PREMOS: how mouse models contribute to a better treatment of human brain disorders

March 21, 2021

A new EBRA cluster will coordinate the predictive use of animal models in brain research

The European Union and its member states have been investing in research to better understand the human brain and its disorders for many years. In 2018, the EU has launched the European Brain Research Area (EBRA) project – a catalysing platform designed to coordinate brain research in Europe and to develop and support global initiatives in this area.

In February 2021 EBRA introduced a new cluster activity called PREMOS to complement its efforts. PREMOS provides researchers with a powerful additional tool: animal (mostly mouse) models to serve as predictive modeling systems for disease areas including neurodevelopmental and neurodegenerative disorders, for example Alzheimer’s or Huntington’s disease. Leading neuroscientists and genetics experts from the INFRAFRONTIER Research Infrastructure will join forces with two other consortia in PREMOS to enhance the translational value of animal models. Their aim is to define the main challenges in using model organisms in basic brain research, to develop ideas for new solutions, and to identify the resources and stakeholders needed to accomplish this goal.

Sabine Hölter (PhD), the head of the Behavioural Neuroscience team at Helmholtz Centre Munich and a long-time member of INFRAFRONTIER, is the coordinator of PREMOS. In our interview, she explains the general plans for the new cluster and the innovative approach PREMOS takes in bringing predictive model systems to brain research.

Dr Hölter: as an expert in experimental psychology, why is brain research so important for you?
Sabine Hölter: I have always been fascinated by how `nature and nurture´ interact to make us who we are. Brain structure and functions are shaped not only by our genes, but also by our environment – the physical as well as the social one. Whatever we experience in life leaves traces in our brain and influences our personality. I never get tired of learning new aspects about this process.

How can the lessons from genetics research with animal models contribute to basic brain research?
Sabine Hölter: Brain structure and functions in all mammals are largely determined by genetic and developmental processes. Precise animal models of human genetic disorders can tell us a lot about how a small genetic change can alter development in ways that increase the risk of psychiatric disorders. They also allow us to compare the functions of gene variants and their respective proteins. Gene variants matter a lot: some can cause disease while others do not – and some can even be protective. What´s more, animal models help to uncover early signs of diseases. This can be clinically useful in developing tools for early diagnosis and thus in improving treatment prospects for patients.

An essential task for PREMOS is described as defining the `main gaps in the translational value of animal models´. What does that mean?
Sabine Hölter: The translation of insights from animal studies to humans can fail for many reasons. For example, studies may not have been designed or performed in the best possible way. Or else they may have been directed at aspects that turn out not to be relevant to the disease being studied. That´s a particular danger if the exact causes of that disease are unknown – which is the case for most complex diseases, including many brain disorders.

How can a research infrastructure like INFRAFRONTIER contribute to this task?
Sabine Hölter: The value of INFRAFRONTIER lies in its expertise in designing and generating mouse models precisely to the needs of clinical scientists. A clinician specialising in a particular disorder can identify in his or her patients the important aspects of the disease – and then ask us to model those aspects in our mice.

Three consortia cooperate as partners in PREMOS. Why is that useful?
Sabine Hölter: The other two consortia alongside INFRAFRONTIER are called PRISM and EQIPD. I am happy that all these platforms have decided to “leave their silos” and join forces to help make animal models more predictive for brain disorders. PRISM focuses on the `reverse translation´ aspect – that means it determines the quantifiable biological markers of clearly characterised patients that need to be modeled in animals. EQIPD is a quality control consortium which specialises in reproducibility. So it ensures that all studies are designed and performed in the best possible way. Each of these aspects is necessary to enhance the translational value of animal models – and to rethink the conditions under which model systems can lead to relevant clinical information.

What are the milestones in the PREMOS working programme?
Sabine Hölter: Our heterogenous group of experts from academia and industry have partially overlapping expertise. We have first to compile a comprehensive list of potential reasons for translational failures. The second step will be to agree which of these reasons might be the most relevant. Then we will incorporate feedback from stakeholders, including clinical researchers and patient organisations. In step 4, we will present the outcome to our partners in policy making and publish our results in a peer-reviewed journal.

Twitter handle: @SabineHoelter

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