Microglia Replacement Therapy Shows Promise in Halting Neurodegenerative Diseases, Advancing from Lab to Clinic in Just Five Years
A groundbreaking approach to treating neurological disorders by replacing damaged immune cells in the brain has rapidly evolved from animal studies to successful human trials, offering new hope for conditions like Alzheimer’s and a rare fatal disease called ALSP.
The brain’s resident immune cells, known as microglia, are vital for central nervous system (CNS) health, providing innate immunity, shaping brain development, maintaining stability, and modulating neurological disorders. However, when these cells acquire harmful mutations, their protective functions are lost. Now, a novel strategy – termed microglia intervention strategy for therapy and enhancement by replacement, or MISTER – is gaining momentum as a potential therapeutic avenue.
Just five years ago, MISTER was largely theoretical. Today, it’s a clinical reality. In 2025, researchers successfully employed this technique to halt the progression of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a devastating neurological disease, in human patients. The findings, detailed in a recent Cell Stem Cell Perspective review, mark a significant turning point in the treatment of brain disorders.
“Over just five years, from 2020 to 2025, microglia replacement has evolved from its first achievement in the mouse model to successful clinical therapy,” stated Bo Peng, professor at Fudan University and the study’s corresponding author.
Understanding Microgliopathies and Therapeutic Targets
The research team’s review highlights the importance of understanding “microgliopathies”—the specific genetic mutations that can impair microglial function—as key targets for therapeutic intervention. Numerous gene mutations within microglia have been linked to a range of CNS disorders.
One prominent example is the TREM2 gene, which codes for a receptor protein on the surface of microglia. When TREM2 is mutated or under-expressed, the ability of microglia to clear amyloid-beta plaques – a hallmark of Alzheimer’s disease – is compromised, accelerating disease progression. “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 explained.
The core concept behind MISTER is to replace these pathogenic microglia with healthy, gene-corrected, or wild-type counterparts, restoring homeostatic function and slowing disease progression.
From Low Engraftment to Clinical Success: A History of Microglia Replacement
The path to clinical success wasn’t straightforward. Early attempts at microglia replacement, relying on bone marrow transplantation, yielded limited results. Yanxia Rao, an investigator at Fudan University and the study’s first author, emphasized the importance of precise terminology in the field. “Establishing an unambiguous and consistent nomenclature is essential for accurate interpretation of experimental data and clinical outcomes,” she said.
Rao clarified the distinctions between microglial repopulation (restoring a population without donor cells), transplantation (establishing donor cells alongside the original population), and replacement (removing original cells and introducing donor cells). Early strategies lacked an efficient and robust replacement method, hindering meaningful therapeutic outcomes.
Principles and Challenges of Effective Microglia Replacement
Researchers identified two crucial principles for successful microglia replacement. First, creating a microglia-free “niche” within the brain is essential to prevent the regulatory functions of existing microglia from inhibiting the establishment of donor cells. Second, suppressing the proliferation of any remaining host microglia is vital to prevent competition with the newly introduced donor cells.
The most widely used approach, Mr. BMT (microglia replacement by bone marrow transplantation), utilizes pharmacological inhibition of CSF1R to eliminate microglia, followed by conditioning with irradiation or chemotherapy to create a prolonged microglia-free environment. Alternatively, repeated depletion-repopulation cycles can impair microglial proliferation by shortening telomeres.
“In just five years, microglia replacement has advanced from the achievement of efficient replacement in animals to the first and successful clinical therapy, transforming from a niche idea into a topic of great interest in neuroscience and cell therapy,” Peng said.
Despite the rapid progress, challenges remain. Ensuring the safety, compatibility, and long-term function of replaced microglia are critical areas for future research. “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,” Peng noted. “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 underscored the need for a broader, more collaborative community to accelerate advancements in the field. Their ultimate goal, Peng stated, is “to conquer neurological diseases.”
More information: A New Paradigm for CNS Disease: The Evolution of Microglia Replacement Therapy, Cell Stem Cell (2025). DOI: 10.1016/j.stem.2025.10.014. www.cell.com/cell-stem-cell/fulltext/S1934-5909(25)00407-2
Provided by Fudan University.
