Monday 4 July 2011
Next generation of Duchenne exon skipping drugs in the pipeline
Research part-funded by the Muscular Dystrophy Campaign in Dr Matthew Wood's laboratory at the University of Oxford, has resulted in the development of the next generation of exon skipping drugs. Testing in mice has shown that this new molecular patch more effectively targets the muscles of the body, including the heart. They hope to test this in boys with Duchenne muscular dystrophy in a clinical trial in 2013. This research is also good news for other neuromuscular conditions such as myotonic dystrophy that affect the heart and for which similar molecular patch technology is showing promise as a potential therapy.
Exon skipping is currently in clinical trial for Duchenne muscular dystrophy. It involves short strands of DNA, known as 'antisense oligonucleotides' (AOs), or 'molecular patches' which can restore production of the protein dystrophin (which is missing in Duchenne muscular dystrophy).
Exon skipping has been successful in restoring dystrophin protein production in the skeletal muscle - the muscle attached to the skeleton that moves the body. This has been proven in mice, dogs and in boys with Duchenne muscular dystrophy in recent clinical trials. However, high doses are required to increase dystrophin to the levels thought to be necessary to protect muscle from damage. Exon skipping has also been largely unsuccessful in the heart so far.
Dr Wood's laboratory recently published results of tests with new molecular patches which are particularly effective throughout the body, including the heart. They plan to take this forward into clinical trial.
What did the research show?
In 2008 Dr Wood and colleagues first showed that in mice exon skipping was vastly improved if the molecular patch was modified by chemically joining them to very small protein molecules known as 'peptides'. The peptides help the molecular patches to penetrate cells, especially the heart. Since then the researchers have been optimising and testing these modified peptide-molecular patches to find the best candidate to take forward to clinical trial.
In the latest research, they tested a range of different peptide-molecular patches by injecting them into a mouse model of Duchenne muscular dystrophy. A single injection of one called "Pip5e-PMO" dramatically increased levels of dystrophin throughout the body. For the first time high levels of dystrophin were restored in the heart.
The newly produced dystrophin protein was shown to be interacting as it should with other proteins in the muscle, indicating that it was working correctly. Encouragingly, the muscle strength of the treated mice was restored almost to normal.
What does this mean for patients?
Most boys with Duchenne muscular dystrophy will develop a heart problem known as cardiomyopathy. It is therefore crucial that the heart muscle, as well as the skeletal muscle, can be treated. This research has shown that this new generation molecular patch may be able to restore dystrophin production in the heart. The higher efficiency of these new molecular patches may also allow them to be administered at lower doses which will not only be less costly but reduce the risk of them being toxic.
Dr Wood and colleagues from the MDEX Consortium were recently awarded a £2.5 million grant by the Wellcome Trust and the Department of Health to allow them to conduct a clinical trial of the new peptide-molecular patch. Currently the researchers are continuing to test the new molecular patch in the laboratory to determine the best dose for clinical trial and to make sure there are no apparent safety issues with it. They anticipate that the trial will start in 2013 and will initially focus on safety testing in nine boys with Duchenne muscular dystrophy.
To date these tests have been conducted only in mice, so we wait with anticipation for the results of the clinical trial which will tell us if this next generation of exon skipping drugs will be safe in humans and improve on the molecular patches currently in clinical trial.
This research is also good news for other neuromuscular conditions such as myotonic dystrophy that affect the heart and for which similar molecular patch technology is showing promise as a potential therapy. The authors of the paper commented that similar peptide modifications could be made to ensure that the hearts of myotonic dystrophy patients are effectively treated when this research comes to clinical trial.
Further Information and links
More information about Duchenne muscular dystrophy.
For more information about exon skipping take a look at our FAQ.
Find out the latest news from the exon skipping clinical trials.
Read about our recent visit to Dr Wood's laboratory.
Read more about the projects we fund in Dr Wood's laboratory:
- Improving exon-skipping for Duchenne muscular dystrophy
- Investigating microRNAs in Duchenne muscular dystrophy.
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The full original paper published in the Molecular Therapy is available by subscription only. The article is written in technical language with no summary in layman's terms. The reference for the paper is:
Yin H, Saleh AF, Betts C, Camelliti P, Seow Y, Ashraf S, Arzumanov A, Hammond S, Merritt T, Gait MJ, Wood MJ. Pip5 Transduction Peptides Direct High Efficiency Oligonucleotide-mediated Dystrophin Exon Skipping in Heart and Phenotypic Correction in mdx Mice.Mol Ther. 2011 Jul;19(7):1295-303.
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