Caltech Researchers Discover an Enzyme that Enables Viral Vectors to Cross the Blood-Brain Barrier

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A recent discovery by Caltech researchers has identified a previously unknown transportation mechanism to enable viral vectors to safely cross the blood–brain barrier, potentially providing an improved approach to treating brain disorders. This new Blood–Cerebrospinal Fluid–Virus-Adjacency Mechanism enables those vectors with proteins called hemagglutinins to cross the barrier by homing in on blood vessels near the choroid plexis before passing through the VR spaces.

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Caltech researchers discovered an enzyme that enables viral vectors to cross the blood-brain barrier, potentially aiding brain disorder drug development and research.

The blood–brain barrier (BBB) is a stringent, nearly impenetrable layer of cells that guards the brain, protecting the vital organ from hazards in the bloodstream such as toxins or bacteria and allowing only a very limited set of small molecules, such as nutrients, to pass through. This layer of protection, however, makes it difficult for researchers to study the brain and to design drugs that can treat brain disorders.

The blood–brain barrier consists of tightly packed cells that line the small vessels of the brain and spinal cord, a unique structure that induces tight junctions between its cells.

Now, a new study from Caltech has identified a previously unknown mechanism by which certain viral vectors—protein shells engineered to carry various desired cargo—can cross through the BBB. This mechanistic insight may provide a new approach to designing viral vectors for research and therapeutic applications. Understanding this and other new mechanisms could also give insight into how the brain’s defenses may be exploited by emergent pathogens, enabling researchers to prepare methods to block them.

The Center for Molecular and Biological Neuroscience at Caltech has used directed evolution to guide the evolution of these vectors and enhance their ability to cross the BBB.

The research was conducted in the laboratory of Viviana Gradinaru (Caltech BS ’05), the Lois and Victor Troendle Professor of Neuroscience and Biological Engineering and director of the Center for Molecular and Cellular Neuroscience, part of the Tianqiao and Chrissy Chen Institute for Neuroscience at Caltech, and appears in the journal Science Advances on April 19. The study’s first authors are Timothy Shay (PhD ’15), the scientific director of Caltech’s Beckman Institute CLOVER Center; bioengineering graduate Xiaozhe Ding (PhD ’23); and CLOVER research associate Erin Sullivan.

The Virchow-Roberts or VR spaces are the small channels that allow the viral vectors to cross the BBB.

Though the BBB serves as the brain’s formidable defense, certain viruses have naturally evolved the ability to bypass it. For decades, researchers have studied how to use these viruses as a kind of BBB-crossing Trojan Horse; to do so, researchers scrape out the original viral cargo carried by the viruses and then use their hollow shell to ferry beneficial therapeutics or tools for research. Viral vectors with the ability to cross the BBB can deliver desired genes to the brain through a simple injection into the bloodstream and thus do not need to be invasively injected into the brain. Unfortunately, most vectors derived from naturally evolved viruses are very inefficient at crossing the BBB, and so they must be administered at high doses, increasing the risk of side effects.

Hemagglutinin is a glycoprotein found on the surface of many viruses that helps them bind to cells, allowing them to pass through the BBB.

Inspired by nature, Gradinaru lab has over the past decade used the process of directed evolution—a technique pioneered at Caltech by Nobel Laureate Frances Arnold—to guide the evolution of vectors and enhance their ability to cross the BBB. Over the years, the group has generated dozens of vectors with different abilities to cross the BBB and target various tissues and cell types in a variety of species. In the process, they noticed that distinct vectors can behave differently across model organisms, suggesting that these vectors may each have identified distinct and efficient paths from the bloodstream to the brain.

The discovery of the BCVA could provide an improved approach to treating brain disorders, allowing for vector administration at lower doses and reducing the risk of side effects.

However, although researchers knew that these vectors could cross, it was still unclear how they were crossing. Where are the entry points in the fortified wall of the BBB? .

In this new study, the team led by Shay, Sullivan, and Ding identified what they call the Blood–Cerebrospinal Fluid–Virus-Adjacency Mechanism of transvascular transport (BCVA). The mechanism enables particular kinds of viral vectors—those that have certain proteins on their surface called hemagglutinin proteins—to cross BBB by homing in on blood vessels near the choroid plexis—the part of the brain that produces the liquid that flows in and around the brain—that are connected to regions of the brain through tiny vents called the Virchow-Roberts or VR spaces.

This finding could also give insight into how emergent pathogens may be able to cross the blood–brain barrier, permitting researchers to develop strategies to block them.

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