Advancing brain immunity: developing translational strategies for microglia replacement and brain macrophage mobilization.

Microglia and monocyte-derived macrophages (MDMs) play essential roles in maintaining brain
health. While microglia are responsible for preserving healthy brain homeostasis, their malfunction is
linked to neurodegenerative disorders like Alzheimer’s disease (AD). MDMs that are recruited during
disease, carry out complementary functions and can help tackle brain pathology. Microglia undergo
life-long self-renewal for which they are dependent on Colony Stimulating Factor 1 (CSF1R)-
signaling. This makes them attractive for cell therapy, aimed at replacing dysfunctional microglia with
healthy or enhanced counterparts. However, a key challenge is developing a translatable strategy for
efficiently replacing microglia with adoptively transferred progenitors. In this project, we propose to
develop innovative strategies that can be used to: (1) obtain efficient replacement of endogenous
microglia with adoptively-transferred iPSC-derived myeloid progenitors, or (2) induce robust
recruitment of host MDMs to the diseased brain to mitigate pathology. These strategies leverage the
innovative use of antisense oligonucleotides (ASOs) and genome engineering. I aim to demonstrate
the therapeutic potential of these approaches in AD, using preclinical models of amyloid pathology,
complemented with single-cell multi-omic profiling. This work will pave the way for novel therapeutic
interventions to treat neurodegenerative disorders.