Developing tools to identify effective treatments for congenital and adult myotonic dystrophy

 Our work aims to measure the toxic RNA in myotonic dystrophy so that we can be confident the drugs we are developing get rid of it.

Background

Myotonic dystrophy type 1 is caused by a mutation in the DMPK gene. This leads to the production of faulty RNA. In a healthy muscle cell, RNA is produced in the nucleus when the gene is switched on. It is then transported out of the nucleus and provides the instructions for the cell machinery to make proteins. In the cells of someone with myotonic dystrophy, the RNA clumps together and gets trapped in the nucleus. Other proteins in the cell bind to the RNA clumps and are unable to carry out their normal function, ultimately leading to the symptoms of the condition.

In work previously funded by Muscular Dystrophy UK, Professor Brook and his team established a drug screening assay, this led to large drugs screens for myotonic dystrophy. They identified a number of compounds that could be developed as potential treatments for myotonic dystrophy, including some that aim to break up the RNA clumps. However, what happens to the RNA after treatment with these molecules is unknown and could have important implications on how effective the therapy is.

 What are the aims of the project?

In this one year project Professor Brook and his team will develop two very sensitive state-of-the-art techniques to study what happens to the faulty RNA molecules following treatment with potential therapies. First, the researchers will develop a high-powered microscopy technique. This will allow the team to accurately visualize the location and measure the amount of faulty RNA molecules in cells from people with myotonic dystrophy.

Next, the researchers will develop a sequencing technique. This will allow them to measure the amount of faulty RNA, down to the level of a single molecule, in cells or biopsies from people with myotonic dystrophy. Finally, Professor Brook and his team will test the effect of five of the potential treatments, identified in the screen and elsewhere, on the faulty RNA using the techniques described above.

Why is this research important?

The toxic role of the faulty RNA in people with myotonic dystrophy is not fully understood. Furthermore, although potential treatments are in development, what happens to the faulty RNA after treatment is not clear. This project will provide valuable tools for researchers to study the RNA in detail following treatment. This is essential to provide a better understanding of how the treatments work and if they could be effective potential therapies.

This project could also increase our knowledge of the molecular mechanisms that underlie myotonic dystrophy.

How will the outcomes of this research benefit people with myotonic dystrophy?

This project will provide researchers with tools to identify promising potential treatments that target the underlying molecular causes of adult and congenital myotonic dystrophy. The knowledge from this research will also inform the development of future treatments.

How might this research impact on other neuromuscular conditions?

The two state-of-the-art technologies could be adapted to study other neuromuscular conditions, such as myotonic dystrophy type 2.

Grant information

Project leader: Professor J David Brook

Institute: University of Nottingham

Condition: Myotonic dystrophy

Duration: one year, starting 2018

Total cost: £74,987

Official title: Analysis of repeat expansion transcripts for congenital and adult DM therapy.

Further information

Find out what other myotonic dystrophy research projects we’re funding

Read our factsheet on myotonic dystrophy