Brain cell transplant stops deadly microglia disease in humans

Scientists successfully replaced diseased brain immune cells in eight patients with fatal neurological diseases, stopping the disease’s progression for two years, representing an effective treatment for onset white blood cells in adults, which has axonal spherical and pigmented glia (ALSP).

The method developed at Fudan University replaces mutated microglia (the immune cells of the brain that are immune to the brain) and has a healthy version by bone marrow transplant.

ALSP usually attacks patients around the age of 43 and proves deadly within 3-5 years, resulting in progressive brain deterioration, motor dysfunction and cognitive decline. So far, treatment for this devastating disease caused by mutations in the CSF1R gene has not yet existed, which weakens the function of microglia.

Cell replacement strategies

This treatment is based on research by a PhD professor who pioneered microglia replacement technology in 2020. His team developed what they call Mister (a strategy for treatment and enhanced microglia intervention through alternative methods) – a method for systematically replacing immune cells in the brain with healthy alternatives.

Microglia are entirely dependent on the survival and function of CSF1R protein. When this protein brings pathogenic mutations, these key brain cells fail, triggering a series of damage in patients with ALSP. Logical solution: Replace failed cells with healthy cells carrying normal CSF1R gene.

First, the researchers created a mouse model that carries the same CSF1R mutation as human patients. These mice faithfully reproduced the markers of ALSP: reduced microglia number, brain calcification, myelin damage, swelling of nerve fibers, motor problems, and decreased cognitive ability. After confirming that the mouse model matched human disease progression, the team performed a bone marrow transplant to introduce healthy microglia.

Excellent recovery results

Microglia substitution has achieved amazing success in mouse models and in human patients:

• Mice study: 91% of brain microglia successfully replaced with healthy cells
• Pathological reversal: Damaged myelin, axonal swelling and spherical formations have been improved
• Functional recovery: Significant improvement in motor performance and cognitive ability
• Human trials: All eight patients had a complete 24-month cessation of disease progression

Clinical trial successful

Human applications have proved to be very simple. Since patients with ALSP already have CSF1R defects, diseased microglia cannot compete effectively with healthy donor cells. This creates what researchers call “competitive disadvantage”, which allows transplanted bone marrow cells to successfully settle in the brain and replace failed microglia.

MRI scans show huge differential treatments. Untreated ALSP patients showed severe brain atrophy and continued to worsen within 12 months. In contrast, all eight patients treated had no disease progression within 24 months of follow-up and retained brain structure and stable cognitive and motor function.

“We have achieved the first time a microglia alternative in animal models and have shown encouraging results in human clinical trials. This is the only effective clinical treatment for ALSP,” explained Peng.

Beyond ALSP Applications

Success has opened up possibilities for the treatment of other neurological diseases involving microglia dysfunction. Because microglia play a crucial role in brain maintenance, immune responses, and disease processes, the ability to systematically replace them can address diseases ranging from neurodegenerative diseases to brain damage.

The study also provides mechanical insight into previously confusing cases: patients with ALSP initially with different diseases unexpectedly stabilized after bone marrow transplantation. The current study explains this mysterious recovery-transplantation inadvertently replaced the patient’s defective microglia.

Single-cell genetic analysis showed that successful microglia replacement restored normal CSF1R signaling pathways and returned other brain cells, especially myelin-producing oligodendrocytes, to a healthier state. This comprehensive cellular recovery explains the wide range of therapeutic benefits of treatment.

This work not only represents progress in treatment, but also establishes alternatives to microglia as viable brain disease treatment strategies, which may open up new avenues for the treatment of diseases that have long resisted effective interventions.

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