Therapeutic potential of human microglial transplantation in a chimeric model of CSF1R-related leukoencephalopathy

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare, autosomal dominant primary microgliopathy caused by mutations in colony-stimulating factor 1 receptor (CSF1R). CSF1R signaling is necessary for microglial differentiation and survival. As a result, ALSP patient brains have fewer microglia and exhibit an array of neuropathologies including axonal spheroids, white matter abnormalities, reactive astrocytosis, and brain calcification. To explore the therapeutic potential of transplanting healthy human microglia, we generated 'hFIRE' mice, a xenotolerant mouse model of ALSP that lacks murine microglia. Remarkably, transplantation of induced pluripotent stem cell (iPSC)-derived microglial progenitors enabled rapid CNS-wide microglial engraftment, restoring a homeostatic microglial gene signature and preventing diverse ALSP-related neuropathologies. To further examine a potential autologous approach, ALSP-patient derived iPSCs were CRISPR-corrected, rescuing mutation-induced deficits in microglial proliferation, enabling brain-wide microglial engraftment, and reducing pre-existing spheroid, astroglial, and calcification pathologies within just 6 weeks. Together with the accompanying study by Munro and Colleagues, these results demonstrate the utility of FIRE mice to model diverse ALSP neuropathologies and provide initial evidence that iPSC-microglia could be further developed as a promising new therapeutic strategy for ALSP and perhaps other microglia-associated neurological disorders. Overall design: hCSF1 and hCSF1-FIRE mice received intracerebroventricular and cortical injections of either phosphate buffered saline (n=5 hCSF1; n=4 hCSF1-FIRE) or human hematopoietic progenitor cells (n=4 hCSF1-FIRE) to examine the effects of loss of murine microglia (hCSF1-FIRE_PBS vs hCSF1_PBS) and whether these deficits were recovered following transplantation of human HPCs (hCSF1-FIRE_HPC vs hCSF1_PBS).