“Gene therapy may one day help many people with drug-resistant epilepsy,” said Professor Matthew Walker of UCL at the Kuopio Neuroscience 50 Symposium.
Held on 15–17 June, the symposium celebrated 50 years of neuroscience research in Kuopio under a theme bringing together its key research areas: Pathogenesis, Early Diagnosis and Modern Care of Neurodegenerative Diseases, Epilepsy and Stroke.
Walker, one of the invited speakers at the symposium, has long been developing gene therapy for drug-resistant focal epilepsy. The treatment will soon enter human trials. The clinical trial will be conducted by EpilepsyGTX, a spin-out company founded by the researchers, which has already raised around €30 million in funding for the study.
“Around one-third of people with epilepsy will not benefit from medication. Surgery is not possible either if the epileptic focus is located in a functionally important area of the brain. In the first phase, we are therefore studying gene therapy in patients who have no other options,” Walker said.
In the gene therapy developed by the researchers, viral vectors injected into the target area of the brain deliver a gene medicine that suppresses the excitability of brain cells.
“Compared with surgery, this is a relatively minor procedure and can also be repeated. In principle, the treatment would be suitable for anyone with epilepsy.”
“Currently, many of those with severe epilepsy benefit from surgery, but in the coming decades, advances in gene therapy and other forms of treatment may mean that epilepsy surgery is seldom needed,” added Reetta Kälviäinen, Professor of Neurology at the University of Eastern Finland and Director of the KUH Epilepsy Centre.
Brain samples from living patients shed light on immune cell function in the brain
“The brain’s immune cells, microglia, play an important role in the brain’s first-line defence and clean-up. However, in many brain diseases, their function is disrupted,” said Research Director Soyon Hong from University College London (UCL).
According to Hong, microglia are also important in maintaining synapses, which mediate communication between neurons.
“Functional synapses are also important for memory processes. In Alzheimer’s disease, synapses begin to die, so we are trying to determine what kinds of changes occur in microglia in this process and what causes them. In the long term, we hope to be able to support normal microglial function.”
Hong’s research group uses animal models of brain diseases. Collaboration with Professors Tarja Malm, Ville Leinonen and Mikko Hiltunen at the University of Eastern Finland has also made it possible to study changes associated with early pathogenic processes in brain tissue samples from living patients. The samples are obtained during shunt surgery from NPH patients at Kuopio University Hospital who also exhibit features of Alzheimer’s disease.
“We currently have extensive collaboration with Professor Malm’s research group. They are carrying out pioneering spatial transcriptomics, which allows gene expression in a brain sample to be examined both in microglia and in other adjacent cells.”
“Using animal models at UCL, we can investigate the effects of the changes observed in human cells in greater detail.”
New genomics methods are being used to identify memory-protecting cell states
Professor Evan Z. Macosko’s research group at the Broad Institute in the United States has developed novel genomics methods that can be used to study changes in cell states related to gene expression, for example in Alzheimer’s disease.
“We are interested in which cell states predict the progression of memory disorders and which, in turn, predict the preservation of memory functions.”
“Using patient samples taken in Kuopio, we have now been able to identify a cell state in microglia that appears to predict memory preservation – even when there is amyloid accumulation characteristic of Alzheimer’s disease in the brain. In these cells, genes related to the clearance of cellular waste and the suppression of inflammation, for example, are particularly active. In the future, it will be interesting to investigate whether cells can be activated into this state.”
According to Macosko, the collaboration with the University of Eastern Finland has been transformative, as living brain tissue is otherwise rarely available for research.
“It is ideal that, in addition to brain samples, other health data and follow-up data on patients are comprehensively also available.”
Among the latest methods developed by Macosko and colleagues is the Slide-tags technique, which makes it possible not only to measure gene activity in individual cells but also to locate their position in the tissue. This also provides information on how surrounding cells and interactions are associated with changes in cell states.
Diabetes and obesity drugs may enhance dementia prevention programmes
In the prevention of memory disorders, the direction of travel is towards increasingly tailored solutions, said Professor Miia Kivipelto.
Led by Kivipelto, the FINGER study has shown that memory disorders may be prevented through a multidomain lifestyle intervention programme that addresses diet, physical activity, cognitive training and the management of factors such as blood pressure, blood glucose and blood lipids.
“This allows us to influence several biological processes at once. Analyses of participants’ blood samples also show that memory disorders do not develop in the same way in everyone. Depending on the individual, early disease mechanisms may be related, for example, to vascular changes, metabolism or inflammation.”
In new studies addressing dementia prevention, more tailored solutions are being combined with the FINGER model according to participants’ individual risk factors. In the ongoing MET-FINGER project, the diabetes drug metformin has been added to the lifestyle intervention programme for individuals who, in addition to being at risk of a memory disorder, also have risk factors for type 2 diabetes. The participants are from Finland, Sweden and the United Kingdom.
“In the future, the idea is to incorporate GLP-1 drugs used to treat diabetes and obesity for people with multiple metabolic and inflammation-related risk factors. These drugs have also been found to have anti-inflammatory effects and, with the help of artificial intelligence, we can select, more accurately than before, the people who are likely to benefit from them.”
In Finland, the FINGER model has also been rolled out in healthcare, but to varying degrees across the wellbeing services counties.
“Funding for this has been available from the Ministry of Social Affairs and Health and experiences have been exchanged in FINGER developer networks. However, training and tools have been requested, and we are currently piloting FINGER ABC training for healthcare professionals.”
The multidisciplinary Neuroscience Research Community, NEURO RC, at the University of Eastern Finland aims to understand the disease-specific and common molecular mechanisms underlying neurodegenerative diseases and epilepsy and to identify novel biomarkers and therapeutic approaches for their prevention and cure. NEURO RC integrates biological neurosciences with data sciences, neuro-innovations and neuro-ethics. Learn more and connect with NEURO RC: https://www.uef.fi/en/research-community/neuroscience-neuro