Novel Molecular Shuttle Could Deliver Targeted, Diverse Therapies to the Brain

The blood–brain barrier (BBB) is a protective filter that lines the brain's blood vessels and is notoriously hard to penetrate, making the treatment of brain disorders very difficult. Strategies designed to breach the BBB include using brain surgery and focused ultrasound waves to create physical openings for the transportation of medicines and employing engineered adeno-associated viruses (AAVs) to ferry genetic payloads into desired locations, but these methods have limitations. Now, researchers at Caltech have developed a new, more effective way to transport potentially life-changing therapeutics across the BBB.

"Despite the economic and social toll of billions of patients suffering from neurological and neuropsychiatric disorders, a major bottleneck remains in successfully delivering therapeutics to the brain to address these conditions," says Viviana Gradinaru (BS '05), the Troendle Professor of Neuroscience and Biological Engineering at Caltech, director and Davis Leadership Chair of the Merkin Institute for Translational Research at Caltech, and a Howard Hughes Medical Institute Investigator. "Our work provides a new and powerful solution for delivery of both preexisting therapeutics that could, in principle, work, but they don't reach the brain, and new therapeutics that haven't been considered yet."

A paper describing the team's new method, called BrainCAB (Brain access through Carbonic Anhydrase-binder Bioconjugation), was published on August 26 in Nature Chemical Biology. Two of the study's co-first authors are Xiaozhe Ding (PhD '23) and Xinhong Chen (PhD '23), who conducted the work first as graduate students in the Gradinaru lab and then as staff of the Beckman Institute CLOVER Center directed by Timothy Shay (PhD '15).

Gradinaru's research group has been investigating delivery systems across the BBB—which shields our brains from bacteria and viruses but also makes it hard to access when help is needed to fight disease—for more than a decade. One line of previous work focused on engineered AAVs, which can carry therapeutic genetic material across the BBB and into cells. Although AAVs are powerful tools for gene delivery, they are not a general means of directly transporting therapeutic biomolecules such as antibodies, proteins, or oligonucleotides into the brain.

Read more on the Caltech website.