Brain Cell Transplants Halt Fatal Microglia Disease in Humans

Scientists have successfully replaced diseased brain immune cells in eight patients with a fatal neurological disorder, halting disease progression for two years in what represents the first effective treatment for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).

The approach, developed at Fudan University, replaces mutated microglia—the brain’s resident immune cells—with healthy versions through bone marrow transplantation.

ALSP typically strikes patients around age 43 and proves fatal within 3-5 years, causing progressive brain deterioration, motor dysfunction, and cognitive decline. Until now, no treatments existed for this devastating condition caused by mutations in the CSF1R gene that cripples microglia function.

Cellular Replacement Strategy

The treatment builds on research by Professor Bo Peng, who pioneered microglia replacement techniques in 2020. His team developed what they call MISTER (microglia intervention strategy for therapy and enhancement by replacement)—methods for systematically replacing brain immune cells with healthy alternatives.

Microglia depend entirely on CSF1R protein for survival and function. When this protein carries disease-causing mutations, these critical brain cells fail, triggering the cascade of damage seen in ALSP patients. The logical solution: replace the failing cells with healthy ones carrying normal CSF1R genes.

First, researchers created mouse models carrying the same CSF1R mutations found in human patients. These mice faithfully reproduced ALSP’s hallmarks: reduced microglia numbers, brain calcification, damaged myelin, swollen nerve fibers, motor problems, and cognitive decline. After confirming the mouse models matched human disease progression, the team performed bone marrow transplants to introduce healthy microglia.

Remarkable Recovery Results

The microglia replacement achieved striking success in both mouse models and human patients:

• Mouse studies: 91% of brain microglia successfully replaced with healthy cells
• Pathology reversal: Damaged myelin, swollen axons, and spheroid formations all improved
• Functional recovery: Motor performance and cognitive abilities significantly enhanced
• Human trials: Disease progression completely halted for 24 months in all eight patients

Clinical Trial Success

The human application proved remarkably straightforward. Because ALSP patients already have defective CSF1R, their diseased microglia cannot compete effectively with healthy donor cells. This creates what researchers call a “competitive disadvantage” that allows transplanted bone marrow cells to successfully colonize the brain and replace failing microglia.

MRI scans revealed the dramatic difference treatment made. Untreated ALSP patients showed severe brain atrophy and continued deterioration over 12 months. In contrast, all eight treated patients showed no disease progression during 24 months of follow-up, with preserved brain structure and stabilized cognitive and motor functions.

“For the first time, we have achieved microglia replacement in animal models and shown promising results in the human clinical trial. This is currently the only effective clinical treatment for ALSP,” explains Peng.

Beyond ALSP Applications

The success opens possibilities for treating other neurological diseases involving microglial dysfunction. Since microglia play crucial roles in brain maintenance, immune responses, and disease processes, the ability to systematically replace them could address conditions ranging from neurodegenerative diseases to brain injuries.

The research also provides mechanistic insight into a previously puzzling case: an ALSP patient initially misdiagnosed with a different condition who unexpectedly stabilized after bone marrow transplantation. The current study explains this mysterious recovery—the transplant inadvertently replaced the patient’s defective microglia.

Single-cell genetic analysis revealed that successful microglia replacement restored normal CSF1R signaling pathways and returned other brain cells, particularly oligodendrocytes that produce myelin, to healthier states. This comprehensive cellular restoration explains the treatment’s broad therapeutic benefits.

The work represents more than a treatment advance—it establishes microglia replacement as a viable therapeutic strategy for brain diseases, potentially opening new avenues for treating conditions that have long resisted effective intervention.

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