Periodic Reporting for period 5 - PHAGO (Inflammation and AD: modulating microglia function focussing on TREM2 and CD33 - Sofia ref.: 115976)
Reporting period: 2020-11-01 to 2022-04-30
Alzheimer’s disease (AD) is an age-related chronic neurodegenerative disease with progressive loss of nerve cells and their connectivity in the brain. Today, over 46 million people live with dementia worldwide and this number is estimated to increase to more than 100 million by 2050.
Phagocytic cells, namely microglia, accumulate around amyloid plaques in the brains of AD patients and show a dysfunctional activation profile. Recent systems biology approaches have identified two innate immune receptor genes TREM2 and CD33/SIGLEC3 as disease relevant players in AD. TREM2 and CD33/SIGLEC3 might be attractive targets for development of treatments, but knowledge on their mechanistic contribution to AD has been poor at the beginning of the PHAGO project.
PHAGO filled this knowledge gap and provided tools and assays for targeting these both innate immune receptors, namely TREM2 and CD33/SIGLEC3. PHAGO enabled rapid transfer of the academic scientific findings on TREM2 and CD33 towards the collaborating pharmaceutical industries. PHAGO disseminated the generated knowledge regarding TREM2/CD33 to relevant stakeholders for further development by presentations and peer-reviewed publications. PHAGO also created a knowledge database containing data generated by PHAGO in addition to publicly available data resources. PHAGO exploited intellectual property related to inventions on TREM2-cleavage and an improved protocol for up-scaled production of microglia-like/-precursor cells and macrophage cell using mesh macrocarriers by filing patent applications.
PHAGO achieved these goals by bringing together experts from industry and academia in a powerful collaboration. In addition, PHAGO reached out to other IMI-collaborative undertakings in order to maximally utilize synergisms throughout the European Research landscape.
Thus, PHAGO paved the way for the future development of drugs that potentially might delay the progression of Alzheimer’s disease by targeting TREM2 or CD33/SIGLEC3.
Phagocytic cells, namely microglia, accumulate around amyloid plaques in the brains of AD patients and show a dysfunctional activation profile. Recent systems biology approaches have identified two innate immune receptor genes TREM2 and CD33/SIGLEC3 as disease relevant players in AD. TREM2 and CD33/SIGLEC3 might be attractive targets for development of treatments, but knowledge on their mechanistic contribution to AD has been poor at the beginning of the PHAGO project.
PHAGO filled this knowledge gap and provided tools and assays for targeting these both innate immune receptors, namely TREM2 and CD33/SIGLEC3. PHAGO enabled rapid transfer of the academic scientific findings on TREM2 and CD33 towards the collaborating pharmaceutical industries. PHAGO disseminated the generated knowledge regarding TREM2/CD33 to relevant stakeholders for further development by presentations and peer-reviewed publications. PHAGO also created a knowledge database containing data generated by PHAGO in addition to publicly available data resources. PHAGO exploited intellectual property related to inventions on TREM2-cleavage and an improved protocol for up-scaled production of microglia-like/-precursor cells and macrophage cell using mesh macrocarriers by filing patent applications.
PHAGO achieved these goals by bringing together experts from industry and academia in a powerful collaboration. In addition, PHAGO reached out to other IMI-collaborative undertakings in order to maximally utilize synergisms throughout the European Research landscape.
Thus, PHAGO paved the way for the future development of drugs that potentially might delay the progression of Alzheimer’s disease by targeting TREM2 or CD33/SIGLEC3.
PHAGO has generated and characterized more than 40 iPSC lines, that will be deposited in the EBiSC2 iPSC repository that are available to the scientific community. PHAGO has generated reporter cell lines for TREM2 and CD33, and showed its suitability for drug screening. PHAGO has shown that TREM2 is cleaved and shed at the extracellular part. PHAGO has demonstrated that the shed soluble wild-type sTREM2 blocks amyloid-β aggregation and neurotoxicity, whereas the Alzheimer's TREM2-R47H mutant increases Aβ aggregation. PHAGO showed that the deletion of Alzheimer's disease-associated CD33 in iPSC microglia resulted in an inflammatory human microglia phenotype. PHAGO demonstrated that human induced pluripotent stem cell-derived microglia-like cells harboring TREM2 missense mutations show specific deficits in phagocytosis and migration. PHAGO has established highly sensitive biomarkers for detecting soluble TREM2 in the CSF of patients and monitored the levels of sTREM2 in carriers with rare TREM2 variants in relation to levels of neurofilament light chain. PHAGO has contributed to elucidate the role of sialylation for regulation of microglial function and for protecting the brain against inflammatory age-related loss of neurons.
PHAGO partners filed two patent applications. Firstly, DZNE (Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. Munich, Germany) showed that antibodies against the stalk region of TREM2 can enhance the protective clearance function of microglia and might have possible future potential for a clinical application. Secondly, Life & Brain GmbH (Bonn, Germany) established an up-scalable technique for production of microglia-like/-precursor cells and macrophage cell using mesh macrocarriers.
To achieve this output, PHAGO had regularly project discussion through reports, teleconferences within and between work packages and remote meetings via videoconferences. In total, six General Assembly Meetings have been organized to discuss the status of the project within the whole consortium.
PHAGO partners filed two patent applications. Firstly, DZNE (Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. Munich, Germany) showed that antibodies against the stalk region of TREM2 can enhance the protective clearance function of microglia and might have possible future potential for a clinical application. Secondly, Life & Brain GmbH (Bonn, Germany) established an up-scalable technique for production of microglia-like/-precursor cells and macrophage cell using mesh macrocarriers.
To achieve this output, PHAGO had regularly project discussion through reports, teleconferences within and between work packages and remote meetings via videoconferences. In total, six General Assembly Meetings have been organized to discuss the status of the project within the whole consortium.
PHAGO has generated a strong platform of iPSC and characterized microglial cells derived from iPSC lines with TREM2/CD33 polymorphisms. These iPSC lines are a unique source for follow-up research and are available via the cell bank of EBiSC (https://ebisc.org/search). See also PHAGO publications on: https://zenodo.org/communities/phago