Researchers at Stanford University have developed a method to efficiently replace microglia, which are brain-specific immune cells, via a modified bone marrow transplant.
They used their approach to ameliorate a mouse model of prosaposin deficiency, an early-onset neurodegenerative disorder that is an atypical form of the lysosomal storage disorder Gaucher disease.
“We have developed a protocol, a way, to essentially replace all microglia in the brain with very similar cells, [and] We have shown that this replacement can be used for a therapeutic application,” Marius Wernig told BioWorld. “By using genetically normal cells, you can rectify the problem. Cure is too much of a word, but certainly treat.”
Wernig is a professor of pathology and a co-director of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University. He is also the corresponding author of the paper describing the findings, which appeared in the March 16, 2022, issue of Science Translational Medicine.
Brain disorders remain among the most challenging conditions in modern medicine. Even when the problem is clear – as is the case in rare monogenic disorders – knowing what the problem is is one thing, and getting the solution into the brain, quite another.
Peripherally administered drugs and biologics are largely prevented from entering the brain by the blood-brain barrier.
Cell replacement therapies are a potential alternative. But cell therapies that have been administered via surgery, such as fetal cell transplants for Parkinson’s disease, can realistically only be delivered to localized spots in the brain.
Another approach has been to try to use a bone marrow transplant to replace microglia in the brain.
However, such attempts were plagued by overall low engraftment and high variability until 2020, when groups at Shenzhen Institutes of Advanced Technology and the University of California at Irvine first reported methods that led to more efficient engraftment.
Last month, a team from the Institut Pasteur reported a method that is similar to that of Wernig’s group, but they did not show any therapeutic effects of the engrafted cells.
In the work now published in Science Translational Medicine, Wernig and his colleagues explored which cell types were best for successful brain engraftment.
Those cells, he said, “happen to be the hematopoietic stem cells themselves – and that’s great news, because these cells can be cultured, expanded, and genetically manipulated.”
The team developed a method that included depleting brain-resident microglia, which led to replacement by what they called circulation-derived myeloid cells (CDMCs) that distributed throughout the brain.
The CDMCs behaved somewhat differently from microglia. In the brains of normal mice, CDMCs were more activated and essentially bigger eaters than microglias. However, Wernig said, “in a disease setting, which is of course much more relevant … it turns out that the transplanted cells are actually much less activated than the normal microglia.”
Wernig argued that this reduced activation is good news, because “presumably the highly activated microglia are contributing to the disease process.”
When the team tested their approach in a mouse model of prosaposin deficiency, a lysosomal storage disorder, the transplanted cells secreted prosaposin, which was taken up and incorporated into the lysosomes of the neurons that lacked the protein. Treated mice had less neurodegeneration and scarring, better motor abilities and balance, and a longer lifespan than untreated controls.
Reducing toxicity, expanding access
At this point, the method has a similar toxicity profile to a regular bone marrow transplant, meaning that even if it were successful in the clinic, it would not be widely useful. HIV infections, after all, can be cured via a bone marrow transplant, but that cure is only ever attempted in cancer patients who need the transplant to survive.
“This particular protocol would not be used for, say, Alzheimer’s disease,” Wernig acknowledged, although he also pointed out that bone marrow transplantation is used for some cases of severe multiple sclerosis (MS).
“MS is an autoimmune disease and microglia are at the center” of regulating the immune response, and may support remyelination after an immune attack, he said. “It’s not too far-fetched to think that that could potentially be combined with our protocol.”
One main focus of the lab is to develop protocols that get rid of the need for chemotherapy, which would make the procedure more palatable for less severe diseases.
If the toxicity can be reduced, the therapeutic potential of the approach might go far beyond fixing monogenic disorders.
“You can think of any type of genetic manipulation that could be beneficial to interfere with a disease process,” Wernig said. “It doesn’t stop with just fixing a specific genetic mutation… This is just the very first obvious thing to try and to do.” But in principle, “you have the entire world of synthetic biology” to combine with the transplant.
Wernig and his laboratory are particularly interested in seeing whether the cells can be engineered to produce biologics. The blood-brain barrier blocks most antibodies from passing, which means therapeutic antibodies need to be given in large doses. That makes them less likely to succeed in the clinic, and even more expensive when they do.
The idea that an antibody is too big to cross the blood-brain-barrier, but a cell that produces such antibodies is not, is counterintuitive.
But “it turns out that cells are smart, molecules are stupid,” Wernig said. “When we provide a permissive environment, they talk to the brain, and the brain lets them in.”
“It’s the job of the immune system to surveil the tissue,” he said. “If the immune system starts to attack the brain, it’s over – but that doesn’t mean that the immune system never has access.”