New Technique Successfully Delivers RNA Drugs into Brain

The blood-brain barrier has been a key complication to delivering gene-silencing or RNA-interference (RNAi) drugs into the brain to treat disorders such as muscular dystrophy, Alzheimer's disease, Parkinson's disease (AD), and other neurologic disorders. However, British researchers have discovered one possible way to penetrate this barrier and deliver RNAi treatments into brain cells.

In a mouse study, investigators from the University of Oxford (UK) revealed that engineered versions of exosomes, which are naturally occurring carriers of RNA molecules and other proteins among cells, were able to deliver small interfering RNAs (siRNA) to specific sites in the brain and turn off an AD gene target called BACE1. The study's findings were published online on March 20, 2011, in the journal Nature Biotechnology.

The team has successfully turned off a gene implicated in AD in the brains of mice by exploiting exosomes --tiny particles naturally released by cells. The exosomes, injected into the blood, are able to deliver a drug across the typically impermeable blood-brain barrier to the brain where it is needed.

Although this is an important and promising finding, there are a number of steps to be taken before this new form of drug delivery can be tested in humans in the clinic. "These are dramatic and exciting results. It's the first time new ‘biological' medicines have been delivered effectively across the blood-brain-barrier to the brain," said Dr. Matthew Wood of the department of physiology, anatomy, and genetics at the University of Oxford, who led the study. "This is the first time this natural system has been exploited for drug delivery," remarked Dr. Wood.

Dr. Matthew Wood Novel drugs based on antibodies, peptides, or more recently, RNA molecules have been developed on many instances to target specific regions of disease pathways. While these have shown good results in the laboratory, too frequently it has proved difficult to get the drugs to the correct areas of the body to see any effect in humans.

Currently, delivering any such type of therapy to the brain would have to involve neurosurgery. Nothing delivered intravenously would be able to cross from the blood into the brain. "The major barrier for these drugs is delivery," noted Dr. Wood. "This problem becomes even greater when you want to reach the brain. The blood-brain barrier--which stops most things in the blood stream from crossing to our brains--is much too great an obstacle."

The Oxford University researchers set out to modify naturally occurring exosomes to deliver a gene therapy. They used an RNA sequence that switches off a gene that is implicated in Alzheimer's disease.

To be able to make the application succeed, the researchers would need to be able to load the exosomes with the RNA, the drug. But they would also need to be able to target the appropriate tissues in the body. First of all, they produced and purified exosomes from mouse cells. They then developed and patented new techniques to both insert RNA molecules into the exosomes and add protein elements into the exosome coat that would target nerve cells.

The exosomes, injected intravenously into mice, crossed the blood-brain barrier and ended up in the brain. Once there, the RNA was able to switch off a gene implicated in the accumulation of malformed protein in AD. This resulted in a 60% decrease in the brain of the problem enzyme encoded by the gene.

"We've shown that a natural system could be exploited to deliver drugs across the blood-brain barrier," explained Dr. Wood. "We believe we can use this same technology for Alzheimer's, motor neuron disease, Parkinson's and Huntington's. All we need is a different RNA each time. The next steps are to test the exosomes in a mouse model of Alzheimer's disease to see if it makes a difference to disease progression."

Dr. Wood also noted that other steps would be needed before exosomes could be evaluated in humans, including safety tests and scaling up the procedures. "Many of these diseases have not been possible to treat in the last 50 years using standard drugs. New drugs have been developed based on complex biological molecules--antibodies, peptides, and RNA--but all require new ways of delivering the drugs. These natural nanoparticles would be administered intravenously or perhaps even orally, and would still reach the brain."

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