Project description
Microglia-based treatment of brain diseases
Microglia are cells that reside in the brain and are involved in maintaining brain health and modulating inflammation. Dysfunctional microglia have been linked to neurological disorders, making them a prime target for therapy. Microglia are capable of self-renewal, offering a unique opportunity for cell therapy. However, there are no current approaches for the specific replacement of microglia. Funded by the European Research Council, the ReplaceMi project aims to develop an innovative strategy to replace embryonic microglia using specific progenitors. Using induced pluripotent stem cells, researchers will identify progenitors that can efficiently engraft in the brain as microglia. ReplaceMi will also investigate how microglia can be transformed into protein production factories to treat neurodegenerative disorders and identify gene networks for improving microglial disease responses.
Objective
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. 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. The ability to replace dysfunctional microglia with healthy or genetically enhanced counterparts may transform the way we treat brain disease. But how can we replace 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. By building on our unpublished observations and developing innovative technologies, I aim to lay the foundation for microglial replacement therapy.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. 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. 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. ReplaceMi has the potential to result in a new and eagerly awaited breakthrough in treating brain disease.
Fields of science
Keywords
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
1050 Bruxelles / Brussel
Belgium