The brain has a unique ecology – sometimes it’s life-saving, sometimes life-robbing. The billions of neurons (nerve cells) of which the brain is composed require the protection of such an ecology. Called the blood-brain barrier, its 400 miles of specialized vasculature prevent substances such as toxins, microbes, and many drugs from having direct contact with brain tissue. Unfortunately, it can also keep out much-needed substances, such as potentially lifesaving antibiotics for infections within the brain, or chemotherapy for brain tumors.
For decades, scientists have been hunting for a way to temporarily open the barrier to administer drugs, then reseal it. Now, a team of researchers at Yale University has developed a tool – an antibody – for opening the blood-brain barrier for several hours to administer drugs directly to the tissue.
“This is the first time we’ve figured out how to control the blood-brain barrier with a molecule,” says team leader Anne Eichmann, PhD, Ensign Professor of Medicine, cellular and molecular physiology at Yale, in a statement.
The development and maintenance of the blood-brain barrier are dependent on what is called the Wnt signaling pathway. Eichmann’s team sought to determine whether this pathway could be modulated to open the barrier on demand.
Kevin Boyé, a postdoctoral associate at Yale, joined Eichmann’s lab to study a molecule known as Unc5B, a membrane receptor in the cellular lining of capillaries. He learned that the receptor is essential for normal vascular development. He discovered, also, that a protein known as Claudin5, important to forming tight junctions between the cells of the blood-brain barrier, also needs Unc5B. Through this new study, the team determined that the Unc5B receptor controls the Wnt pathway.
When Boyé removed the receptors in adult mice with an already established blood-brain barrier, he found that the barrier remained open. He discovered another molecule, Netrin-1, also caused a blood-brain barrier defect when it was removed.
Next, the team developed an antibody that could block the action of Netrin-1 from binding to its receptor. Upon injecting the antibody, the team disrupted the Wnt signaling pathway, causing the blood-brain barrier to open temporarily, on demand. “It was quite a fascinating journey, especially the development of our blocking antibodies,” says Boyé, “To see that we can open the blood-brain barrier in a time-sensitive fashion to promote drug delivery.”
Because the blood-brain barrier blocks entry to all but a tiny subset of small molecules, neurological conditions such as Alzheimer’s disease, multiple sclerosis, brain tumors, and depression are extremely difficult to treat. Control over the barrier will be helpful for future drug treatments.
“This paves the way to more interesting basic research around how the body builds such a tight barrier to protect its neurons and how can it be manipulated for drug delivery purposes,” says Eichmann. The team hopes to apply its findings to chemotherapy delivery for treating tumors in the brain and other regions of the central nervous system.
The research is published in the journal Nature Communications.
