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A specialized cellular network that protects the brain has proved a hurdle to therapeutic drug delivery. Now researchers have found a way to breach the blood–brain barrier, which safeguards the brain from potentially dangerous molecules in the bloodstream. Manjunath Swamy, an immunologist at the CBR Institute for Biomedical Research in Boston, Massachusetts, and his colleagues had previously shown that small interfering RNA molecules (dubbed siRNAs) could treat viral brain infection when delivered directly to the brain. Now they may have found an easier way to deliver siRNAs — using a key peptide from the rabies virus that is able to traverse the blood–brain barrier (see page 39).

Was your goal simply to cross the blood–brain barrier?

Not exactly. We've been working on treatments for severe viral brain diseases. We've shown that synthetic siRNAs drastically suppress viral encephalitis. We started this line of research to find a better way to deliver these siRNAs to the brain.

What led you to try the rabies virus?

Twenty-five years ago, researchers trying to find the rabies-virus receptor showed that a protein on the virus binds to a neuronal receptor to infect brain cells. There were indications that you didn't need the virus, or even the entire viral protein, but simply a short protein fragment to bind to brain cells.

What else was needed to engineer this peptide fragment to deliver the siRNA?

We added a positively charged amino acid to the peptide so it could bind to the siRNA. After intravenous delivery, we found siRNA localized in brain cells. When we treated mice infected with the encephalitis virus with siRNA the survival rate was 80%.

Are there any risks associted with crossing the blood–brain barrier?

So far we've found the peptide to be nontoxic, but we need to understand how it is metabolized before it can be used in humans. We also don't know what happens to the specific neuronal receptor, which is involved in neurotransmission.

What ripple effects might your findings have in the greater research community?

This delivery approach has huge potential. The blood–brain barrier poses a problem for delivering promising gene therapy and RNA-interference agents. Researchers have already shown that siRNAs might be effective in neurological disorders such as Alzheimer's disease. The good thing about this peptide carrier is that you can attach any siRNA, and possibly antibodies or enzymes, to it.