The Stanford University School of Medicine team used non genetically matched healthy precursor cells to replace more than half of the diseased microglia in mice with Sandhoff disease, extending the lifespan of the experimental mice from 135 days to 250 days, and restoring their motor function and exploratory behavior to almost normal levels. This is also the first time that a "ready to use" cell therapy blueprint has been provided for fatal brain diseases such as Tay Sachs disease and Sandhoff disease that are currently incurable. Both TaySachs disease and Sandhoff disease belong to lysosomal storage disorders. Due to a lack of key enzymes, the child experiences rapid degeneration within a few months after birth and typically dies before the age of two due to the accumulation of metabolic waste in the "scavenger" microglia and adjacent neurons. Previous attempts at hematopoietic stem cell transplantation required systemic chemotherapy to clear the marrow, and healthy cells had difficulty crossing the blood-brain barrier, with a success rate of less than 30%, accompanied by rejection or graft-versus-host reactions. The team adopted the "brain specific transplantation" strategy this time: first, low-dose radiation was used to temporarily eliminate the original microglia in the mouse brain, supplemented with drugs. Then, microglial precursor cells from non matching donors were directly injected into the ventricles, and two approved immunomodulatory drugs were given to block peripheral immune attacks. The results showed that after 8 months, the new cells still accounted for over 85% of the total number of microglia in the brain and did not spread to other parts of the body. Behavioral tests were equally exciting: all untreated mice died at 135 days, while the 5 mice that received transplantation were still alive at the end of the experiment; They not only dared to enter the center of the open field, but also had significantly better grip strength in their hind limbs than the control group. Organizational analysis revealed that lysosomal enzymes secreted by donor microglia were taken up by neighboring neurons, suggesting that the "extracellular purchase" mechanism may be the key to therapeutic efficacy. This achievement simultaneously solves three major problems: no need for systemic toxicity pretreatment, no need for gene editing to supplement missing enzymes, and avoiding rejection reactions. The radiation dose, microglial scavenger, and immunosuppressant used in the plan have been applied to other diseases and have the potential to quickly enter clinical practice. At the same time, this therapy does not rely on the patient's own cells and is expected to become a "shelf product" like blood transfusions in the future, significantly reducing costs and waiting times. The team pointed out that common neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease are also accompanied by microglial dysfunction, which may be the "slow version" of lysosomal diseases. If the subsequent human trials are successful, the beneficiaries will not only be rare disease patients, but also millions of neurodegenerative disease patients. Next, the team plans to validate the safety of this therapy in larger animal models that are closer to humans and discuss the design of early clinical trials with the US Food and Drug Administration. Cell therapy attempts to bring new hope for the treatment of lysosomal storage disorders and neurodegenerative diseases by transplanting healthy cells to replace damaged neurons or activating endogenous repair mechanisms. Taking the latter as an example, neurodegenerative diseases such as Alzheimer's disease and ALS still urgently require more effective drugs and therapies. The latest research adopts the strategy of "brain specific transplantation", which does not require systemic toxicity pretreatment and avoids rejection reactions, providing a new idea for treating such diseases with cell therapy. In the future, combining cutting-edge technologies such as gene editing and targeted delivery, cell therapy is expected to have greater potential in related medical fields. (New Society)