Improving exon-skipping for Duchenne muscular dystrophy

Dr Wood and PhD student Corinne Betts at the University of Oxford aim to investigate ways to improve upon the current exon-skipping technology. Building on previous research, they will look at using short protein fragments, called peptides, to improve the delivery of the molecular patches to the heart in mouse models of Duchenne muscular dystrophy.

What are the researchers aiming to do?

Duchenne muscular dystrophy is caused by a fault in the gene that carries the instructions for the dystrophin protein. This fault means that the cell is unable to produce any functional dystrophin protein, leading to muscle damage and wasting. A number of possible treatments are being investigated including the use of ‘molecular patches’, also called antisense oligonucleotides (AOs). AOs are like very small pieces of DNA which allow the cell to “skip over” the faulty part of the gene when making a protein. This allows the cell to start producing a shortened but functional dystrophin protein. It is thought that this could potentially transform the symptoms of Duchenne muscular dystrophy to those akin to Becker muscular dystrophy, a milder form of the disease.

Researchers are facing several major challenges with this new technology. One of these is finding ways to improve the delivery of the AO’s to the heart. Almost all boys with Duchenne muscular dystrophy will develop a heart problem known as cardiomyopathy, and about one third will die from heart failure. It is therefore crucial that the heart muscle, as well as the skeletal muscle can be treated with the AOs to help prevent the heart complications occurring.

Dr Wood and his team have previously discovered that short protein fragments known as peptides can be attached to the AOs to dramatically improve their delivery into cells. They have found several promising peptides that, when attached to the AOs are highly effective in a mouse model of Duchenne muscular dystrophy. Using these peptides appears to allow a much greater restoration of dystrophin protein in all tissues including the heart, brain and eye than just using the AO alone.

The aim of this project, therefore, is to further investigate the use of these peptides to enhance the delivery of AOs. Dr Wood and his student will be using a mouse model to determine which dose of peptide-AO gives the best result. They will investigate how often it must be administered and the best way to give the drug. They will test several routes of administration including into the vein (intravenous) and under the skin (sub-cutaneous). An important part of the project will involve trying to determine why these peptides are so effective at improving delivery, so they will also plan to try to understand how they work, which could open the possibility of improving their activity.

How will the outcomes of the research benefit patients?

This research will increase scientists’ knowledge of the best and most efficient ways to deliver the AOs to all the tissues in the body, allowing for increased restoration of dystrophin protein. It will build on the already large body of work that has been carried out into AOs and exon skipping and provide new data that may inform future clinical trials. Making the delivery method more efficient could also allow clinicians to give a smaller dose of the drug, while still achieving the same effect, thus minimising any chances of adverse reactions to the drug.

There are concerns that any improvements in muscle function without correcting the heart problems might worsen the heart disease by increasing the workload of the heart. This means it is important that treatments are developed that are effective at restoring dystrophin in both skeletal and heart muscle. It is hoped this project will help to address this problem.

Grant information

Project Leader: Dr Matthew Wood
Location: University of Oxford
Condition: Duchenne muscular dystrophy
Duration: 4 years, started 2010
Total Project Cost: £117,480
Official Title: Novel exon skipping peptide-PMOs for correction of heart dystrophin expression and function in mouse models of Duchenne muscular dystrophy.

Further information and links

Find out more about Duchenne muscular dystrophy.

Read more about antisense oligonucleotides and exon-skipping.

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