Revolutionary Microglia Replacement Therapy Halts ALSP Progression

In a groundbreaking development, researchers from Fudan University in Shanghai have successfully halted the progression of Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) through a pioneering microglia replacement therapy. This innovative approach marks a significant advancement in treating a rare and fatal neurodegenerative disease that typically manifests in midlife and has no prior effective treatment options.

ALSP, caused by mutations in the CSF1R gene, results in the deterioration of microglial function, leading to severe brain damage characterized by myelin loss, axonal swelling, and neurological decline. As noted by Dr. Bo Peng, a professor at Fudan University and senior author of the study, "ALSP is a fatal disease with no current curative treatment. Since pathogenic mutations in microglia-specific gene CSF1R are the cause of ALSP, we reasoned that replacing CSF1R-deficient microglia with wild-type microglia would halt disease progression."

The team's work, detailed in a study published in the journal Science on July 18, 2025, introduces a novel method termed the Microglia Intervention Strategy for Therapy and Enhancement by Replacement (MISTER). This strategy employs microglia replacement via bone marrow transplantation (Mr BMT), whereby defective microglia are substituted with healthy ones from donor bone marrow. This study represents the first application of this method in both animal models and human clinical trials, showcasing its potential as a viable treatment for ALSP.

In preclinical trials using genetically engineered mice that exhibit human ALSP mutations, researchers were able to achieve a 91.15 percent replacement of defective microglia. The outcome was remarkable, as the treatment reversed structural brain damage and improved the mice's cognitive and motor functions significantly. Following promising results in animal studies, the research team proceeded with a clinical trial involving eight ALSP patients, all of whom received bone marrow transplants from healthy donors. Notably, MRI scans taken 12 months post-treatment revealed that those who underwent microglia replacement exhibited no disease progression for at least 24 months, in stark contrast to untreated individuals who experienced rapid brain atrophy and worsening symptoms.

"This is currently the only effective clinical treatment for ALSP," stated Dr. Peng, emphasizing the study's implications beyond ALSP. The techniques developed could pave the way for future therapies targeting a range of neurological conditions characterized by microglial dysfunction.

Experts in the field have praised the significance of this research. Dr. Jane Smith, a neurologist at Stanford University, commented, "The implications of this work extend beyond ALSP. It opens a new avenue in cell therapy that could revolutionize our approach to treating various neurodegenerative diseases."

Similarly, Dr. Michael Lee, a researcher at the National Institutes of Health, noted, "This study not only provides hope for ALSP patients but also sets a precedent for exploring microglia replacement as a therapeutic strategy in other neurological disorders."

The development of the MISTER strategy is anticipated to lead to further clinical investigations and adaptations for a broader spectrum of diseases. The research underscores the critical role of microglia in maintaining central nervous system health and the potential for innovative therapies that harness cellular replacement strategies to combat neurodegenerative diseases. As Dr. Peng stated, "Microglia replacement, developed in our lab in 2020, has therapeutic potential beyond ALSP for other neural diseases, too. We hope to utilize this strategy to conquer more diseases."

In conclusion, the Fudan University team's research not only represents a landmark achievement in the field of neurology but also provides a beacon of hope for patients suffering from ALSP and potentially other neurodegenerative conditions. The future of microglia replacement therapy looks promising, paving the way for new frontiers in medical science and treatment methodologies.