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Strengthening regional stem cells based research for advancement of multi modal innovative strategy for modelling neurodevelopmental disorders

Periodic Reporting for period 1 - STREAMLINE (Strengthening regional stem cells based research for advancement of multi modal innovative strategy for modelling neurodevelopmental disorders)

Reporting period: 2022-07-01 to 2023-09-30

Neurodevelopmental disorders (NDDs), caused by alterations in early brain development, are a group of complex and heterogeneous disorders that give rise to psychiatric conditions such as autism spectrum disorders, intellectual disability, schizophrenia, and bipolar disorder. The prevalence of NDDs is estimated to be 10 to 15% of all births and it has been increasing worldwide over the last years, bringing a large societal and financial burden in Europe and worldwide.
Studies of the mechanisms underlying NDDs are challenging since over 1000 genetic loci have shown an association with increased risk for these disorders. Therefore, focusing on syndromes with a defined genetic origin associated with a high risk for NDDs represents a good approach for modelling diseases in vitro and get closer to understanding both the causes and potential therapeutic strategies. One of the syndromes with known genetic origin associated with a high risk for NDDs is 22q11.2 Deletion Syndrome (22q11.2DS) caused by microdeletion of the region q11.2 of chromosome 22. 22q11.2DS is one of the strongest known risk factors for the development of psychiatric illness (54% of the patients were diagnosed with at least one psychotic symptom of moderate to high severity) and one of the highest known genetic risks for schizophrenia (about 25% of patients with 22q11.2DS develop schizophrenia).

Patients with NDDs and mental health problems are geographically dispersed. In the Western Balkan Region research focused on NDDs is still facing limitations due to insufficient funding and gaps in technologies. The establishment of high-capacity regional center with similar research capacity and codes of practice compared to EU countries is needed to build global research activity. The goals of STREAMLINE are to enhance strategic networking and reinforce the research and innovation potential of the Institute of Molecular Genetics and Genetic Engineering (IMGGE) to develop IMGGE as a high-capacity hub for research of NDDs in the Western Balkans which can integrate with similar centers in Europe. This will be achieved by twinning IMGGE with three top-class research institutions in Europe: Cardiff University (CA), Maastricht University (UM), and the Centre for Research and Technology Hellas (CERTH). The project objectives are: a) to enhance the current and scale up the overall strategic networking activities between the IMGGE and internationally-leading European partners and regional partners; b) to raise the research profile of research staff and scientific attractiveness of IMGGE in the field of NDDs; c) to strengthen research management capacities and administrative skills of the IMGGE staff and d) to become a regional leader in innovations tackling NDDs. Objectives will be achieved through networking, staff exchanges, trainings, summer schools, symposia, workshops, participation at conferences and dissemination in the scientific community, industries, and the public. Also, STREAMLINE HUB will be established for the continual regional education of researchers in the field of stem cell-based NDDs modelling, drug testing, and personalized medicine.
STREAMLINE aims to contribute to the increase of European critical mass for the NDD research field by strengthening strategic networking and by implementing novel methodologies crucial for prosperous biomedical research of NDDs in Serbia and the Western Balkan Region.
STREAMLINE Exploratory research project aims to study molecular mechanisms underlying intrafamilial phenotypic variability seen in patients with 22q11.2DS. In the Project, two families with the inherited form of 22q112DS were selected and their iPSCs were generated. So far, the research staff of IMGGE were trained for cell reprogramming at the Cardiff University and this methodology was successfully implemented at IMGGE. Obtained iPSCs are differentiated into neural progenitors, astrocytes and/or neurons. Also, whole genome sequencing (WGS) was performed to detect additional genetic variation present in affected children.
Currently, one researcher has been trained for RNA seq and two for Bioinformatics data analysis and formation of a digitalized repository at the UM. Furthermore, to properly manage the Project, a Digital project management handbook, Risk management strategy, and Data management plan were developed. In the previous period, the strategic networking of STREAMLINE partners was strengthened through applying to three projects, two of which were approved for financing, and through the organization of two workshops.
One of the aims of STREAMLINE is to strengthen the research management capacities and administrative skills of IMGGE staff. In the previous period, six trainings covering six different topics were provided by experts from partner institutions. Also, one staff exchange for administrative staff was finished and one is currently going on focused on the Research governance and European consortium administration.
To form a collaborative ecosystem for research of NDDs in the Western Balkan region, the Spring school "iPSCs as a tool for modelling disease and discovering molecular mechanisms of NDDs" and two symposia, gathering patients with 22q11.2DS their families, patients’ associations and experts from different fields, were held.
STREAMLINE is directed to reinforce scientific and innovation capacities for all actors in the R&I system in widening countries, increase the attractiveness and retention of research talents, and raise participation successes in Horizon Europe and consortium leadership roles. It will provide access to new research avenues, creativity and development of new approaches, and increased mobility of qualified scientists at IMGGE enabling the establishment of IMGGE as a high-capacity regional center with equivalent research capacity and codes of practice as similar centers in Europe. Furthermore, it will advance understanding of molecular mechanisms underlying NDDs, and contribute to the search for more complete diagnostic and therapeutic approaches.
STREAMLINE graphical abstract