrophin protein. However, depending on the target gene and the molecular patch used, molecular patches can also be used to stop genes producing a functional protein.
Prof Dickson has already provided proof of principle, in mice, that it is possible to use exon skipping to block the activity of myostatin (you can read the news story here). He now plans to follow this up by testing a number of different molecular patches for their ability to block myostatin activity in cells grown in the laboratory. Patches that have the greatest ability to block myostatin will then be tested further in mdx mice (a mouse model of Duchenne muscular dystrophy).
The next step will be to test the best patches together with molecular patches used to restore dystrophin. This combination therapy may prove to be more effective than each treatment on its own for Duchenne muscular dystrophy.
It is hoped that this research may lay the groundwork for a clinical trial to test exon skipping to block myostatin activity. For Duchenne muscular dystrophy this could boost the effectiveness of other treatments being developed that restore dystrophin production.
Although the focus of this particular project is on Duchenne muscular dystrophy, it could potentially benefit people with a range of neuromuscular conditions although it is important to note that while blocking myostatin will make the muscles stronger, the underlying genetic mutation is still present. For milder conditions, such as FSH or limb girdle muscular dystrophy , it is thought that the increase in muscle strength that is expected to occur after blocking myostatin may be quite beneficial and could have a positive impact on everyday activities. In more severe conditions, such as Duchenne muscular dystrophy, however, it is likely that this approach would work best in conjunction with other types of therapy so that both the primary cause of the muscle condition is treated and the muscle strength and size is built up.
Speaking about being awarded the grant, Professor Dickson said:
For many severe and often incurable inherited diseases, collaboration between scientists and patient organisation like MDC is vital. We are pleased and excited by our latest results which suggest that muscle wasting and weakness associated with many neuromuscular diseases may be amenable to treatment by a process called Exon Skipping. The research funding from MDC is allowing us to advance quickly and effectively with this new technique
Project leader: Prof George Dickson
Location: Royal Holloway - University of London
Conditions: Duchenne muscular dystrophy, general
Duration: 3 years, starting 2012
Total project cost: £124,696
Official title: Combination Antisense Treatment for Duchenne Muscular Dystrophy: Open Reading Frame Rescue of Dystrophin in conjunction with Destructive Exon Skipping of Myostatin mRNA
Learn more about Duchenne muscular dystrophy
Read about Prof Dickson's work on myostatin in our research news
Find out how exon skipping works
Latest research news for Duchenne muscular dystrophy
Learn more about Prof Dickson's other research grants
Read about our other Duchenne muscular dystrophy research projects
It is only through your contributions that we can continue to fund the vital work that takes us closer to finding treatments and cures for muscle disease. Donate now and help change the lives of thousands of people living with muscle disease.