Brazilian and US researchers have developed a molecule called FRW that, in tests with mice, proved capable of binding to blood vessels in the brain but not in other organs when injected into the bloodstream. They used the technique to produce the first ever complete map of the vasculature of the brain, paving the way for the creation of novel diagnostic imaging strategies and therapies for diseases such as Alzheimer’s and Parkinson’s.
The research was supported by São Paulo Research Foundation — FAPESP and led by Ricardo José Giordano, a professor at the University of São Paulo’s Chemistry Institute (IQ-USP) in Brazil and head of its Vascular Biology Laboratory. The results are published in Proceedings of the National Academy of Sciences (PNAS).
As Giordano explained, the main obstacle to the development of drugs capable of binding to blood vessels in the brain is the blood-brain barrier, a selectively permeable cellular boundary that protects the central nervous system from potentially toxic substances in the bloodstream. However, this research shows that FRW binds precisely to endothelial cell junctions in the blood-brain barrier.
In addition to producing a complete map of the brain’s vasculature, therefore, the new technique could also be used to detect the kind of gap in the blood-brain barrier that may be one of the causes of neurodegenerative diseases such as Alzheimer’s and Parkinson’s.
“Theoretically speaking, if FRW doesn’t bind to the cerebrovascular system, it’s a sign that the barrier is impaired,” Giordano told.
To perform the study, the researchers used a library of bacteriophages, usually called phages — viruses that infect bacteria and can be used to deliver molecules because they are inoffensive to other organisms.
“Each of the phages in the library has been modified by genetic engineering to have a different surface peptide [protein piece] from that of the original virus. This peptide carries a marker that’s detected when it binds to specific proteins, be they in the cerebrovascular system, in tumors, kidneys or other regions of the organism,” Giordano said.
The technique is known as phage display and won the 2018 Nobel Prize in Chemistry for its creators, George P. Smith and Gregory P. Winter. Smith first described phage display in 1985. In the following decade, the technique was adapted for application to living animals by Renata Pasqualini, a Brazilian-born researcher at Rutgers University in the US and one of the authors of the article in PNAS.
The research led by Giordano began in 2011 as part of a project for which São Paulo Research Foundation — FAPESP awarded a scientific initiation scholarship to Fenny Hui Fen Tang, first author of the article. Tang continued to focus on this research interest for her master’s and again for her doctorate, recently completed at IQ-USP.
FAPESP also provided funding to Giordano via a Young Investigator Grant and a Regular Research Grant.
To arrive at the molecule, the researchers injected mice with an entire library comprising some 10 billion…