Penn and UCI discover new method for brain cell immunotherapy

Headshots of Matthew Blurton-Jones, F. Chris Bennett, MD, Sonia Lombroso, and Jean-Paul Chadarevian
Matthew Blurton-Jones, Ph.D.; Chris Bennett, MD; Sonia Lombroso and Jean-Paul Shadarevian

Philadelphia –A promising new approach may safely replace microglia — the only members of the immune system in the brain — according to new research in 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 also replenishing them with replacement cells implanted in their place. These results published in Journal of Experimental MedicineIt may hold the potential to treat and even prevent neurodegenerative disorders.

When intact, microglia act as the resident disease-fighters on the central nervous system’s front line. But there is evidence that they can become dysfunctional in many neurological conditions.

Until recently, scientists were mainly looking for the mechanisms that lead to dysfunction in microglia and trying to find drugs to alter their activity. “But with this study, we’ve found a way to harness microglia themselves to treat those diseases,” said Matthew Blurton-Jones, PhD, professor of neurobiology and behavior at UCI.

“There’s a hitch because once our microglia develop where they’re supposed to be in our brains, they don’t give up on that space,” he said. Chris Bennett, MD, assistant professor of psychiatry at Penn. They block the ability to deliver new cells to replace them. If you want to insert donor microglia, you have to deplete the host microglia to open the chamber.”

Microglia depend on signaling by a surface protein called CSF1R for their survival. The FDA-approved cancer drug pexidartinib has been found to block these signals, causing them to wane. This process appears to provide a way to clear space in the brain to insert healthy donor microglia. However, there is a dilemma: unless pexidartinib is stopped before donor microglia are added, it will also be eliminated. But once the drug is terminated, the host microglia regenerate too quickly to be effectively put into donor cells.

“Our team believed that if we could overcome the brain’s resistance to accepting new microglia, we could successfully transplant them into patients using a safer and more effective process in order to target a broad number of diseases,” said the co-first author. Sonia Lombroso, a PhD student at Penn State and a member of Bennett’s lab. “We decided to investigate whether we could make donor microglia resistant to a drug that kills their host counterparts.”

The researchers used gene-editing CRISPR technology to create a single amino acid mutation, known as G795A, which they inserted into donor microglia cells produced from human stem cells or a mouse microglia cell line. They then injected donor microglia into humanized rodent models while administering pexidartinib, with exciting results.

“We discovered that this small mutation caused donor microglia to resist the drug and thrive, while host microglia continued to die,” said co-first author Jean-Paul Chadarevian, a UCLA PhD student who is a member of Blurton. Jones lab. This discovery could lead to several options for developing new microglia-based therapies. Pexidartinib is already approved for clinical use and appears to be relatively well tolerated by patients.”

The approaches can range from fighting disease by replacing dysfunctional microglia with healthy ones to designing microglia that can recognize impending threats and hit them with therapeutic proteins before they cause damage.

The Penn-UCI team believes that therapies based on this type of microglia method could be developed within a decade. Their next investigation includes studying in rodent models how to use this approach to attack brain plaques associated with Alzheimer’s and other similar diseases.

Support for the project was provided 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.

Penn Medicine is one of the world’s leading academic medical centers dedicated to missions related to medical education, biomedical research, and excellence in patient care. Penn Medicine consists of Raymond and Ruth Perlman of the University of Pennsylvania School of Medicine (Founded in 1765 as the first medical school in the country) W University of Pennsylvania Health Systemwhich together constitute a $9.9 billion project.

Perelman College of Medicine has been ranked among the best medical schools in the United States for more than 20 years, according to a US News & World Report survey of research-oriented medical schools. The school is consistently among the nation’s largest recipients of funding from the National Institutes of Health, with $546 million awarded in fiscal year 2021.

Patient care facilities in the University of Pennsylvania Health System include: University of Pennsylvania Hospital and Penn Presbyterian Medical Center – recognized as one of the best “Honor Roll” hospitals in the country by US News & World Report – Chester County Hospital; Lancaster Public Health; Penn Medicine; Princeton Health; and Pennsylvania Hospital, the nation’s first hospital, founded in 1751. Additional facilities and institutions include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health, Princeton House Behavioral Health, and others.

Penn Medicine is powered by a talented and dedicated workforce of more than 47,000 people. The organization also has alliances with top community health systems in both southeastern Pennsylvania and southern New Jersey, providing more options for patients no matter where they live.

Penn Medicine is committed to improving life and health through a variety of community programs and activities. In fiscal year 2021, Penn Medicine provided more than $619 million to benefit our community.

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