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Microglia replacement halts the progression of microgliopathy in mice and humans

Jingying Wu,Yafei Wang,Xiaoyu Li,Pei Ouyang,Yuanyuan Cai,Yang He,Mengyuan Zhang,Xinghua Luan,Yuxiao Jin,Jie Wang,Yujie Xiao,Yuqing Liang,Fang Xie,Yousheng Shu,Jiong Hu,Chunkang Chang,Jieling Jiang,Dong Wu,Youshan Zhao,Taohui Liu,Yuxin Li,Xiaojun Huang,Yao Li,Junfang Zhang,Yuwen Cao,Xin Cheng,Ying Mao,Yanxia Rao,Li Cao,Bo Peng

Colony-stimulating factor 1 receptor ( CSF1R ) is primarily expressed in microglia. Its monoallelic mutation causes CSF1R-associated microgliopathy (CAMP), a major form of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and a fatal neurological disease without clinical cure. We developed mouse models harboring human hotspot mutations of CAMP and replaced CSF1R-deficient microglia with CSF1R-normal cells through microglia replacement by bone marrow transplantation (Mr BMT), which attenuated pathology in mice. We further demonstrated that, in the context of CSF1R deficiency, traditional bone marrow transplantation (tBMT) in ALSP functions similarly to Mr BMT, efficiently replacing microglia and reducing disease progression. We then replaced CSF1R-deficient microglia in eight patients by tBMT. The disease progression was halted during the 24-month follow-up. Together, microglia replacement corrects pathogenic mutations and halts disease progression in mice and humans.