Mouse Study Shows: "Cell Replacement" in the Brain Doubles Lifespan of Diseased Animals
Beijing, August 10 (Science and Technology Daily) — A landmark study published in the latest issue of Nature reports that a team from Stanford University School of Medicine replaced over half of the diseased microglia in mice with Sandhoff disease using non-genetically matched healthy precursor cells. This intervention extended the experimental mice’s lifespan from 135 days to 250 days, with their motor function and exploratory behavior nearly returning to normal levels. It also marks the first time a blueprint for "off-the-shelf" cell therapy has been provided for currently incurable fatal brain diseases such as Tay-Sachs and Sandhoff disease.
Tay-Sachs and Sandhoff disease are both lysosomal storage disorders. Affected children lack a key enzyme, leading to the accumulation of metabolic waste in microglia (the brain’s "scavenger cells") and adjacent neurons. Rapid degeneration begins months after birth, and most children die before the age of two. Previous attempts at hematopoietic stem cell transplantation required full-body chemotherapy to clear bone marrow, and healthy cells struggled to cross the blood-brain barrier, resulting in a success rate of less than 30% along with rejection or graft-versus-host disease.
The team adopted a "brain-region-specific transplantation" strategy: first, low-dose radiation combined with drugs was used to temporarily clear existing microglia in the mice’s brains. Then, microglial precursor cells from non-matched donors were directly injected into the brain ventricles, followed by two approved immunomodulatory drugs to block peripheral immune attacks. Results showed that the new cells accounted for over 85% of total microglia in the brain after 8 months and did not spread to other parts of the body.
Behavioral tests were equally encouraging: all untreated diseased mice died by 135 days, while all 5 transplanted mice remained alive at the end of the experiment. They not only ventured into the center of open fields but also showed significantly better hindlimb grip strength than the control group. Histological analysis revealed that lysosomal enzymes secreted by donor microglia were taken up by adjacent neurons, suggesting a "cellular outsourcing" mechanism may be key to the therapy’s efficacy.
The achievement addresses three major challenges: no need for full-body toxic preconditioning, no gene editing required to supplement missing enzymes, and avoidance of rejection. The radiation dose, microglia-clearing agents, and immunosuppressants used in the protocol are already approved for other diseases, enabling potential rapid progression to clinical trials. Additionally, the therapy does not rely on the patient’s own cells, holding promise to become an "off-the-shelf product" like blood transfusions, significantly reducing costs and waiting times.
The team notes that common neurodegenerative diseases such as Alzheimer’s and Parkinson’s also involve microglial dysfunction, potentially representing "slow versions" of lysosomal disorders. If subsequent human trials succeed, beneficiaries could extend far beyond children with rare diseases to millions of patients with neurodegenerative conditions. Next, the team plans to verify the therapy’s safety in larger animal models more similar to humans and discuss designing early clinical trials with the U.S. Food and Drug Administration.