Core Viewpoint - The research presents a novel allogeneic brain microglia replacement therapy that does not require myeloablation, showing significant potential for treating lysosomal storage disorders and improving patient outcomes [3][4][7]. Group 1: Research Findings - The study developed a brain-specific, efficient microglia replacement therapy that effectively treated a mouse model of lysosomal storage disease, nearly doubling their lifespan and restoring motor coordination [4][7]. - The research revealed that hematopoietic stem cells are not necessary for reconstructing the brain's myeloid compartment, as Sca1+ progenitor cells can efficiently replace microglia without the need for systemic myeloablation [7][8]. - In the Sandhoff disease mouse model, over 85% of microglia were replaced by the injected Sca1+ progenitor cells, leading to significant survival improvements, with some mice living up to 250 days compared to an average of 135 days for untreated mice [7][8]. Group 2: Implications for Future Treatments - The findings suggest a pathway for developing allogeneic microglia therapies for brain diseases, overcoming the limitations of traditional hematopoietic stem cell transplantation [8]. - The study also demonstrated that human-induced pluripotent stem cell-derived myeloid progenitor cells exhibit similar implantation potential, indicating cross-species conservation of this therapeutic approach [8]. - Another related study highlighted the role of microglia in maintaining brain homeostasis and the potential for therapeutic interventions in neurodegenerative diseases like Sandhoff disease [11].

Core Viewpoint - The study presents a novel microglia replacement therapy that effectively halts the progression of the lethal brain disease ALSP in both mice and humans, demonstrating clinical feasibility and long-term efficacy [3][9]. Group 1: Disease Background - Microglia are crucial immune cells in the central nervous system, and their dysfunction can lead to various CNS diseases. CSF1R mutations are linked to congenital microglial deficiency and ALSP, a severe condition with an average survival of only 3 years post-onset in China [2][5]. Group 2: Research Development - The research team developed a microglia replacement strategy, termed MISTER, which replaces pathogenic microglia with wild-type cells to potentially treat ALSP. This strategy was inspired by earlier findings and aimed to address the limitations of previous mouse models [6][7]. Group 3: Experimental Findings - The study utilized two newly generated mouse models that accurately replicate key features of human ALSP, including reduced microglial numbers and cognitive decline. The replacement of mutant microglia with wild-type cells significantly improved neurological function and halted disease progression [7][9]. Group 4: Clinical Application - In a clinical trial involving 8 ALSP patients, the microglia replacement therapy showed promising results, with increased brain glucose metabolism and stable cognitive function over a 24-month follow-up period. This marks the first systematic validation of microglia replacement in human patients [8][9]. Group 5: Implications for Future Research - The findings support the potential of microglia replacement strategies not only for ALSP but also for other CNS diseases associated with microglial dysfunction, indicating a broader therapeutic application [9].