Grant: Project Grant

Cerebral cavernous malformations (CCM) are clusters of fragile blood vessels in the brain that can leak or bleed, sometimes causing stroke, seizures, and neurological disability. In people with CCM, the cells lining brain blood vessels lose their ability to form a strong barrier, allowing harmful substances to leak into brain tissue. This barrier breakdown is linked to inherited or spontaneous genetic changes that disrupt key cellular signals. Our research aims to restore the brain's protective blood vessel barrier using a new type of targeted therapy we have developed. This therapy, called an FZD4-LRP6 surrogate, is new type of antibody that can "switch on" a natural repair pathway normally used during development to build and maintain the blood-brain barrier. By selectively activating this pathway, we hope to strengthen the junctions between blood vessel cells and reduce leakage. We will test this therapy in human stem cell-derived brain blood vessel models, advanced "blood-brain barrier-on-a-chip" systems, and mouse models of CCM. These experiments will tell us if the therapy can repair barrier defects, prevent new lesions from forming, and reduce the risk of bleeding. If successful, this approach could offer the first treatment aimed at correcting the underlying problem in CCM rather than only managing symptoms. Beyond CCM, this strategy could also lead to new therapies for other brain conditions where blood vessels become leaky, including multiple sclerosis, traumatic brain injury, and certain forms of dementia.