Developing a utrophin drug for Duchenne and Becker muscular dystrophies
Professor Dame Kay Davies and colleagues at the University of Oxford are searching for drugs that could increase the amount of a protein called utrophin, in the muscles. It is thought that utrophin may be able to compensate for the lack of dystrophin in Duchenne muscular dystrophy. If successful, this treatment approach would apply to all boys and young men with Duchenne and Becker muscular dystrophy.
Contents:
- What are the researchers aiming to do?
- How will the outcomes of the research benefit patients?
- Grant information
- Further information and links
What are the researchers aiming to do?
Duchenne and Becker muscular dystrophies are caused by mutations in the dystrophin gene. This gene contains the instructions for making dystrophin protein which acts as a shock absorber to prevent damage when the muscle contracts. Although both conditions are caused by mutations in the dystrophin gene, boys with Duchenne muscular dystrophy have more severe symptoms because their muscles produce almost no dystrophin. People with Becker muscular dystrophy have milder symptoms because they have some dystrophin in their muscles, but it's not enough or it is smaller so doesn't function well. It is thought that utrophin, a protein naturally present in our body in small amounts, may be able to compensate for the lack of dystrophin in boys with Duchenne muscular dystrophy since both proteins are structurally similar and appear to have very similar functions. Research in mice and dogs lacking dystrophin has shown that increasing the levels of the utrophin protein can prevent muscle damage.
Professor Dame Kay Davies' laboratory at the University of Oxford has been researching utrophin for more than 20 years. In recent years, in collaboration with Oxford biotechnology company Summit plc and pharmaceutical company BioMarin, they found a promising drug - BMN-195 (previously called SMT C1100) - that was able to increase the amount of utrophin in a mouse model of Duchenne muscular dystrophy. The mice that had been treated with the drug had muscles that appeared healthier when look at under a microscope - they had less inflammation and scar tissue (fibrosis). BMN-195 was recently tested in a phase I clinical trial, but unfortunately even at high doses only small amounts of BMN-195 entered the bloodstream and so not enough of the drug was reaching the muscles.
Since the work in animal models of Duchenne muscular dystrophy suggested that increasing utrophin is potentially a good therapeutic strategy, Prof Davies and her colleagues have gone back to the drawing board in order to find more drugs that may be able to increase utrophin.
Professor Davies will work together with two other researchers in Oxford to screen many thousands of drugs using innovative new mouse and cell-based models developed in a previous Muscular Dystrophy Campaign-funded grant. The genetically engineered mouse emits light if a drug is able to increase the amount of utrophin in its body. Cells from these mice can also be grown in the laboratory and these will be used as a first step to quickly screen thousands of drugs. The amount of light emitted from the cells can be visualised and measured using sophisticated equipment and any promising candidate drugs will then be tested in more detail in the mouse.
How will the outcomes of the research benefit patients?
There are currently no specific treatments for Duchenne and Becker muscular dystrophies although a number of ideas are being investigated. In particular, exon skipping and ataluren are currently in clinical trial for Duchenne muscular dystrophy but these approaches will only be applicable to a proportion of boys and young men with Duchenne muscular dystrophy because they act based on the specific genetic change that a person has.
This research could discover new drugs that have the potential to treat all people with both Duchenne and Becker muscular dystrophies. It is thought that such a therapy would be safe because utrophin is already present in the body so increasing the levels of utrophin would not illicit an immune response.
Professor Dame Kay Davies, University of Oxford said:
We are delighted with this funding from MDC as it will enable us to build on our previous work which demonstrated the proof of principle of finding a drug which increases utrophin levels. We are excited because our improved cell line for screening will allow us to find new drugs for increasing utrophin in DMD patients more rapidly.
Grant information
Project leader: Professor Dame Kay Davies
Location: University of Oxford
Conditions: Duchenne muscular dystrophy, Becker muscular dystrophy
Duration: 2 years
Total project cost: £98,446
Official title: Development of therapy for DMD through utrophin upregulation
Further information and links
Read about the encouraging utrophin research results in mice
Learn more about Duchenne muscular dystrophy and Becker muscular dystrophy
The latest research news for Duchenne muscular dystrophy
Other Duchenne muscular dystrophy research projects we fund
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