University of California, Irvine scientists have unveiled a groundbreaking new way to deliver disease-fighting proteins throughout the brain, potentially revolutionizing the treatment of Alzheimer’s disease and other neurological disorders. By engineering human immune cells called microglia the researchers have created living cellular “couriers” capable of responding to brain pathology and releasing therapeutic agents exactly where needed.
The National Institutes of Health-supported study, published recently in Cell Stem Cell, demonstrates for the first time that induced pluripotent stem cells (iPSC)- -derived microglia can be genetically programmed to detect disease-specific brain changes – like amyloid plaques in Alzheimer’s disease – and to then specifically respond to pathology by releasing enzymes that help break down those toxic proteins. As a result, the cells were able to reduce inflammation, preserve neurons and synaptic connections and reverse multiple other hallmarks of neurodegeneration in mice.
For patients and families grappling with Alzheimer’s and related diseases, the findings offer a hopeful glimpse at a future where microglial-based cell therapies could precisely and safely counteract the ravages of neurodegeneration.
“Delivering biologics to the brain has long been a major challenge because of the blood-brain barrier,” said Mathew Blurton-Jones, Professor of Neurobiology and Behavior and co-corresponding author of the study. “We’ve developed a programmable, living delivery system that gets around that problem by residing in the brain itself and responding only when and where it’s needed.”
Using CRISPR gene editing, the team modified human microglia to produce neprilysin – an enzyme known to degrade beta-amyloid – under the control of a promoter that only activates near plaques. The result was a highly targeted and pathology-responsive therapy. In Alzheimer’s mouse models, these engineered microglia reduced the buildup of beta-amyloid and protected against damage to neurons and synapses, curbed inflammation and even lowered a biomarker of neuronal injury in the blood.
“Remarkably, we found that even localized microglial engraftment could reduce toxic amyloid levels and other AD-associated neuropathologies throughout the brain,” said Jean Paul Chadarevian, post-doctoral scholar leading this study in the Blurton-Jones Lab. “And because the therapeutic protein was only produced in response to amyloid plaques, we found this approach was highly targeted yet broadly effective.”
In addition to Alzheimer’s, the study explored how human microglia respond in models of brain cancer and multiple sclerosis. In both cases, the engineered cells adopted unique gene expression profiles – highlighting the potential to tailor them to a variety of central nervous system diseases.
“This work opens the door to a completely new class of brain therapies,” said Robert C. Spitale, professor of pharmaceutical sciences. “Instead of using synthetic drugs or viral vectors, we’re enlisting the brain’s immune cells as precision delivery vehicles.”
The researchers note that much work remains to translate this platform into human trials, including demonstrating long-term safety and developing methods for scalable manufacturing. However, because the microglia are derived from iPSCs, they could potentially be produced from a patient’s own cells, reducing the risk of immune rejection.
This study is a collaboration between UC Irvine’s Department of Neurobiology & Behavior, the Institute for Memory Impairments and Neurological Disorders and the Sue and Bill Gross Stem Cell Research Center.
The research was supported by grants from the NIH (National Institute of Aging), the California Institute for Regenerative Medicine and the Cure Alzheimer’s Fund.
