Tuesday 18 January 2011
Encouraging new findings for Duchenne exon-skipping research
Research part-funded by the Muscular Dystrophy Campaign by Professor George Dickson at Royal Holloway University of London has shown in mice that long term administration of the exon skipping drug - antisense oligonucleotides - can help to prevent muscle damage and maintain muscle strength. The researchers gave mice repeated injections of the drug at either a low or a high dose and found that even the low dose was beneficial when given over a long period of time.
Duchenne muscular dystrophy is caused by a mutation in the gene that carries the instructions for the dystrophin protein. The mutation means that no dystrophin protein is produced which causes progressive weakening and wasting of the muscles. A technology called exon skipping is currently in clinical trial as a potential treatment for Duchenne muscular dystrophy.
Exon skipping works by using a short piece of synthetic DNA, called an antisense oligonucleotide (AO), or "molecular patch" to mask part of a gene - an exon - so that the cell skips over it when the protein is being produced. The AOs are designed to specifically mask the part of the dystrophin gene that contains a mutation, allowing a shortened but functional version of the protein to be made.
At present these drugs have only been tested for short lengths of time in clinical trials. The most recent trials have involved boys with Duchenne muscular dystrophy being treated for 12 weeks. Researchers are still trying to determine the dose and frequency of dosing that will provide the most benefit. As most drugs are associated with at least some potential side effects, by using the smallest possible dose, the possibility of these side effects occurring can be minimised and also reduce the cost of the treatment. Prof Dickson tested two doses of AO over the long term to see how well they would promote dystrophin production and slow muscle damage.
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What does the research show?
Based on previous work, Professor Dickson and his colleagues suggested that low doses of AO given in repeated cycles might be an effective way to promote dystrophin production and prevent muscle damage. A mouse model of Duchenne muscular dystrophy - "mdx" mice - were injected once per week for four weeks and then had six weeks of no treatment (one treatment cycle). This cycle of treatment was then repeated either twice (total length of 20 weeks) or five times (50 weeks). The doses being tested were equivalent to those being used in boys with Duchenne muscular dystrophy in the recent clinical trial.
At both the high and the low doses and following both the 20 and 50 week treatments, the dystrophin protein could be detected in all of the muscles that were tested. There was more dystrophin detected after 50 weeks of treatment compared to 20 weeks. By 50 weeks of treatment, there was little difference in the amount of dystrophin detected between the mice treated with the low and high doses.
The increase in dystrophin protein following AO treatment appeared to have a protective effect on the muscle and the mice were more physically active. Importantly the diaphragm (the breathing muscle) which is severely affected in both mdx mice and humans with Duchenne muscular dystrophy showed significant improvement in treated mice.
Professor Dickson found that even at the lowest dose after 20 weeks (two cycles of treatment) there was a significant increase in the muscle strength of the treated mice compared to the untreated mice. The higher of the two doses generally provided greater protection against muscle damage and better maintenance of muscle strength.
What does this mean for patients?
This study tested the long term effects of exon skipping for the first time and provides further evidence of the potential of this technique for treating Duchenne muscular dystrophy.
The pharmaceutical companies Prosensa (in partnership with GSK) and AVI Biopharma are currently conducting clinical trials testing slightly different forms of the molecular patches which are producing promising initial results. However, researchers don't know yet how much dystrophin protein is required in muscle cells to halt or slow the progression of symptoms for boys with Duchenne muscular dystrophy. Professor Dickson's research will be important for informing future clinical trials in terms of which doses and dosing regimes to test.
Dr Marita Pohlschmidt, Director of Research at the Muscular Dystrophy Campaign, said:
Finding the right dose of this new potential drug is key to its success and we are proud that the research we fund continues to shed light on this. Professor Dickson's work has provided us with a good indication of what dose might be effective to improve muscle function in boys with Duchenne muscular dystrophy and we hope that these results are confirmed in clinical trials.
Professor George Dickson from Royal Holloway University of London said:
Duchenne dystrophy is very serious inherited disorder which affects one in 3,000 boys from age four onwards. It is a progressive and severe muscle wasting disease which is currently untreatable. These latest exciting and encouraging results suggest that current ongoing clinical trials of exon skipping in muscular dystrophy patients have great promise as a long-term treatment.
Further information and links
More about Professor George Dickson's research.
Read the latest exon skipping clinical trial news:
Comment on this research and ask questions in the TalkMD forum.
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