Fighting Alzheimer’s and other neurodegenerative diseases by inserting healthy new immune cells into the brain has made a leap to reality.
Neuroscientists at the University of California, Irvine and the University of Pennsylvania have overcome a significant hurdle in their quest by finding a way to safely thwart the brain’s resistance to them.
Their discovery of brain cells called microglia heralds a myriad of possibilities for treating and even preventing neurodegenerative diseases.the team paper Journal of Experimental Medicine.
Link to study: https://rupress.org/jem/article/220/3/e20220857/213788/Engineering-an-inhibitor-resistant-human-CSF1R
When microglia are healthy, they act as the central nervous system’s resident frontline disease fighters. “But there is overwhelming evidence that it can be dysfunctional in many neurological conditions,” said Mathew Blurton, professor of neurobiology and behavior at the UCI and co-lead author of the study. “Until recently, scientists focused primarily on the mechanisms that cause microglia to malfunction, trying to find drugs that alter their activity. But this study has shown that microglia themselves can be harnessed.” We have discovered a potential way to treat these diseases using
Co-lead author Frederick “Chris” Bennett, assistant professor of psychiatry at the University of Pennsylvania, added: that space. They block their ability to deliver new cells to take their place. If you want to insert donor microglia, you must deplete the host microglia to make room. “
Bennett and his lab partnered with Blurton-Jones and his lab on this project.
Microglial survival depends on signaling by a cell surface protein called CSF1R. The FDA-approved cancer drug pexidartinib has been shown to block their signaling and kill them. This process appears to provide a way to clear space in the brain for the insertion of healthy donor microglia. Microglia will also be eliminated unless pexidartinib is discontinued prior to adding donor microglia. However, when the drug ends, host microglia regenerate too quickly to enter donor cells effectively.
This puzzlement challenges efforts to treat people with certain rare and severe neurological conditions. No. Currently, clinicians are using bone marrow transplants and chemotherapy to try to introduce new immune cells that resemble microglia into the brain. However, this approach can be toxic and should be done before symptoms of crabbe appear.
“Our team believes that if we can overcome the brain’s resistance to accepting new microglia, we can successfully transplant them into patients to target a multitude of diseases using a safer and more effective process. Penn, Ph.D., student and member of the Bennett Lab: “We decided to investigate whether donor microglia could be rendered resistant to agents that would eliminate their host counterparts.”
The researchers used CRISPR gene-editing technology to create a single amino acid mutation known as G795A and introduced it into donor microglia generated from human stem cells or mouse microglial cell lines. We then injected donor microglia into a humanized rodent model while receiving pexidartinib, with exciting results.
“We found that this one small mutation causes donor microglia to resist the drug and proliferate, while host microglia continue to die,” said a student, member of the Blurton-Jones Lab. “This finding may lead to many options for developing new microglia-based therapies. Pexidartinib is already approved for clinical use and appears to be relatively well tolerated by patients.”
Approaches range from combating disease by replacing dysfunctional microglia with healthy microglia to engineering microglia that can recognize imminent threats and attack them with therapeutic proteins before they cause harm.
The UCI-Penn team believes that this type of microglia-based therapy could be developed within a decade. Their next investigation included work in rodent models to explore how this approach could be used to attack brain plaques associated with Alzheimer’s disease and combat crabbe and other similar diseases. I am researching.
Original: Research has discovered how our brains can turn into smarter disease fighters
Than: University of California, Irvine | University of Pennsylvania
