Brain diseases don’t affect every cell in the brain. They affect specific, vulnerable cell types. Finding ways to target those cells precisely is at the heart of a major research effort underway at the WaNBRC and partner institutions that’s opening doors toward treating conditions like epilepsy and Parkinson’s disease.
The work is part of a national research effort funded by the National Institutes of Health (NIH) called the BRAIN Initiative, through a program nicknamed the “Brain Armamentarium.” NIH created this program because most of today’s research and medical tools are capable of switching a whole region of the brain on or off, but not of reaching only the cell types actually involved in a disease.
Our scientists, working with colleagues at other Armamentarium partners, are building something far more precise: viral tools, called “enhancer AAVs,” that can be engineered to switch on a gene in one specific type of brain cell and leave its neighbors alone. Think of it like the difference between playing piano with boxing gloves versus with your bare fingers.
The delivery vehicle for these tools is an adeno-associated virus, or AAV. It’s a type of virus that’s already used in FDA-approved gene therapies and human clinical trials. AAV doesn’t cause disease; scientists simply use it as a way to carry a therapeutic instruction into the cells that need it.
“It’s a suite of tools for manipulating specific types of cells in the brain,” said Greg Horwitz, Chief of the Neuroscience Unit at the WaNBRC. “The brain is made up of many different types of neurons, and standard techniques manipulate them all essentially identically, turning them all off or all on. What we need to do is be able to manipulate them individually.”
But before these tools can be used in people, scientists have to know whether they work the same way in a brain like ours. Macaques, whose brains share structural and genetic similarities with the human brain, are the most reliable model available short of testing in a human being, which isn’t currently possible. Research
Two recently published studies show why this matters. In one, published in Science Translational Medicine, researchers used an enhancer tool to deliver a replacement gene to a specific class of brain cells in mice with Dravet syndrome, a severe and often fatal childhood epilepsy. The treated mice stopped having seizures and survived at dramatically higher rates than untreated mice. That result came directly out of tool development validated through nonhuman primate research at WaNBRC. In another study, published in Neuron, a different targeting tool was used to reach a specific brain cell population to reduce dyskinesia in mice. Dyskinesia is the uncontrolled, involuntary movements that are among the most disabling side effects of long-term Parkinson’s disease treatment.
This foundational research lays the groundwork for potential treatments for epilepsy, Parkinson’s disease and other brain disorders. It also advances our understanding of animal neurobiology and could improve veterinary care. At the WaNBRC, studies are conducted under the close oversight of our Institutional Animal Care and Use Committee, with animal welfare central to how the work is carried out.
This is the kind of work that keeps the WaNBRC at the forefront of turning basic brain biology into hope for human and animal health.