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Microglia replacement halts the progression of microgliopathy in mice and humans
Jingying Wu1,2, Yafei Wang2, Xiaoyu Li2
1Department of Neurology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract:
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.
Insights
Microglia replacement therapy halts progression of CSF1R-associated microgliopathy (CAMP), a fatal neurological disease. Bone marrow transplantation effectively replaces deficient microglia, correcting mutations and stopping disease in mice and patients.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- Colony-stimulating factor 1 receptor (CSF1R) mutations cause CAMP, a fatal neurological disease.
- CAMP is a form of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).
- Current treatments for ALSP are limited.
Purpose of the Study:
- To investigate microglia replacement as a therapeutic strategy for CAMP.
- To evaluate the efficacy of bone marrow transplantation in halting disease progression.
Main Methods:
- Developed mouse models with human CAMP hotspot mutations.
- Utilized microglia replacement by bone marrow transplantation (Mr BMT) in mice.
- Administered traditional bone marrow transplantation (tBMT) to ALSP patients.
Main Results:
- Microglia replacement attenuated pathology in mouse models.
- tBMT effectively replaced CSF1R-deficient microglia and reduced disease progression in mice.
- Disease progression halted in eight ALSP patients following tBMT over 24 months.
Conclusions:
- Microglia replacement is a viable therapeutic approach for CAMP.
- Bone marrow transplantation can correct pathogenic mutations and halt neurological disease progression.
- This study offers a potential cure for a fatal neurological disorder.
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