Rabies virus helps provide a means to get RNAi therapy past the blood-brain barrier

BOSTON—One of the biggest barriers to effective drugs for neurological and neurodegenerative disorders is the blood-brain barrier, which is designed to keep pathogens out of the brain. But that also means keeping most small- and large-molecule drugs out, a problem that researchers at the Immune Disease Institute (IDI)—formerly the CBR Institute for Biomedical Research—believe they have overcome with a little help from the rabies virus.

To overcome the blood-brain barrier problem, researchers led by Dr. Manjunath Swamy employed a modified rabies virus glycoprotein (RVG) peptide that slipped past the blood-brain barrier in mice and delivered small interfering RNAs as a therapy to neuronal cells in the brain. The siRNAs reportedly succeeded in silencing specific genes in the brain without side effects. If it holds true for humans, it would mean a non-invasive, intravenous means of delivering, throughout the brain, RNAi therapy and potentially could also deliver DNA for gene therapy.

Although the research focused on RNAi therapy, the implications are much broader for the pharmaceutical community and extend far beyond RNA- and DNA-based therapies, according to Dr. Priti Kumar, the lead author of a paper published in the June 17, 2007 issue of Nature that outlines the IDI research findings. The delivery technology, which has been dubbed CORVUS, also promises to be a way to potentially deliver a wide variety of more conventional drugs, in the form of antibodies, proteins, and other compounds.

The value isn't even restricted to therapeutic purposes, as the same technology could be used to gain a greater understanding of the basic biology of the brain, for purposes ranging from diagnostics to therapeutics, she says.

The IDI researchers are already looking ahead, Kumar says, and are interested to find out if the same delivery technology could work in the central nervous system, for purposes such as reaching the spinal neurons.

"That could be revolutionary in terms of pain receptors and finding ways to study and deal with pain," she notes.

In addition to looking at other areas of the central nervous system aside from the brain, the team is also interested in improving the way that RNA or other therapeutics could be delivered.

"We are trying to improve our method of getting siRNAs in, and we're looking at a liposomal approach that would likely be able to carry a lot more cargo," Kumar says. "A single liposome could carry a lot of siRNA molecules, for example."

The work to overcome the blood-brain barrier dilemma with the CORVUS technology—or something similar—would be of great use in cutting down how many late-stage clinical trials fail when candidate drugs are blocked by the blood-brain barrier, say Swamy and Kumar. In fact, the ability to send therapies selectively to the brain could, they say, revolutionize the treatment of such diseases as Alzheimer's and Parkinson's; multiple sclerosis, schizophrenia and other psychiatric illnesses; encephalitis, meningitis and other fatal infections; and central nervous system traumas, among other illnesses.