This research was funded by a grant awarded to Muscular Dystrophy UK by the the Big Lottery Fund.
What were the researchers aiming to do?
Duchenne muscular dystrophy is caused by a fault in the gene that carries the instructions for the dystrophin protein. Dystrophin is an important structural protein of muscle cells. Without it, the cells are less durable and more likely to develop small tears in response to outside forces being put on the muscle, for example during contraction. Recent research has suggested that an approach called exon skipping might be able to slow or even halt the muscle damage seen in Duchenne muscular dystrophy.
Exon skipping involves administering small pieces of DNA called molecular patches or antisense oligonucleotides (AO) to muscle cells. The patch tells the cell to skip over the fault in the gene so that the muscle ignores the fault when it produces the dystrophin protein. This leads to a slightly shorter, but mostly functional dystrophin protein being produced. The overall aim of this project was to build on previous research into exon skipping and develop improved methods for delivering the molecular patches to all the muscles of the body.
What did their research show?
Prof Wells and his team used an animal model of Duchenne muscular dystrophy – the mdx mouse – to test different doses of the AOs. They discovered that if 20% of the muscle fibres produced dystrophin protein a beneficial effect could be seen on muscle function. This gives clinical trial organisers a realistic goal for the amount of dystrophin that should provide a benefit to the boys with Duchenne muscular dystrophy.
While exon skipping has been shown to be successful in the skeletal muscle – the muscle attached to the skeleton that moves the body – there have been problems in getting the AOs to the heart muscle. Getting the molecular patches into the heart muscle is particularly important as many young men with Duchenne muscular dystrophy develop a condition called cardiomyopathy which is a major cause of death. Prof Wells therefore explored ways of improving the delivery to the heart and found that combining microbubbles with ultrasound helped. Microbubbles are small gas-filled bubbles, less than 1 millimeter in diameter, normally used to increase the contrast on an ultrasound scan allowing clinicians to see more detail in the area of interest. Using standard diagnostic ultrasound equipment focused on the heart the team found that the microbubbles improved delivery of AOs to the heart and that repeated treatment improved the efficiency of this delivery with no ill effects.
Another challenge facing researchers has been maximizing the efficiency of delivering the AOs to the whole body – systemic delivery. Knowing what factors affect delivery is vital if they are going to overcome these problems. In a series of experiments carried out by Prof Wells and his team, it was discovered that the cells that line blood vessels – the vascular endothelium – are a barrier to the AOs. This gives the researchers a target to focus on and work is now ongoing to devise ways to allow the AOs to cross the vascular endothelium more efficiently and thus allow it to get to the muscles more easily.
How will the outcomes of the research benefit patients?
The results of this research will inform the current and future clinical trials for exon skipping. It will help researchers to develop ways to improve systemic (whole body) delivery of the molecular patches giving this promising technology a greater chance of success in slowing or even halting the progression of Duchenne muscular dystrophy
Grant information
Project Leader: Prof Dominic Wells
Location: Imperial College London
Condition: Duchenne muscular dystrophy
Duration: 3 years, completed September 2009
Total Project Cost: £286,206
Official Title: Non-invasive imaging in man for the development of novel approaches to therapy of Duchenne muscular dystrophy
Further information and links
Read more about how exon skipping works
Read about the MDEX consortium, the group who are leading on the exon skipping trials in the UK.
More information about Duchenne muscular dystrophy
News from the UK exon skipping clinical trial
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