The team has successfully switched off a gene implicated in Alzheimer’s disease in the brains of mice by exploiting exosomes, the nano-sized particles naturally released by cells. The exosomes, injected into the blood, are able to ferry a drug across the normally impermeable blood-brain barrier to the brain where it is needed.
Although this is said to be a significant and promising result, there are a number of steps to be taken before this type of drug delivery can be tested in humans in the clinic. The study, partly funded by the Muscular Dystrophy Campaign, is published in Nature Biotechnology.
‘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 study lead Dr Matthew Wood of the Department of Physiology, Anatomy and Genetics at the University of Oxford.
Exosomes, the small capsules produced by most cells in the body in varying amounts, are thought to be one of the ways cells communicate with each other and the body’s immune system. When exosomes break off from the outer walls of cells, they can take various cellular signals and genetic material with them, transporting this material between different cells.
This led the researchers to study whether exosomes could be adapted for delivering drugs to different cells and tissues of the body.
Novel drugs based on antibodies, peptides or more recently RNA molecules have been developed on many occasions to target specific parts of disease pathways. While these have shown good results in the lab, too often it has proved difficult to get the drugs to the right part of the body to see any effect in humans.
Delivering any therapy of this type to the brain would currently involve neurosurgery since nothing delivered intravenously would be able to cross from the blood into the brain.
‘The major barrier for these drugs is delivery,’ said 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 team set out to adapt 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.
First the scientists produced and purified exosomes from mouse cells. They then developed and patented new methods to insert RNA molecules into the exosomes and to 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 build up of malformed protein in Alzheimer’s disease. 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,’ said 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.’