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].

Core Insights - The research published in "Science" confirms that replacing pathogenic microglia in the central nervous system can successfully block adult-onset leukodystrophy (ALSP), a condition with no effective treatment options available globally [1][2] - The study represents a full chain from genetic mechanisms to clinical validation, marking a new phase in brain disease cell repair and potentially expanding to other neurological disorders [1][2] Group 1: Research Findings - The research team achieved over 90% efficient replacement of microglia in animal models and completed two years of follow-up with multiple ALSP patients, demonstrating that traditional bone marrow cell transplantation (tBMT) can innovate mechanisms to replace microglia and prevent disease progression [1][2] - ALSP is a hereditary neurodegenerative disease with an average lifespan of only 3 to 6.8 years post-onset, caused by genetic mutations leading to dysfunctional microglia that degrade cognitive and motor functions [2] Group 2: Future Implications - The study establishes a treatment paradigm of "gene mutation-cell function abnormality-precise replacement," providing hope for ALSP patients and aiming to extend the technology to other neurological diseases characterized by microglial dysfunction [3] - The research team has publicly shared the microglial replacement operational protocol globally, with plans to promote the application of this technology in more clinical scenarios [3]