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

Hematopoietic cell transplantation after 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 for genetic manipulation of donor or host. The high chimerism resulted from a 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 for Prosaposin deficiency, which is characterized by a progressive neurodegeneration phenotype. 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 started in young adulthood. This proof-of-concept study suggests that efficient microglia replacement may have therapeutic efficacy for a variety of neurological diseases. Description Highly efficient, nongenetic microglia replacement was therapeutic in a mouse model of a progressive neurodegenerative brain disease. Efficient replacement Cell therapies have the potential of being an effective approach for treating neurodegenerative conditions. However, the need for local delivery and the poor distribution of the transplanted cells hinder the development of effective treatments. Here, Shibuya et al. developed an efficient microglia replacement approach in rodents using circulation-derived myeloid cells (CDMCs). The cells broadly incorporated in the brain and generated microglia-like cells more efficiently than bone marrow transplant. In a mouse model of progressive neurodegeneration, CDMC-mediated microglia replacement reduced cell loss and brain inflammation, improved motor behavior, and extended life span. The results suggest that this approach might be therapeutic in multiple neurological conditions.