New gene therapy strategy uses the brain's own glymphatic transport system for drug delivery

A new study describes a gene therapy strategy that uses the brain's own glymphatic transport system to distribute engineered viral vectors throughout the brain. The approach addresses two major challenges in neurological medicine-reaching therapeutic targets behind the blood-brain barrier and limiting unwanted effects elsewhere in the body-and could pave the way for new treatments for diseases including multiple sclerosis, Huntington's disease, and rare childhood white matter disorders.

The platform pairs specially engineered adeno-associated viruses (AAVs) with a delivery strategy that harnesses the brain's natural fluid transport pathways. Together, these innovations enabled researchers to deliver therapeutic genes broadly throughout the brain, preferentially targeting human glial cells while minimizing exposure to other cell types and organs.

"Gene delivery to the brain has always faced two major obstacles," said Steve Goldman, MD, PhD, co-director of the University of Rochester Medicine Center for Translational Neuromedicine and lead author of the study, which appears in Nature Biotechnology. "You need a way to get therapies into the brain selectively and efficiently, and you need vectors that can deliver those therapies to the right cells once they get there. This work addresses both challenges simultaneously."

A longstanding focus on glial cells

Goldman has spent much of his career advancing understanding of glial cells-the support cells of the nervous system that help maintain brain function, produce myelin, and regulate neuronal health. His laboratory has been a pioneer in developing human glial progenitor cell models and investigating how glial dysfunction contributes to neurological disease.

That work has helped reshape how scientists think about disorders traditionally viewed as diseases of neurons alone, demonstrating that glial cells can play a central role in both disease progression and recovery. In Huntington's disease, for example, Goldman's team found that healthy human glial progenitor cells could outcompete and replace diseased cells in the brain, highlighting the therapeutic potential of targeting glia.

Over the last decade, we've learned that many neurological disorders involve glial dysfunction as a major driver of disease. That realization has created an urgent need for tools that can safely and efficiently deliver therapies to these cells throughout the brain."

Steve Goldman, MD, PhD, co-director, University of Rochester Medicine Center for Translational Neuromedicine

Engineering viruses to target human glia

To develop those tools, the researchers engineered a library of modified AAV5 viral vectors. Each contained small changes to its outer protein shell, or capsid, which determines the types of cells a virus can infect. The team then screened the vectors in mice whose brains had been transplanted with human glial progenitor cells. Using a genetic tracking system, the researchers identified the viral variants that most effectively infected the human glial cells in the environment of the living brain.

"Human cells display different molecular signatures than mouse cells, and cells behave differently in the brain than they do in a dish," said Goldman. "By selecting vectors under biologically relevant conditions, we were able to identify candidates with a strong preference for human glia."

The resulting vectors preferentially targeted human glial progenitor cells and their descendants, including astrocytes and oligodendrocytes, while showing limited infection of peripheral tissues.

Rethinking drug delivery through the glymphatic system

Developing the right vector solved only half the problem. The team also needed a better way to distribute those vectors throughout the brain. To do so, they turned to the glymphatic system, a network of fluid-filled pathways that circulates cerebrospinal fluid through the brain to clear metabolic waste. This system was first described by URochester Medicine neuroscientist Maiken Nedergaard, MD, DMSc, who worked with Goldman's team to design a strategy to co-opt the glymphatic pathways for viral delivery.

The researchers delivered the engineered AAVs into the cisterna magna, a fluid-filled compartment at the base of the brain, while using hypertonic treatment to enhance fluid uptake into the glymphatic network. The approach enabled the vectors to spread broadly through the brain tissue, while largely circumventing the blood-brain barrier.

Because the vectors were concentrated in the brain, the strategy also reduced exposure to peripheral organs such as the liver, a common source of toxicity in conventional systemic gene therapy approaches.

"The glymphatic system is changing the way we think about brain drug delivery," Goldman said. "Rather than trying to force therapies across the blood-brain barrier from the bloodstream, we can use the brain's own transport pathways to distribute them more effectively where they are needed."

Potential applications across neurological disease

The researchers believe the platform may be particularly valuable for disorders affecting glial cells, especially diseases of the brain's white matter. Among the most immediate targets are pediatric lysosomal storage diseases and other inherited disorders in which glial cells lack critical enzymes.

"These are diseases where the biological target is well defined," Goldman said. "If you can deliver the corrective gene broadly throughout the brain, there is a real opportunity to change the course of disease."

The approach may also eventually support therapies for multiple sclerosis, age-related white matter loss, and Huntington's disease, as well as other neurodegenerative disorders in which glial dysfunction contributes to disease progression.

Looking ahead

The study establishes a framework not only for delivering gene therapies to glial cells in the brain but also for discovering and optimizing new vectors tailored to specific cell types. Goldman's team is already exploring the use of artificial intelligence to design viral capsids with desired targeting characteristics, potentially accelerating the development of next-generation gene therapies.

"We envision a future in which vectors can be designed for specific diseases and specific cell populations," Goldman said. "This study shows that by combining targeted vector engineering with glymphatic delivery, we can begin to build that future."