New study highlights how to deliver a protein to the brain quickly

Many diseases originate from a protein that is not working properly. Now a multidisciplinary research team with Texas A&M AgriLife and Texas A&M University, both USA, has found a way to deliver a protein to the brain quickly, effectively and in a short time, with therapeutic and scientific implications. The study was recently published in scientific advances.

Potential uses for the method in the future could include spinal cord injury repair and a range of other localized injection applications.

“We found that we could successfully introduce a protein into the brains of mice,” said Dr. Jean Philippe Pellois. “Proteins are large molecules that cannot easily enter cells or cross cell membranes, but we devised a trick to make it happen.”

Both the protein and its delivery system naturally break down after they have fulfilled their role.

“We wanted to make sure that we have reagents that are very cell-friendly, that can enter the cells without destroying them and then leave them without a trace,” explains Pellois.

Because proteins can have powerful effects, cells are picky about which proteins they ingest.

“Cells have the equivalent of the digestive tract, called the endocytic pathway,” Pellois said. “We manage to get a cell to take in proteins and our mode of transport. Once the transporter is internalized into the endocytic pathway, it allows the proteins to enter the rest of the cell, particularly the nucleus, where we can trigger a response.”

Other labs have discovered that the human immunodeficiency virus contains a small sequence of amino acids – a peptide – that cells prefer to take up. The team further improved the ability of this peptide to enter cells. Once inside the cell, the peptide exits the cell’s “digestive tract” and the target protein arrives as well.

“People have used part of this peptide with an interesting protein,” said Dr. Cedric Geoffroy. “Our system goes one step further. You don’t have to modify the protein – most are supplied.”

The team mixed the target protein and peptide in solution and then injected the mixture into the brains of mice and found that their protein easily enters brain cells. The mice were specially bred so that the protein produced a visual signal, fluorescence, when it arrived as intended. In fact, brain cells near the injection site only began to fluoresce after the protein and its carrier were injected together.

“When the protein enters cells, those cells become red fluorescent,” Pellois said. “So if we look at whether the cells fluoresce, we can tell whether the protein has entered.”

The researchers say the study provides the evidence needed to show the method works in a living brain.

Further work will focus on improving the method to target only one cell type, he said. Another limitation is that the method currently only works with local injections. Nevertheless, the study opens up many potential applications.

“A key application would be using this approach for localized injections, for example at the site of a spinal cord injury,” Pellois said. “We’re also exploring the possibility of doing this in knee joints for cartilage repair or to fight inflammation that can cause diseases like arthritis.”

“This could also improve drug delivery. If you have a cancer drug that is very toxic, this method could reduce the amount of drug we administer,” Geoffroy concluded.