A novel approach to treating Alzheimer’s disease is showing early promise, utilizing a therapy originally developed for cancer treatment. Researchers have engineered chimeric antigen receptor (CAR) T cells – immune cells genetically modified to target specific proteins – to reduce amyloid plaques in the brains of mice, a hallmark of the disease. The findings, published on in the journal PNAS, represent the first application of CAR-T cell therapy to a neurodegenerative disease.
CAR T cell therapy has revolutionized the treatment of certain cancers by harnessing the power of the immune system to destroy malignant cells. The process involves extracting a patient’s T cells, genetically modifying them to express a receptor (the CAR) that recognizes a specific antigen on cancer cells, and then infusing these modified cells back into the patient. This allows the T cells to specifically target and eliminate cancer cells.
Now, researchers at Washington University School of Medicine in St. Louis and the Weizmann Institute of Science in Israel have adapted this technology to target amyloid beta, a protein that accumulates in the brains of individuals with Alzheimer’s disease, forming plaques that disrupt neuronal function. “We report the first CAR-T cell approach for a neurodegenerative disease,” said Jonathan Kipnis, PhD, the Alan A. And Edith L. Wolff Distinguished Professor of Pathology and Immunology at WashU Medicine. “It represents an exciting step towards finding novel therapies for Alzheimer’s disease.”
The study builds upon Dr. Kipnis’s extensive work in neuroimmunology, the field exploring the interplay between the immune system and the brain. His lab previously discovered the meningeal lymphatics, a network of vessels that drain fluid and waste from the brain, and demonstrated that T cells can play a neuroprotective role in spinal cord recovery. This foundational research paved the way for exploring the potential of CAR-T cell therapy in neurodegenerative diseases.
The collaborative effort between WashU Medicine and the Weizmann Institute of Science, formalized through a joint research program launched last year, was crucial to the study’s success. Researchers, led by co-senior author Ido Amit, PhD, a professor of immunology at WIS, worked together to engineer the CAR-T cells.
In the study, researchers removed T cells from healthy mice and genetically modified them to recognize amyloid beta proteins. These engineered cells were then injected into 6-month-old mice that had already developed amyloid plaques, mirroring the pathology seen in Alzheimer’s patients. The mice received three injections of either the modified CAR-T cells or control, non-modified T cells, spaced ten days apart.
Ten days after the final injection, the researchers observed a significant reduction in amyloid beta plaques in the brains of mice treated with the engineered CAR-T cells compared to those receiving the control cells. Importantly, the brains of the CAR-T cell-treated mice also showed signs of improved health, specifically a reduction in the activation of microglia and astrocytes. These brain cells become activated in response to plaque buildup and contribute to neuroinflammation, a key driver of disease progression. Reducing their activation suggests a calming of the inflammatory response within the brain.
“In future research, we will explore how our engineered CAR-T cells improve brain health in Alzheimer’s disease,” said Pavle Boskovic, PhD, a postdoctoral fellow in the Kipnis lab and the study’s first author. “We also aim to explore using them in mouse models of other neurodegenerative diseases that feature inflammation, with the hope that one day such cells can be safely and effectively used as a therapeutic to help people impacted by neurodegenerative disease.”
While these findings are promising, it’s crucial to remember that this research is in its early stages. The study was conducted in mice, and further research is needed to determine whether this approach will be safe and effective in humans. The complexities of the human brain and immune system present significant challenges, and translating these results to clinical practice will require extensive investigation.
The potential of adapting this versatile technology to treat other neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Parkinson’s disease, is also being explored. The ability to engineer T cells to deliver therapeutic agents directly to the brain offers a novel strategy for tackling these devastating conditions. However, significant hurdles remain, including ensuring the engineered cells reach the target areas in the brain and minimizing potential side effects.
This research represents a significant step forward in the search for new treatments for Alzheimer’s disease and other neurodegenerative disorders. By leveraging the power of the immune system, scientists are opening up new avenues for therapeutic intervention, offering hope for individuals and families affected by these debilitating conditions. The ongoing collaboration between WashU Medicine and the Weizmann Institute of Science will undoubtedly play a crucial role in advancing this promising field.
