UC Irvine researchers contribute to new toolkit for battling brain disorders
image: Brain endothelial cells (BEC) targeted by a BEC-enhancer AAV vector tool, developed by the Xu Lab and the Center for Neural Circuit Mapping team. Viral labeling (green) overlaps with endothelial cells (magenta) and protein markers for brain blood vessels (blue).
Credit: Xu Lab
The National Institutes of Health is funding research to develop a set of gene delivery systems for cells in the brain and spinal cord as part of its Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative. This initiative has supported the Armamentarium for Precision Brain Cell Access, a consortium of researchers creating next-generation biological tools for battling brain disorders.
New studies stemming from the Armamentarium consortium outline findings that advance tools based on Adeno-associated virus (AAV) vectors. An announcement about the work explains how an AAV “acts like a shuttle capable of transporting specially designed DNA into the cell.”
Two of the studies on these AAV tools were conducted by collaborative teams organized by Xiangmin Xu, PhD, UC Irvine Chancellor’s Professor of anatomy and neurobiology and director of the campus’s Center for Neural Circuit Mapping.
“This Armamentarium’s collection of work enables new tools that help to deepen our understanding of the human central nervous system structure and function,” says Xu. “Our own brain-targeting technology could help treat Alzheimer’s disease and many other neurological disorders.”
Targeting Brain Endothelial Cells
One of the two papers, “Specific targeting of brain endothelial cells using enhancer-AAV vectors,” by Eric Velazquez-Rivera, Oyshi Dey, Nayoon Sophie Kim, Wenhao Cao, Qiao Ye, Hai Zhang, Jonathan T. Ting, Bing Ren, Todd C. Holmes, and Xiangmin Xu, appears online in the May 21, 2025 release of Neuron. This collaboration between researchers at UC Irvine, UC San Diego and the Allen Institute for Brain Science targets certain blood vessels in the brain.
“Blood flow through the brain goes through a special set of blood vessels that provides special protection to the brain,” explains Velazquez-Rivera, a postdoctoral researcher in the Xu Lab. This special vasculature is a key component of the blood brain barrier (BBB). “Drug delivery to the brain is a big challenge due to this barrier, but we have developed a way to circumvent the BBB with a technology that targets brain vasculature with minimal unwanted side effects.”
Leveraging the differences in these blood vessels compared to the rest of the body, the researchers developed a new technology, based on genomic enhancer sequences and recombinant AAV vectors, that targets the brain’s endothelial cells (BEC) with high specificity.
“We tested our BEC-targeting technology in an Alzheimer’s disease mouse model with very aggressive pathology and, remarkably, it was still specific and effective,” says Velazquez-Rivera. “The capability to target with high specificity the endothelial cells in the brain can open the door to the development of new gene therapy vectors for a broad array of neurological diseases.”
The researchers hope to eventually use the BEC-enhancer AAV to deliver therapeutic drugs to the brain. “Our BEC AAV vector tools could be used for brain-targeted gene therapy to ameliorate neurological diseases,” says Velazquez-Rivera. “It may even be used someday to treat stroke victims.”
One of the senior authors, Todd Holmes, PhD, professor of physiology and biophysics at UC Irvine, recalls the origins of the work. “Just over five years ago, Dr. Xu and I and UCI School of Medicine colleagues developed a bold vision that we could work towards curing then-untreatable diseases by creating new technologies and by partnering with some of the best minds in the fields of neuroscience, genomics, virology, biomedical engineering, computer science and mathematics,” he says. “This paper, and other recent papers from our scientific dream team, are products of that vision.”
Targeting Forebrain Excitatory Neurons
The other paper, “An AAV capsid proposed as microglia-targeting directs genetic expression in forebrain excitatory neurons,” by Wenhao Cao, Zhiqun Tan, Bereket T. Berackey, Jason K. Nguyen, Sara R. Brown, Shiyang Du, Bin Lin, Qiao Ye, Magdalene Seiler, Todd C. Holmes and Xiangmin Xu, appears online in the May 21, 2025 release of Cell Reports Methods. This work targets excitatory neurons, cells that are actively involved in cognitive memory and spatial navigation. Specifically, it examines AAV-MG1.2, a tool that enables targeted gene delivery to excitatory neurons in the brain.
“Our group found that AAV-MG1.2 actually achieves specific genetic expression in an entirely different brain cell type: excitatory neurons in the forebrain region across different animal species,” says Cao, a graduate student researcher in the Xu Lab. He stresses that this finding disproves earlier claims. Furthermore, the researchers were able to validate applications for this AAV tool in the neural circuit tracing and reveal input connections for excitatory neurons in both hippocampal and cortical regions — areas that are important for cognition, learning and memory.
“Our study expands the existing toolbox for targeting excitatory neurons and presents AAV-MG1.2 as a useful tool for targeting functional payloads to subsets of excitatory neurons in the forebrain across different species,” says Cao. “When coupled with functional enhancer elements designated for distinct excitatory neuronal subtypes, AAV-MG1.2 opens up a promising avenue for exploring specific brain cell subtypes, which could eventually lead to clinical applications that facilitate targeted therapy.”
The researchers will continue to explore the inner workings of AAV-MG1.2. “The biological mechanism underlying AAV-MG1.2’s specific targeting of excitatory neurons remains unclear,” says Cao. “Elucidating this mechanism will be critical for expanding the toolbox of AAV-based tools used in neuroscience research.”
The two publications were supported by and coordinated through the BRAIN Initiative Armamentarium for Precision Brain Cell Access consortium. The research reported was supported by the NIH BRAIN Initiative under award number U24MH133236. Additional support was provided by other U.S. federal grants (R01FD007478 and U01AG076791). The UCI Center for Neural Circuit Mapping, supported by the UC Irvine School of Medicine and Office of Research, contributes to a broad collaborative infrastructure that provides resources required for the studies.