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A new approach is promising for the treatment of frontotemporal dementia in preclinical trials
Last reviewed: 02.07.2025
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Frontotemporal dementia is an incurable brain disease that causes memory loss, speech disorders, and personality changes. In 5-12% of cases, the disease is triggered by a decrease in progranulin levels. A deficiency of this protein leads to disturbances in the breakdown of proteins, which causes the accumulation of insoluble toxic proteins. This, in turn, leads to brain inflammation, neuronal death, and significant functional impairment of the central nervous system.
Frontotemporal dementia is inherited in 40% of cases: carriers of the corresponding genetic mutation inevitably develop the disease. Researchers from the LMU Faculty of Medicine and the German Center for Neurodegenerative Diseases (DZNE), in close collaboration with Denali Therapeutics from San Francisco, have developed a new therapeutic approach to replace the missing protein in the brain. They published their results in the journal Science Translational Medicine.
Therapeutic approach
"We inserted the progranulin gene into the virus genome," explains Dr. Anja Capel, a senior researcher at the LMU Biomedical Center and one of the lead authors of the paper. The team then injected the modified viruses into the bloodstream of mouse models. "The virus targets liver cells, which start producing progranulin in large quantities and secrete it into the blood."
The approach thus avoids directly introducing viruses into the brain, which carries the risk of serious side effects.
To make this peripheral approach work, the researchers used a trick to bypass the blood-brain barrier, which normally blocks the exchange of biomolecules between the blood and the brain. A special "brain shuttle" developed by Denali Therapeutics allows substances to be transported efficiently across this barrier.
Significant reduction in symptoms in mouse model
"After a single administration of the virus, we checked whether the symptoms were reduced," says Professor Dominique Paquette from the Institute for Stroke and Dementia Research (ISD), another lead author and member of the SyNergy excellence cluster. It turned out that disturbances in protein degradation, the accumulation of insoluble toxic proteins, brain inflammation, movement disorders and neuronal death were significantly reduced. "The next step was to investigate whether this approach could be transferred to humans using stem cell models." Here, too, a significant reduction in disease symptoms was observed. The researchers have thus demonstrated that forms of frontotemporal dementia based on a partial loss of progranulin can be treated in preclinical trials using replacement therapy.
The importance of interdisciplinary collaboration
Such comprehensive, multidisciplinary research is only possible in a team. "I am pleased that our SyNergy excellence cluster provides us with unique opportunities in this regard. At the same time, this study highlights the importance of strengthening our collaboration with leading biotech companies so that we can implement our research into clinical practice as quickly as possible for the benefit of patients," says Professor Christian Haass from the LMU Biomedical Center, one of the leading researchers and spokesperson for SyNergy.