Penn and UCI discover novel approach to brain cell immunotherapy

Headshots of Mathew Blurton-Jones, F. Chris Bennett, MD, Sonia Lombroso and Jean Paul Chadarevian
Mathew Blurton-Jones, PhD; F. Chris Bennett, MD; Sonja Lombroso; and Jean Paul Chadarevian

PHILADELPHIA-A promising new approach could safely replace microglia — the only member of the immune system in the brain — according to new research conducted on mouse models by neuroscientists at the Perelman School of Medicine at the University of Pennsylvania and the University of California, Irvine. The researchers used a selective microglia-killing drug to get rid of old microglia while simultaneously refilling them with transplanted replacement cells in their place. These results, published in the Journal of Experimental Medicinemay have the potential to treat and even prevent neurodegenerative diseases.

When microglia are healthy, they serve as the central nervous system’s resident disease fighters on the front lines. However, there is evidence that they can become dysfunctional in many neurological disorders.

“Until recently, scientists have focused primarily on the mechanisms that drive microglial dysfunction, trying to find drugs to alter their activity. But with this study, we found a way to potentially use microglia themselves to treat these diseases,” said Mathew Blurton-Jones, PhD, professor of neurobiology and behavior at UCI.

“There’s a stumbling block, because once our own microglia have evolved where they’re supposed to be in our brain, they don’t give up that space,” he said F. Chris Bennett, MD, an assistant professor of psychiatry at Penn. “They block the ability to supply new cells that would take their place. If you want to use donor microglia, you have to deplete the host microglia to make room.”

Microglia depend on signaling from a protein on their surface called CSF1R for their survival. The FDA-approved cancer drug pexidartinib has been found to block this signaling and turn it off. This process appears to provide a way to make room in the brain to accommodate healthy donor microglia. However, there is a dilemma: if pexidartinib is not stopped before the donor microglia are added, they will also be eliminated. But once the drug is stopped, the host’s microglia regenerate too quickly to effectively take up the donor cells.

“Our team believed that if we could overcome the brain’s resistance to uptake of new microglia, we could successfully transplant them into patients using a safer and more effective procedure to combat a large number of diseases,” said the co-first author Sonja Lombroso, a Penn PhD student and member of the Bennett Lab. “We decided to investigate whether we could make the donor microglia resistant to the drug that eliminates their host counterparts.”

The researchers used CRISPR gene editing technology to create an amino acid mutation known as G795A, which they introduced into donor microglia made from human stem cells or a mouse microglial cell line. Then they injected the donor microglia into humanized rodent models while administering pexidartinib, with exciting results.

“We discovered that this one small mutation caused the donor’s microglia to resist the drug and thrive while the host’s microglia continued to die,” said co-first author Jean Paul Chadarevian, a UCI PhD student and Blurton-Jones member Laboratory. “This finding could lead to many options for the development of new microglia-based treatments. Pexidartinib is already approved for clinical use and appears to be relatively well tolerated by patients.”

Approaches could range from fighting disease by replacing dysfunctional microglia with healthy ones, to designing microglia that can recognize impending threats and target them with therapeutic proteins before they cause harm.

The Penn-UCI team believes treatments based on this type of microglia approach could be developed within a decade. Her next investigations include studying in rodent models how the approach can be used to attack the brain plaques associated with Alzheimer’s and other similar diseases.

The project was supported by the National Institutes of Health, the National Science Foundation, the Paul Allen Frontiers Group, the Klingenstein-Simons Fellowship Award in Neuroscience, and the Susan Scott Foundation.

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