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Epilepsy: developing a new drug treatment for a rare and debilitating form of the condition

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Updated on

What did the project achieve?

Pyridoxine-dependent epilepsy (PDE) is a rare inherited form of childhood epilepsy. While seizures can usually be controlled with lifelong supplementation with a vitamin called pyridoxine, this does not prevent wider neurological symptoms, such as delayed development and learning disabilities.

“We’ve made important progress towards our goal to develop a much-needed new drug treatment for children with PDE,” says Professor Wyatt Yue of Newcastle University Biosciences Institute. “We hope this work will lay the foundations for an effective treatment that will greatly improve the lives of children and their families affected by this rare and debilitating condition.”

Professor Yue’s team is working to create a new treatment that can prevent the build-up of the toxic chemical in the body that causes the symptoms of PDE. Their strategy focuses on identifying a drug compound that blocks a key enzyme involved in producing this harmful substance.

In earlier work, the researchers identified several potential compounds. Through extensive laboratory experiments, they have now narrowed this down to a small group of promising candidates. Working with colleagues at Aston University, they have also tested how well these compounds work in relevant cell models, with encouraging results.

“However, new evidence has now emerged suggesting that targeting a different part of the enzyme could be an even more effective approach,” says Professor Yue. “We’ve already begun searching for compounds that act on this part of the enzyme – and in our early experiments, we have identified several promising options to explore.”

The team will continue to build on the knowledge and tools developed during this project to further investigate and refine the most promising candidate compounds identified so far. 

“Thanks to this work, we’ve refined our strategy for developing a new drug treatment that tackles the root cause of the neurological symptoms in children with PDE,” says Professor Yue. “We now have a much clearer understanding of how best to target this enzyme with a drug – crucial knowledge that will guide our next steps towards a future treatment.”

This research was completed on

Pyridoxine-dependent epilepsy (PDE) is a rare inherited form of childhood epilepsy that typically appears shortly after birth but can start later in childhood. A child’s seizures are usually controlled with lifelong supplementation with a vitamin called pyridoxine, but many will also have delayed development and learning disabilities. Professor Wyatt Yue is aiming to develop a new drug that can address the root cause of children’s long-term neurological symptoms. He hopes this work will ultimately lead to a new treatment that will greatly improve the lives of children and their families who are affected by this rare and debilitating condition.

This project is jointly funded by Action Medical Research and LifeArc.

How are children’s lives affected now?

Children affected with PDE typically start having seizures soon after birth, which are not controlled with conventional anti-epileptic medications. They may also have other symptoms – such as unusual eye and facial movements – before they develop seizures. Many mothers will remember feeling rhythmic movements in their womb, which are likely to have been the developing baby having seizures.

The ALDH7A1 enzyme, which is faulty in children with PDE, plays a role in breaking down an amino acid called lysine.  This leads to a build-up of toxic chemicals in the child’s body – and the resulting chemical imbalances can lead to seizures, and delayed development and learning disabilities.

“Taking lifelong large daily supplements of pyridoxine can usually control their seizures,” says Professor Yue. “But this doesn’t address the long-term neurological symptoms – and so new treatments are urgently needed to improve the lives of children with PDE and their families.”

How could this research help?

“Our goal is to develop a new drug treatment that can prevent the build-up of the toxic chemical in the body that causes the disease,” says Professor Yue.

The researchers aim to achieve this by lowering the activity of another enzyme, which is responsible for an earlier step in lysine breakdown.  This approach – which is called substrate reduction therapy – has already been successfully applied to other rare diseases.

“We have previously identified several potential drug compounds – and we will now make tiny changes to their chemical structures and evaluate their properties in the laboratory,” says Professor Yue.

The team will then test the effects of the most promising drug candidates in cell studies, selecting the best ones for future development into treatments for patients.

If we can successfully identify a drug that can tackle the root cause of the neurological symptoms of PDE, this would greatly improve the quality of life of children affected by this debilitating condition.

Professor Yue

Research table

Project details

Project Leader Professor Wyatt W Yue, MBiochem PhD
Location Newcastle University Biosciences Institute
Project Team Professor Paul E Brennan, BSc PhD
Dr Cassandra J Adams, BSc DPhil
Other Locations Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford
Grant Awarded
Grant Amount £246,406
Start Date
End Date
Duration 24 months
Grant Code (GN number) GN2890

 

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