A new approach to the treatment of muscular dystrophy offers hope to sufferers for a reversal of the disease's devastating effects, writes Dick Ahlstrom
RESEARCHERS AT NUI Maynooth have helped to confirm the effectiveness of a promising new treatment for muscular dystrophy. They showed that the experimental gene therapy actually reverses some of the secondary damage caused by the life-threatening disease.
The findings, just published in the on-line version of the journal Proteomics, are particularly important for Ireland.
The progressive muscle wasting disorder is our most common gender-specific inherited disease. It affects about one in 3,500 boys here and depending on the type, is almost always fatal, shortening life expectancy to about 20 years.
The research was a collaboration involving Prof Kay Ohlendieck and Dr Philip Doran at Maynooth and Prof Steve Wilton and Dr Sue Fletcher from the centre for neuromuscular and neurological disorders at the University of Western Australia.
It builds on initial work done by Wilton, who developed a gene therapy to reverse the central cause of the disease. The disease causes muscle weakness and eventual cell death when a key muscle protein, the dystrophin protein, is not working properly due to mutation.
The most common and unfortunately life-threatening form is Duchenne Muscular Dystrophy, explains Ohlendieck, head of NUI Maynooth’s department of biology, and a Science Foundation Ireland principal investigator. It typically sees the child forced to use a wheelchair by the age of 10 or 12 and these patients seldom live beyond their mid-20s.
A related but much less dangerous form is Becker’s Muscular Dystrophy. Here the dystrophin protein is shortened but is partly functional and the person usually survives into old age, he says.
Wilton’s therapy involves using “anti-sense probes” to silence small parts of the dystrophin protein, the elements that render the protein wholly inoperable. It does this by intervening in the stage just before formation of the protein when the code for producing it is still in its “messenger RNA” form, Ohlendieck says.
The probes go to predefined locations along the RNA chain and eliminate specific “exons”, the building blocks of the protein which are assembled using the RNA instructions. “Because it skips over the defective exon it eliminates that but allows the rest of the protein to be made,” he says.
The resultant protein is foreshortened but it is able to carry out at least some of its functions. In effect it performs as it does in the less severe Becker’s form of the disease.
“It transforms a really severe muscular dystrophy to a manageable form,” he says.
The unanswered question however was whether this change also altered the way that other muscle proteins performed. There are many secondary effects if the dystrophin protein does not work.
Ohlendieck met Wilton at a conference and they agreed to collaborate in important follow-up research. “What we have done is gone to the next step and looked at how all the secondary muscle proteins are affected by the treatment. We did it using proteomics, looking at thousands of muscle proteins.”
An analysis using cultured muscle tissue showed that once the partially functional dystrophin was available the secondary downstream changes were reversed. “It is not fully functional but it is good enough to reverse all the secondary abnormalities,” he says.
This gives additional momentum to the use of the approach to treat the disease in humans. Clinical trials are already under way in the US and UK with results expected by 2010, he says. Their work, funded by Muscular Dystrophy Ireland, the Health Research Board and Science Foundation Ireland, provides important additional biochemical proof that the exon skipping therapy is good enough to reverse pathological changes in related downstream proteins.
Ohlendieck views the work as “very encouraging”. “We now know that this approach is the right one and most likely to achieve results for sufferers. It offers a real hope for a reversal of the devastating effects of muscular dystrophy.”