Treatment of a genetic brain disease by CNS-wide microglia replacement

Hematopoietic cell transplantation following myeloablative conditioning has been used to treat various genetic metabolic syndromes but is largely ineffective in diseases affecting the brain presumably due to poor and variable myeloid cell incorporation into the central nervous system. Here, we developed and characterized a near-complete and homogeneous replacement of microglia with bone marrow cells in mice without the need of genetic manipulation of donor or host. The high chimerism resulted from a remarkable competitive advantage of scarce donor cells during microglia repopulation rather than enhanced recruitment from the periphery. Hematopoietic stem cells but not immediate myeloid or monocyte progenitor cells contained full microglia replacement potency equivalent to whole bone marrow. To explore its therapeutic potential we applied microglia replacement to a mouse model of a neuronopathic form of Gaucher disease which cannot be rescued by peripheral interventions such as enzyme replacement therapy. We found a reduction of cerebellar neurodegeneration and gliosis in treated brains, improvement of motor and balance impairment, and life span extension even with treatment initiation as late as at adolescence. This proof-of-concept study suggests that efficient microglia replacement may have therapeutic efficacy for a variety of neurological diseases.