Could We Restore the Blood-Brain Barrier?

The blood-brain barrier:  a layer of cells between blood vessels and the rest of the brain, kicks out toxins, pathogens and other undesirables that can sabotage the brain’s precious gray matter and its overall health. 

“A leaky blood-brain barrier is a common pathway for a lot of brain diseases, so to be able to seal off the barrier has been a long sought-after goal in medicine,” said Calvin Kuo, MD, PhD, the Maureen Lyles D’Ambrogio Professor and a professor of hematology.

A recent paper of Calvin Kuo, MD, PhD, and colleagues describes a treatment that could be instrumental in restoring the barrier’s normal function. 

“We have evaluated a new therapeutic class of molecules that can be used to treat a leaky blood-brain barrier; previously, there were no treatments directed at the blood-brain barrier specifically,” Kuo said.

The researchers started their quest by looking at WNT signaling, a communication pathway used by cells to promote tissue regeneration and wound healing. WNT signaling helps maintain the blood-brain barrier by promoting cell-to-cell communication that lines brain blood vessels.

“The opportunity arose to test a novel WNT signaling pathway that would turn on signaling in the blood-brain barrier by binding very selectively to a receptor called frizzled.”Kuo said

Scientists have been focusing on frizzled, a protein receptor that initiates the WNT pathway, for blood-brain barrier therapies since mouse mutations in the frizzled gene cause blood-brain barrier abnormalities.

Chris Garcia, PhD, developed prototype therapeutic WNT pathway molecules in the lab, including a molecule that activates the frizzled receptor FZD4. Collaborators at a research company created L6-F4-2, a FZD4 binding molecule that activates WNT signaling 100 times more efficiently than other FZD4 binders.

When the team activated WNT signaling at a higher rate, they saw an increase in blood-brain barrier strength.

The researchers wanted to study what happens when the natural molecular key for frizzled is missing, and whether it can be replaced successfully with L6-F4-2. So they turned to Norrie disease, a genetic abnormality that results in a leaky blood-retinal barrier.

In Norrie disease, the development of blood vessels of the retina is hindered, resulting in leaky blood vessel connections, improper development and blindness.

Norrie disease results from mutations in the NDP gene, which provides instructions for making a protein called Norrin, which is the key that fits the lock of the FZD4 receptor and turns it on. In the study’s mice, the gene is inactivated, and the key is missing causing a leaky barrier and blindness. The scientists replaced the missing Norrin protein with L6-F4-2, which they call a surrogate.

When L6-F4-2 replaced the missing Norrin protein, the blood-retinal layer was restored in the mice. The finding shows that, in mice, the blood-brain barrier could be restored by drugs that activate FZD receptors and the WNT signaling pathway.

“We hope this will be a first step toward developing a new generation of drugs that can repair the blood-brain barrier, using a very different strategy and molecular target than current medications,” Kuo said.


Jie Ding, Sung-Jin Lee, Lukas Vlahos, Kanako Yuki, Cara C. Rada, Vincent van Unen, Meghah Vuppalapaty, Hui Chen, Asmiti Sura, Aaron K. McCormick, Madeline Tomaske, Samira Alwahabi, Huy Nguyen, William Nowatzke, Lily Kim, Lisa Kelly, Douglas Vollrath, Andrea Califano, Wen-Chen Yeh, Yang Li, Calvin J. Kuo. Therapeutic blood-brain barrier modulation and stroke treatment by a bioengineered FZD4-selective WNT surrogate in mice. Nature Communications, 2023; 14 (1) DOI: 10.1038/s41467-023-37689-1

Stanford Medicine. “Restoring the blood-brain barrier?.” ScienceDaily. ScienceDaily, 20 June 2023. <>.

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Photo by Kelli McClintock