SubsidieMeestersMicroglia engineering and replacement to treat brain disease
The ReplaceMi project aims to develop a translatable strategy for replacing dysfunctional microglia with healthy progenitors to treat neurodegenerative diseases through innovative technologies.
Projectdetails
Introduction
Microglia are highly versatile brain resident cells that offer tremendous therapeutic opportunities. They are instrumental for maintaining healthy brain physiology and act as the primary modulators of neuroinflammation and disease.
Importance of Microglia
Microglial dysfunction has been convincingly linked to a myriad of neurological disorders, making these cells a prime target for therapeutic intervention. Remarkably, microglia are embryo-derived cells that self-maintain for life, with negligible replacement by the bone marrow. This astonishing self-renewal capacity offers a unique opportunity for cell therapy.
Therapeutic Potential
The ability to replace dysfunctional microglia with healthy or genetically enhanced counterparts may transform the way we treat brain disease. However, challenges arise in replacing a cell that is so adept at self-renewal in a tissue that is shielded from the periphery. Currently, there are no translatable approaches for the specific replacement of microglia. Furthermore, bone marrow progenitors are unable to adopt the embryonic microglial phenotype.
Research Objectives
By building on our unpublished observations and developing innovative technologies, I aim to lay the foundation for microglial replacement therapy. We intend to develop an original and translatable strategy for the specific and near-complete replacement of embryonic microglia with adoptively transferred progenitors.
Methodology
Next, by combining iPSC differentiation with genetic barcoding, single-cell analysis, and in vivo screening, we aim to identify progenitors that efficiently traffic to the brain and engraft as bona fide microglia.
Future Directions
Moreover, we will investigate how we can transform microglia into local protein production factories, as a potential basis to treat neurodegenerative diseases. Finally, we will set up in vivo pooled CRISPR screens to identify the gene networks that can modulate and positively enhance microglial disease responses.
Conclusion
ReplaceMi has the potential to result in a new and eagerly awaited breakthrough in treating brain disease.
Financiële details & Tijdlijn
Financiële details
| Subsidiebedrag | € 2.000.000 |
| Totale projectbegroting | € 2.000.000 |
Tijdlijn
| Startdatum | 1-8-2023 |
| Einddatum | 31-7-2028 |
| Subsidiejaar | 2023 |
Partners & Locaties
Projectpartners
- VRIJE UNIVERSITEIT BRUSSELpenvoerder
Land(en)
Vergelijkbare projecten binnen European Research Council
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|---|---|---|---|---|
A novel and empowered TARGETed gene addition approach at a relevant microglia locus for the treatment of inherited NeuroMetabolic DiseasesDevelop a targeted gene addition approach at a microglia locus in HSCs to safely and effectively treat inherited neurometabolic diseases by enhancing timely microglia-like cell engraftment. | ERC Advanced... | € 2.495.250 | 2022 | Details |
Microglia As conTroller of braIn metaboLism During AgingThis project aims to investigate how microglia, via the Trem2 gene, influence hypothalamic metabolism and energy homeostasis, with potential implications for treating immunometabolic dysfunction. | ERC Advanced... | € 2.500.000 | 2023 | Details |
Deciphering the microglia-neuron interactions in human Alzheimer's diseaseThis project aims to elucidate how human microglia contribute to neuronal toxicity in Alzheimer's disease using a pioneering xenograft model to explore their interactions and secretome. | ERC Starting... | € 1.500.000 | 2023 | Details |
Dissection of Microglial State Biology in Brain RepairThis project aims to elucidate the dynamics and functions of microglial states during brain repair using a spatiotemporal atlas and novel molecular tools to enhance understanding of neuroinflammation. | ERC Starting... | € 1.684.803 | 2024 | Details |
TREM2 MICROglia ENGENEering for treating dementiaS (TREM2MICROENGINES)TREM2MICROENGINES aims to restore TREM2 expression in microglia of Alzheimer's and Nasu–Hakola disease patients to enhance neuroinflammation response and reduce amyloid-β accumulation. | ERC Proof of... | € 150.000 | 2022 | Details |
A novel and empowered TARGETed gene addition approach at a relevant microglia locus for the treatment of inherited NeuroMetabolic Diseases
Develop a targeted gene addition approach at a microglia locus in HSCs to safely and effectively treat inherited neurometabolic diseases by enhancing timely microglia-like cell engraftment.
Microglia As conTroller of braIn metaboLism During Aging
This project aims to investigate how microglia, via the Trem2 gene, influence hypothalamic metabolism and energy homeostasis, with potential implications for treating immunometabolic dysfunction.
Deciphering the microglia-neuron interactions in human Alzheimer's disease
This project aims to elucidate how human microglia contribute to neuronal toxicity in Alzheimer's disease using a pioneering xenograft model to explore their interactions and secretome.
Dissection of Microglial State Biology in Brain Repair
This project aims to elucidate the dynamics and functions of microglial states during brain repair using a spatiotemporal atlas and novel molecular tools to enhance understanding of neuroinflammation.
TREM2 MICROglia ENGENEering for treating dementiaS (TREM2MICROENGINES)
TREM2MICROENGINES aims to restore TREM2 expression in microglia of Alzheimer's and Nasu–Hakola disease patients to enhance neuroinflammation response and reduce amyloid-β accumulation.
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IMPROVING THE EFFECTIVENESS AND SAFETY OF EPIGENETIC EDITING IN BRAIN REGENERATION
REGENERAR aims to develop a non-viral delivery system to reprogram glial cells into neurons for treating CNS injuries, focusing on safety, targeting, and stakeholder collaboration.
Towards the clinical implementation of TREM2 Microglia Engineering for treating DementiaS
TREM2MEDS aims to transition a novel gene therapy for Alzheimer’s and Nasu-Hakola Diseases from preclinical validation to a Phase I clinical trial, targeting TREM2 dysfunction in microglia.
AI-powered platform for autologous iPSC manufacturing
The project aims to develop an AI-guided microfluidic device for the standardized, cost-effective mass production of personalized iPSCs to enhance cancer therapies and tissue regeneration.
NOn-VIral gene modified STEM cell therapy
This project aims to develop a high-throughput protocol for producing gene-corrected CAR T cells and blood stem cells using optimized photoporation and CRISPR technology for enhanced clinical application.
Opto-Electronic Neural Connectoid Model Implemented for Neurodegenerative Disease
The project aims to develop a novel human brain-organoid model, called connectoids, to replace animal testing for Parkinson's disease, enhancing therapy monitoring and reducing societal burdens.