One of the greater challenges in neurological drug development is getting drugs to the brain at all. The blood-brain barrier is specifically meant to keep many molecules away from the brain — and what's more, the same chemical characteristics that allow compounds to get through the blood-brain barrier tend to allow the body to metabolize them more easily. As a net result, the success rate for neurological drug development is even more dismal than the already pretty dismal average.

But a paper published in advance online publication on the Nature web site this week describes proof-of-concept studies for a new way to deliver molecules across the big divide: hitch them to a piece of rabies virus.

The researchers, who hail from Harvard Medical School's CBR Institute and department of pediatrics, the University of Iowa, and Samchully Pharmaceuticals Co. Ltd. and Hanyang University of Seoul, South Korea, used a peptide of about 30 amino acids length that is usually a part of the rabies virus envelope.

In the research described in the Nature paper, the team attached short interfering RNA molecules to the transport peptide via a bridge consisting of a chain of nine arginines. The arginines are highly positively charged, and will bind nucleic acids via electrostatic interactions.

But the delivery system also could be conjugated to the surface of nanoparticles packed with antibodies or small molecules, which would greatly expand its potential uses. "We believe it has enormous possibilities," senior author Manjunath Swamy, an investigator at the CBR Institute, told BioWorld Today. He added that his team was not aware of "any particular limit" to what could be transported across the blood-brain barrier at this point.

The rabies virus carrier peptide with its attachment is able to cross the blood-brain barrier. Once it has made it into the brain, it binds to receptors for the neurotransmitter acetylcholine. However, this does not mean that delivery is limited to cholinergic neurons: Swamy said that the binding site for the glycoprotein is widely expressed on both neurons and glia throughout the brain.

The scientists first tested their invention on cells in culture, and found that neurons, but not control cells, took up siRNA that shuts down the production of green fluorescent protein. Production of green fluorescent protein in engineered neurons was reduced by more than 90 percent.

When they injected engineered mice with the carrier peptide bound to different siRNAs, the conjugates were able to significantly reduce the production of green fluorescent protein as well as endogenous proteins. The silencing was specific to the brain of the animals, and liver and spleen were not affected.

In a final set of experiments, the researchers infected mice with viral encephalitis and then treated them with intravenous administration of either protective or control siRNAs bound to the delivery protein or another part of the rabies virus that does not cross the blood-brain barrier. Eighty percent of the mice treated with the protective siRNAs bound to the effective carrier survived, while the viral encephalitis was uniformly fatal to animals in the various control groups.

The limits of the new technology are not yet clear, but "we are already delivering things that are larger than what can normally cross" the blood-brain barrier, Ryan Dietz of the Office of Technology Development at the CBR Institute told BioWorld Today. "So the proof of concept is there." Dietz said the Institute "is looking to collaborate with companies with dovetailing capabilities" to commercialize the technology. SiRNa companies are an obvious target group, but given the possibility of delivering packaged antibodies and small molecules, Dietz believes that the potential group of collaborators is much wider - and could include compounds that have previously failed in clinical development due to delivery problems or side effects.