Friday 23 October 2009
Encouraging new exon skipping results in a mouse model for Duchenne
Researchers led by Prof. Dame Kay Davies in Oxford have reported encouraging results from a study where exon skipping was tested in a severely affected mouse model for the condition. The mice showed remarkable improvement in their symptoms after treatment.
Exon skipping is a gene therapy approach that is currently in clinical trial for Duchenne muscular dystrophy. It involves short strands of DNA, known as 'antisense oligonucleotides', or 'molecular patches' which can restore production of the protein dystrophin (which is missing in boys with Duchenne muscular dystrophy).
Recent research has shown that modifying the molecular patches by chemically joining them to very small protein molecules known as 'peptides' increases their efficiency. These peptides help the molecular patches to penetrate cells more efficiently. Previously these modified molecular patches known as 'PPMOs' have been tested in the 'mdx mouse', which, like to boys affected by Duchenne muscular dystrophy have a mutation in the dystrophin gene. However, the mdx mouse has relatively mild symptoms. The reason for this is thought to be that the closely related protein 'utrophin' partially compensates for the lack of dystrophin in these mice. This study therefore tested the PPMOs in a mouse model that lacks both dystrophin and utrophin resulting in severe muscle wasting, impaired mobility and premature death.
Contents:
- What does the research show?
- What does this mean for patients with Duchenne muscular dystrophy?
- Background
What does the research show?
Mice lacking both dystrophin and utrophin were injected with PPMOs weekly which resulted in a remarkable improvement in symptoms. The treated mice had dramatically improved mobility compared to untreated mice and were captured on video running around like normal healthy mice. The strength of the limb muscles was also measured and they were considered almost as strong as healthy mice. Most of the untreated mice died by 10 weeks of age but the treated mice still looked very healthy by the end of the study at 26 weeks of age.
What does this mean for patients with Duchenne muscular dystrophy?
This research provides further evidence of the potential of this technique for treating Duchenne muscular dystrophy. The mouse model used in this study, which has symptoms which closely resemble those of boys with Duchenne muscular dystrophy, is an exciting tool to measure the effectiveness of the treatment.
To date these tests have been conducted only in mice, so further research is required to determine if this technique will be as effective in humans as it is in the mouse. There are currently clinical trials in progress in the UK and the Netherlands testing slightly different forms of molecular patches (without the peptide modification) which are producing promising initial results.
Dr Marita Pohlschmidt, Director of Research at the Muscular Dystrophy Campaign said:
The Muscular Dystrophy Campaign has supported this technology from the start and we are encouraged to see how well this is working in an animal model of Duchenne muscular dystrophy. The charity has funded Prof Kay Davies' research for over 20 years, and she recently has been awarded an additional grant for the next two years to continue her work on improving this promising approach.
Background
Exon skipping works by masking the faulty part of the dystrophin gene, allowing a shortened but functional dystrophin protein to be produced. It is thought that this could potentially transform the symptoms of Duchenne muscular dystrophy to those akin to Becker muscular dystrophy, a more mild form of the disease.
Further information and links
Read more about how exon skipping works.
More about the UK exon skipping trial
Read about this breakthrough in The Times online
Watch the video of the mice
The full original paper published in 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:
Goyenvalle A, Babbs A, Powell D, Kole R, Fletcher S, Wilton SD, Davies KE. Prevention of Dystrophic Pathology in Severely Affected Dystrophin/Utrophin-deficient Mice by Morpholino-oligomer-mediated Exon-skipping. Mol Ther. 2009 Oct 20.
