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What did the project achieve?
“This project has generated further evidence on the safety and effectiveness of a promising new treatment for children with Hunter syndrome,” says Professor Brian Bigger of the University of Edinburgh. “It has also provided valuable insights that could help guide the development of future treatments for other inherited conditions with similar underlying causes, particularly those that mainly cause symptoms outside the brain.”
Hunter syndrome, also known as mucopolysaccharidosis type II (MPS II), is a rare genetic disease that almost exclusively affects boys. It is caused by the absence of an enzyme needed to break down certain complex sugars. As a result, these sugars build up in the body and cause progressive symptoms in many organs and tissues, including the brain, liver, lungs, bones, eyes, skin and heart. Although enzyme replacement therapy can help improve some symptoms and quality of life, it is not effective at treating neurological symptoms because the enzyme does not reach the brain efficiently.
To address this challenge, Professor Bigger’s team has developed a stem cell gene therapy, now being tested in early clinical trials. This involves taking stem cells from the bone marrow, adding a working copy of the faulty gene in the laboratory, and then returning these modified cells into the body so they produce the missing enzyme. However, getting enough of this enzyme into the brain remains a challenge.
In previous research, the team found that attaching a small protein tag to the enzyme boosted its uptake into the brain compared with the untagged version. This study aimed to identify alternative protein tags that might work even better. The researchers initially tested several small protein tags to see whether they could improve the delivery of the enzyme into brain, heart, bone and eye cells grown in the laboratory.
“We identified one tag that outperformed the current version used in our gene therapy in a range of cell types, but further experiments showed it did not help to improve brain symptoms,” says Professor Bigger. “However, it may be more effective at correcting symptoms of the disease in other organs, such as the heart.”
These findings suggest that this protein tag could be useful for treating other rare diseases caused by enzyme deficiencies, where the main symptoms affect organs other than the brain.
This research was completed on
This project is jointly funded by Action Medical Research and LifeArc.
How are children’s lives affected now?
In Hunter syndrome, a faulty gene leads to a deficiency of an enzyme called iduronate-2-sulfatase (IDS), which breaks down large sugars. This leads to an abnormal accumulation of these large molecules in the child’s body, causing a wide range of symptoms affecting many tissues and organs – including their brain, liver, lungs, bones, eyes, skin and heart. Sadly, their lives will often be cut tragically short.
“A child with the most severe form of the condition will usually start to experience symptoms between two and four years of age,” says Professor Bigger. “They will have progressive learning difficulties and behavioural problems due to a build-up of complex sugars in their brain.”
Although therapies that aim to replace the faulty enzyme can be effective at treating some symptoms, the blood-brain-barrier prevents these treatments from crossing into the brain efficiently.
“There is an urgent need to develop better treatments for boys with this devastating condition – especially those that can reach inside the brain,” says Professor Bigger.
How could this research help?
“Our aim is to improve the effectiveness of our innovative stem cell gene therapy at getting the enzyme into the brain in patients with Hunter syndrome,” says Professor Bigger.
Professor Bigger’s team previously developed the approach that involves taking stem cells from bone marrow, inserting a correct copy of the IDS gene, and then transplanting them into the body. These cells then produce the IDS enzyme, treating the symptoms of the disease.
“Unfortunately, we’ve so far struggled to have much of an impact on brain symptoms as we can’t get high enough levels of the enzyme into these cells,” says Professor Bigger.
The researchers are now investigating if they can boost the levels of the enzyme in the brain by adding on a small protein tag that helps it to cross the blood-brain-barrier.
“If we can show this approach is both safe and effective, this laboratory research could help pave the way for a future clinical trial in boys with Hunter syndrome,” says Professor Bigger.
Research table
Project details
| Project Leader | Professor Brian W Bigger BSc PhD |
| Location | Centre for Regenerative Medicine, Institute for Regeneration and Repair, The University of Edinburgh |
| Project Team | Dr Shaun R Wood BSc MRes DPhil |
| Grant Awarded | |
| Grant Amount | £249,458 |
| Start Date | |
| End Date | |
| Duration | 36 months |
| Grant Code (GN number) | GN2823 |
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