From mice to humans in five years: Microglia replacement paving the way for neurodegenerative disease therapies

Tiny charming immune cells called microglia protect the central nervous system (CNS) in a multitude of ways: They provide innate immunity, shape neurodevelopment, maintain homeostasis and modulate neurological disorders. That functionality can be lost, however, when microglia acquire mutations. An concept to correct this by replacing the mutated microglia with genetically typical cells — now called microglia intervention strategy for therapy and enhancement by replacement, or MISTER — emerged five years ago and was successfully achieved in mice. This year, researchers successfully used the approach to halt a fatal neurological disease ALSP (adult-onset leukoencephalopathy with axonal spheroids and pigmented glia) in human patients. 

The team that made both achievements reflected on the work, where the field stands and what’s next. They published their Perspective review on Dec. 4 in Cell Stem Cell.

“Over just five years, from 2020 to 2025, microglia replacement has evolved from its first achievement in the mouse model to successful clinical therapy,” said corresponding author and team leader Bo Peng, professor at Fudan University.

In the review of published scientific literature, including their own work, the researchers first summarize microgliopathies — the pathogenic mutations microglia can acquire — as therapeutic targets. Many microglial gene mutations related to disorders of the central nervous system are well known, Peng said. For example, TREM2 is a gene that expresses a receptor protein on the surface of microglia. When TREM2 is mutated or under-expressed, the microglial engulfment to Aβ is impaired, accelerating the progression of Alzheimer’s disease.

“TREM2 mutations may not be sufficient to cause Alzheimer’s disease independently, but they can act as pathogenic amplifiers that synergistically drive disease risk,” Peng said, noting that’s just one example. “Microglial gene mutations can either cause or accelerate the course of CNS disorders. Conceptually, replacing pathogenic microglia with gene-corrected or wild-type counterparts offers a promising therapeutic avenue to restore homeostatic function and mitigate disease progression.”

From there, the researchers detail the history of microglia replacement from what first author Yanxia Rao, investigator at Fudan University, called the “pre-replacement era of low engraftment to efficient and clinical meaningful strategies.” Engraftment refers to bone marrow transplantation, which had little success for microglia replacement, according to Rao.

Rao noted that the language here is important, with imprecise terminology used interchangeably but incorrectly earlier on in the field compared to what is now accepted.

“Establishing an unambiguous and consistent nomenclature is essential for accurate interpretation of experimental data and clinical outcomes,” Rao said.

For example, a microglial repopulation refers to restoring a population without donor cells, a transplantation refers to establishing donor cells without removing the original population, and a replacement refers to removing the original cells and introducing donor cells.

“Even though microglia replacement is recognized for its potential for disease treatment, early approaches in the pre-replacement era lacked an efficient and robust strategy for microglia replacement, which is key for a meaningful and effective therapy,” Rao said.

The researchers explained that multiple studies led to understanding the two principles upon which successful microglia replacement may be achieved. The first is that there must be an area in the brain free of microglia to prevent normal regulatory function that would prevent donor cells from establishing themselves. The second is to also suppress any residual host microglia cells — any original cells left over — from proliferating, which would create a competitive environment that would make it more difficult for donor cells to establish themselves before residual microglia rapidly repopulate the whole CNS.

From those two principles, multiple approaches were developed, including the most widely implemented Mr BMT (microglia replacement by bone marrow transplantation, aka mrBMT), which Peng and his team used to correct gene mutations and halt a microglial disease in humans.

“In just five years, microglia replacement has advanced from the achievement of efficient replacement in animals to the first and successfully clinical therapy, transforming from a niche idea into a topic of great interest in neuroscience and cell therapy,” Peng said. “Overall, microglia replacement is a newly emerging but rapidly progressing field. Challenges in safety, compatibility and long-term function remain, yet they represent solvable design targets. With continued mechanistic insight, clinical innovation, and broad collaboration, microglia replacement can mature from early breakthroughs into a generalizable platform across neurological diseases.”

Peng and Rao noted that a larger community of contributors from a broader range of specialties would benefit the field. The ultimate goal?

“To conquer neurological diseases.” Peng said.