Looking for drugs to treat myotonic dystrophy

Prof David Brook

Prof Brook, based at the University of Nottingham, completed a two year project where he and his colleagues developed a cell-based drug screen for myotonic dystrophy.  As a result of the work completed during the Muscular Dystrophy Campaign-funded grant, Professor Brook then secured a further grant of £160,000 from the Medical Research Council to try and find a drug that could be used to treat myotonic dystrophy.

What were the researchers aiming to do?

Myotonic dystrophy is the most common form of muscular dystrophy in adults and is thought to affect around 7,500 people in the UK.  It exists in two forms – DM1 and DM2 – both caused by the expansion of a repeated piece of DNA code. Healthy individuals normally have up to 30 copies of the triplet repeat, but individuals with DM1 can have many hundreds of copies.  Myotonic dystrophy causes muscle weakness and stiffness but can also affect other parts of the body causing, for example, cataracts and abnormalities in the heart, brain and hormonal systems.

In the simplest terms, a cell is a little like a fried egg. The yolk is the nucleus – where the DNA is stored – and the white is cytoplasm, where proteins are made. In order for the cell to make a protein, the instructions that are in the DNA must be taken from the nucleus to the protein-producing machinery in the cytoplasm. The cell does this by creating a messenger molecule called RNA. It is thought that in DM the expanded repeats cause the RNA to become trapped in the nucleus in small clumps that can be seen under the microscope. The trapped RNA binds to proteins in the nucleus and prevents them carrying out their normal function. In particular, a protein called ‘muscleblind’ is trapped in these clumps. This protein is involved in the processing or “splicing” of several genes which have important roles around the body, such as controlling muscle contraction.

Professor Brook wanted to devise a system, called an assay, to find new drugs that could treat the symptoms of DM.  This assay needed to be able to easily measure if a chemical or drug was able to either help the trapped RNA get out of the nucleus or if it was able to restore the activity of some of the proteins that are affected in DM.  Using cells from DM patients, grown in the laboratory, and cutting edge technology, Professor Brook hoped eventually to be able to screen thousands of chemical compounds using the cells. During the course of this project he aimed to test and validate the assay to ensure that it worked efficiently and to a consistent standard.

What did their research show?

Professor Brook used a type of skin cell, called a fibroblast, from people with DM.  He grew these in the laboratory in such a way that they can be kept indefinitely and used for many experiments.  These cells were to form the basis of the assays.

They used fluorescent “tags” that would stick to the clumps of RNA and protein in the nucleus of the DM cells and allow them to be seen under the microscope.  If a drug was given to the cells and the clumps lessened or disappeared, then that drug would be investigated further for it potential to treat DM.

As well as looking at the appearance of the clumps in the nucleus, it was important to look at another hallmark of DM – the faulty processing (or splicing) of genes.  To achieve this, they genetically engineered cells which emitted either a red or a green light.  The amount of each colour light seen down the microscope would tell the researchers if the genes are being processed correctly.  Myotonic dystrophy cells produce mostly green light whereas unaffected cells produced both red and green.  The aim is to identify a drug or a chemical that makes the myotonic dystrophy cells emit both red and green light, instead of just green, which would indicate that the normal processes had been restored by the treatment.

Professor Brook needed to be able to test thousands of drugs and chemicals using these assays.   As you can imagine this would be an incredibly repetitive task for a human to carry out, not to mention that doing this by hand could take years.  Instead the group used state-of-the art imaging and tissue culture robotics available at Nottingham University and can screen thousands of compounds per week. 

What are the next steps?

The aim now is to test large numbers of molecules with the assays to see whether any of the chemicals can reduce the number of clumps in the myotonic dystrophy cells and restore normal gene processing.  Building on the work carried out in the Muscular Dystrophy Campaign funded grant, Professor Brook secured a further grant of £160,000 from the Medical Research Council to conduct this screen of molecules.  He and his colleagues are testing hundreds of thousands of small molecules for their potential to be used as a treatment in myotonic dystrophy.  Any positive results will be further analyzed in animal models to determine how useful they might be.

How will the outcomes of the research benefit patients?

This research is still some years away from a patient benefit.  It none the less represents an excellent step forward in the development of a treatment for myotonic dystrophy.  If any of the molecules tested are shown to have a positive effect in the assays, they will need to undergo further testing in laboratory-grown cells and animal models ensure the same effect can be seen in a whole animal.  The most promising candidate drug would then be tested in a clinical trial.

Grant information

Project Leader: Professor David Brook
Location: University of Nottingham
Condition: Myotonic dystrophy
Duration: 2 years, completed October 2010
Total Project Cost: £24,000
Official Title: Assays for drug discovery in myotonic dystrophy

Further information and links

Read about other myotonic dystrophy research we are funding

Share your views on this research in “The Lab” section of TalkMD forum.


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