Getting medicines into the brain is one of the biggest challenges in treating neurological disorders. The blood-brain barrier, a protective layer lining the brain’s blood vessels, is designed to keep harmful substances out — but that same defence can prevent potentially useful medicines from reaching the brain.Researchers at Caltech have now developed a small-molecule delivery system that could provide a new way around this problem. Called BrainCAB, the technology uses a modified version of a drug commonly prescribed as an eye drop for glaucoma to act as a molecular shuttle, carrying therapeutic molecules across the blood-brain barrier.
Why the blood-brain barrier is such a challenge
The blood-brain barrier protects the brain from potentially harmful substances circulating in the bloodstream. But when a patient needs treatment for a brain disorder, the barrier can become an obstacle.Existing approaches include brain surgery, focused ultrasound and engineered adeno-associated viruses (AAVs) designed to transport genetic material across the barrier. However, each approach has limitations, particularly when researchers want to deliver larger therapeutic molecules such as antibodies, proteins or RNA medicines.Caltech researchers have been investigating ways to cross the blood-brain barrier for more than a decade.Their breakthrough came from an earlier discovery involving carbonic anhydrase IV (CA-IV), an enzyme found on the surface of blood vessels in the brain. In 2023, the team found that CA-IV can act as a receptor allowing certain engineered AAVs to cross the blood-brain barrier through a natural process called receptor-mediated transcytosis.The researchers then wondered whether the same biological pathway could be used without a virus.
From a glaucoma drug to a molecular shuttle
The key was brinzolamide, a drug commonly used in prescription eye drops to treat glaucoma.Structure modelling by researcher Xiaozhe Ding showed that brinzolamide could bind to CA-IV at a site similar to where certain AAVs interact with the receptor.That prompted researchers from the laboratories of Caltech neuroscientist Viviana Gradinaru and chemist Sarah Reisman to modify the molecule so that it could continue binding to CA-IV while also carrying therapeutic cargo.“The fun thing about chemical synthesis is that it’s very modular,” Reisman said, according to Caltech. “Once you have your idea, you can make changes to the molecule and ask how it affects the activity.”The resulting system, BrainCAB, is designed to attach to therapeutic molecules and effectively use CA-IV as an entry point across the blood-brain barrier.
How BrainCAB works
The researchers describe BrainCAB as a molecular shuttle.After being administered intravenously, the modified small molecule binds to CA-IV on cells lining the brain’s blood vessels. That interaction triggers transcytosis, allowing the shuttle and its attached therapeutic cargo to move across the blood-brain barrier and into the brain.The team tested the system in rodents and nonhuman primates, two important preclinical models.As a proof of concept, they attached BrainCAB to atezolizumab, an antibody-based cancer immunotherapy used against cancers including lung and liver cancers that can spread to the brain.The researchers found that BrainCAB substantially increased the amount of the antibody reaching the brain.
Why a small molecule could make a difference
Caltech says the compact format of BrainCAB could offer several potential advantages over protein-based shuttle systems.A small-molecule carrier may be less likely to trigger an unwanted immune response and may have less effect on the physical properties of the therapeutic cargo. Its modular chemistry could also make it easier to manufacture and adapt for different types of medicines.“This 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,” Viviana Gradinaru said, according to Caltech.The researchers believe the platform could eventually be adapted beyond antibodies to other therapeutic approaches, including RNA medicines.
Human trials are still ahead
The findings, published in Nature Chemical Biology, are still at the preclinical stage. The researchers stress that BrainCAB requires further refinement and testing with different drugs before its potential in human treatment can be established.Caltech has filed a patent application for the technology, which has been licensed to Receptive Bio, a startup co-founded by Ding and Xinhong Chen, two of the study’s co-first authors.The team is now working on further preclinical development with the longer-term goal of moving towards human clinical studies.Researchers are also exploring whether future versions could carry multiple types of cargo or target particular brain cell types.If that work succeeds, BrainCAB could represent more than a new way to cross the blood-brain barrier. It could offer researchers a modular delivery platform for medicines that have long been limited by one fundamental problem: they can treat the brain in theory, but cannot get through its protective barrier in practice.Disclaimer: This article is based on research reported by Caltech and published in Nature Chemical Biology. The findings are preliminary and have not been independently verified by TOI Education.
