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What did the project achieve?
Our laboratory research has improved the understanding of the biological mechanisms involved in Vici syndrome*, a rare and severe genetic condition that affects virtually any part of the body,” says Professor Heinz Jungbluth and Dr Manolis Fanto of King’s College London. “We’ve also created a new platform to test potential treatments or dietary approaches that could help improve the lives of children affected by this devastating condition - and others that are closely related to it – in the future.”
Vici syndrome is caused by faults in the EPG5 gene, which provides the instructions for making a protein involved in autophagy – a vital process cells use to clear out aging or damaged components. When this process doesn’t work properly, it can lead to widespread problems in the body and symptoms similar to those consistent with premature aging.
Children with Vici syndrome often have eye and heart problems, delayed development, progressive deterioration of the nervous system, seizures, and frequent infections due to a weakened immune system. Sadly, there is no cure and the most severely affected children do not live beyond their fifth birthday.
“Although Vici syndrome is rare, more recently we have discovered that faults in the EPG5 gene can also cause a much wider range of conditions that affect the brain and nervous system, including various forms of cerebral palsy, other movement disorders and early-onset Parkinson’s disease,” says Professor Jungbluth.
In this project, the researchers focused on developing a range of laboratory models to better understand how faults in the EPG5 gene cause Vici syndrome and related conditions – and more generally, how problems with autophagy contribute to other, more common neurological diseases.
One of their most recent discoveries involved using cutting-edge gene editing technologies to create a fruit fly model lacking the EPG5 gene. They used this model to study the role of this gene in development, ageing – and seizures, which affect around two in three children with Vici syndrome.1
“The results from our experiments have provided crucial information on how deficiencies in autophagy lead to seizures,” says Professor Jungbluth and Dr Fanto. “Importantly, these insights also suggest potential dietary strategies that could help control seizures and improve the quality of life of children with Vici syndrome and related disorders linked to defective autophagy.”
*While this project initially aimed to study three rare and incurable neurodevelopmental conditions, the researchers focused their efforts on the mechanisms underlying Vici syndrome as the most representative of the three conditions. Due to their close links, any results from the in-depth investigation of Vici syndrome are also likely to be relevant to these closely linked disorders.
This research was completed on
Thousands of families across the UK are coping with the challenge of caring for children with rare and devastating diseases for which there are no cures. Together, these diseases severely affect many forgotten children, but the rarity of each individual disease can hinder efforts to develop treatments. Dr Heinz Jungbluth, of King’s College London, is searching for treatments for three rare diseases that are all linked to faults in an important quality control process within cells. Targeting processes like this, which are common to several different diseases rather than just one disease in isolation, offers hope to more children.
How are children’s lives affected now?
More than 5,000 rare diseases have been identified.1 Although each disease is rare – affecting no more than one in 2,000 people – together they affect seven per cent of the UK population.1 Many dramatically affect people’s lives.
“We’re studying three rare diseases that are classified as ‘early onset neurodevelopmental disorders’, which include some of the most devastating conditions known in humans,” says Dr Jungbluth. “Children with these conditions often have severe learning disabilities and may never be able to walk. Blindness, hearing loss and seizures are common complications. Sadly, there is no cure for most of these conditions and children’s life expectancy can be markedly reduced.”
“The understanding of the genetic changes that cause neurodevelopmental disorders has increased rapidly in recent years, but the development of new treatments has lagged frustratingly behind,” adds Dr Jungbluth “We urgently need new treatments.”
How could this research help?
“Our ultimate goal is to find treatments for three rare and incurable diseases that have all been linked to faults in a natural process called autophagy,” says Dr Jungbluth. “Autophagy helps nerves and other cells to develop normally and keep healthy. It can be thought of as cells eating parts of themselves that are faulty or unnecessary'.
“We’re generating models of the diseases using fruit flies, whose cellular quality control processes are similar to those of humans, so we can better understand what goes wrong and, more importantly, test a range of gene therapies and drugs to find out whether they are possible treatments,” continues Dr Jungbluth. “Treatments that show promise are then being tested in human cells.”
“Our work could help in the development of new treatments for a wide range of disorders that are linked to defective autophagy – both rare diseases like the ones we’re studying and more common problems such as epilepsy, dementia and cerebral palsy,” adds Dr Jungbluth.
References
1. National Institute for Health Research. Rare Diseases Translational Research Collaboration (TRC). http://www.nihr.ac.uk/about/rare-diseases-translational-research-collaboration.htm Website accessed 28 February 2016.
| Project Leader | Dr Heinz Jungbluth MD PhD |
| Project Team | Dr Manolis Fanto PhD |
| Project Location | Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, St Thomas' Hospital, King’s College London |
| Project duration | 3 years |
| Date awarded | 8 January 2016 |
| Project start date | 1 March 2016 |
| Project end date | 31 December 2022 |
| Grant amount | £197,474 |
| Grant code | GN2446 |
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