Duchenne Muscular Dystrophy (DMD) is a devastating muscle wasting disease. As well as affecting muscles in the body, it can also affect the brain. Around a third of patients with DMD show some learning difficulties and behavioural problems. These range from severe autism to obsessive compulsive disorders (OCD) and attention deficit hyperactivity disorders (ADHD). For many young patients and their families, learning difficulties and behavioural problems can affect family life more than their muscle problems.

Duchenne UK is pleased to be funding a project to investigate whether or not a treatment known as exon skipping can help restore dystrophin in the brain. The process is known as antisense oligonucleotide (AON)-mediated exon-skipping.

Duchenne UK has awarded £45,000 to Leiden University Medical Center to investigate the use of antisense oligonucleotide (AON)-mediated exon-skipping to treat the brain of a DMD animal model system. 

Antisense oligonucleotide (AON)-mediated exon-skipping is a technique which allows the production of a shorter dystrophin protein in patients with DMD, by restoring the genetic code. It is known that the shorter protein is partially functional in muscle, and hopefully also in brain.

Existing exon-skipping therapies are usually administered by an injection. This method is effective at delivering the treatment to some tissues, such as muscles, however the treatment does not reach the brain. For this reason, current exon-skipping therapies are not effective at treating the learning difficulties and cognitive effects associated with DMD.

This one-year project entitled, “CNS dystrophin and antisense oligonucleotides: Investigating the applicability of AON-mediated exon-skipping to treat the DMD brain”, is designed to optimize treatment of the brain in a DMD mouse model by local injection, and to evaluate if and how the brain pathology can be restored with AON-mediated exon skipping.

Comments on this project from our PAB members:  

We believe that patients should be at the heart of drug development, and patient and parent involvement is essential to Duchenne UK.  To ensure this, our Patient Advisory Board (PAB) reviews each of the projects under consideration for funding. Our PAB is made up of parents of children and young adults of different ages, who advise and give feedback on the projects. We are very grateful to all members of our PAB for their invaluable support and advice helping Duchenne UK to accelerate DMD research.

Katrina Ruthven, Duchenne UK PAB member said, "I’m particularly interested in the Antisense oligonucleotide, I believe we absolutely need to be further investigating and trying to improve the impact of the lack of dystrophin in the brain and CNS. " 

Vici Richardson, Duchenne UK PAB member said, "Research into any area of the effects on the brain is most welcome and I would be very interested following this." 

You can read more about exon-skipping on our website here:

https://www.duchenneuk.org/exon-skipping

Q&A on this project:

Q: Why is this project important for the Duchenne community?

A: Around 30% of people with DMD display mild to more severe leaning difficulties and behavioural problems ranging from obsessive compulsive disorders to autism.

Q: How does a mutation in the dystrophin gene effect the brain? Isn’t dystrophin a protein found in muscles?

A: Yes, in muscle, the dystrophin protein provides a structural link to maintain muscle structure. However, the dystrophin gene also produces four brain specific dystrophin proteins. Two of these are long (like the muscle dystrophin) and two are shorter. The production of the long brain dystrophins is lost for all Duchenne patients. However, whether the shorter dystrophins can be produced depends on the location of the mutation in the dystrophin gene. The effect of lack of the long or the short dystrophins is not well understood, but it is thought that the more brain dystrophins you miss, the more severe the cognitive effect will be.

Q: What is the aim of this project?

A: This project is designed to restore the long dystrophin in the brain of mice, to study how this improves behaviour and learning. 

Q: If this project is successful what would be the next steps?

A: Once we have shown that it is feasible to restore dystrophin in the brain in animal models, future studies will be needed to study how long the effect lasts. Furthermore, additional longer term studies will be needed in this and other animal models to study the full effect of dystrophin restoration in brain. Eventually, if all goes well, we hope to prepare for clinical trials in patients. However, only if this approach is safe and effective in mice.

Q: How is this project different to current exon skipping therapies in development?

A: Current exon skipping therapies are delivered by IV injection into the blood. This method delivers the treatment to all the 750+ muscles of the body. However, the treatment cannot reach the brain. By delivering the treatment directly into the central nervous system we hope exon skipping may be effective at treating the learning difficulties and cognitive effects of DMD.

 

If you have any questions please email us: [email protected]

 

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NOTES FOR EDITORS

 

What is Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy is the most common fatal genetic disease diagnosed in childhood. Children born with DMD cannot produce the protein dystrophin which is vital for muscle strength and function. Muscle weakness starts in early childhood. Many use a wheelchair by around the age of 12. As deterioration continues it leads to paralysis and early death, often in their 20s. It almost exclusively affects boys. There is no cure. In the UK there are around 2,500 boys affected and around 300, 000 worldwide. It is classified as a rare disease.

 

Who are Duchenne UK?

Duchenne UK is a lean, ambitious and highly focused charity with a clear vision: to fund and accelerate treatments and a cure for Duchenne muscular dystrophy. The charity has been formed by the coming together of Joining Jack and Duchenne Children's Trust, the two biggest funders of research in the UK in the last three years. Its president is HRH The Duchess of Cornwall. Its patrons include the broadcasters Krishnan Guru-Murthy and Mary Nightingale, and the sports stars Owen Farrell, Kris Radlinski and Andy Farrell. 

 

How to donate?

Duchenne UK is entirely reliant on donations to fund research for treatments and a cure to DMD. This can be done via:

  • Direct Debit – Duchenne Direct
  • Individual Donation – Donate
  • If you are a family or friend affected by DMD you can set up your own fund with Duchenne UK – Family and Friend Funds
  • Take part in one of our fundraising events – Events
  • Text DUCH10 £10 to 70070

 

For more information and interview requests:

Visit www.duchenneuk.org

Molly Hunt – Communications Manager, Duchenne UK

E: [email protected]