Until now, the only attempts at targeted drug delivery and gene therapy in the brain have involved opening the skull and injecting substances into particular areas, which is risky. This is necessary because the cells lining blood vessels in the brain are tightly bound together to keep out infectious agents. This blood-brain barrier also keeps out large-molecule drugs, and the lipid particles or viruses used to carry DNA in gene therapy.
But Ferenc Jolesz and his team at Brigham and Women's Hospital in Boston have found a way to temporarily open the barrier. First, tiny protein bubbles, which are already used by doctors to improve ultrasound images of blood vessels, are injected into the bloodstream. Then an ultrasound beam is focused on a specific region, which bursts the bubbles in the blood vessels in that area. Earlier this year, Jolesz's team reported that the resulting shock waves make the blood-brain barrier permeable, so large particles can get into the brain both between cells and through cell membranes.
Now his team has shown this method could be used to deliver genes to the brain. They injected three rabbits with the bubble mixture and focused an ultrasound beam on several different spots in their brains. Then they injected the rabbits with a modified herpes virus- a common tool in gene therapy.
The virus reached the brain areas on which the beam had been focused, the team will tell a meeting later this month. The method sidesteps the two obstacles that make the brain hard to treat: the skull and the blood-brain barrier.
The researchers plan to make delivery even more specific by putting the viruses inside the bubbles themselves. They think this method will also work with large-molecule drugs. But Jolesz cautions that it will take many experiments to show that the technique is safe and effective enough for gene therapy.
"Applications could include the treatment of cancer and different neurodegenerative diseases," says gene therapy expert Richard Mulligan of Harvard Medical School. But he adds that it's not enough to get viruses to the right place in the body. They must also be able to deliver genes to the target cells, and the genes must be properly expressed.
Various other groups are looking at the ultrasound technique as a way to improve gene delivery elsewhere in the body. "I think it has a great deal of promise," says Christopher Newman of the University of Sheffield. Ultrasound is attractive because it has a very strong safety record, he says.
Author: Sylvia Pagan Westphal, Boston
New Scientist issue: 3 August 2002
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