Treating the brain is very difficult because of the "blood-brain barrier" created by the tight junctions between the cells lining the capillaries. Only molecules recognised by the cell receptors can get in, unless they are very small. The viruses most gene therapists use to deliver genes are too big, and have to be injected directly instead. Even then, the genes are not expressed widely and evenly throughout the brain.
"Quite frankly, the existing delivery systems have been woeful failures," says William Pardridge of the University of California, Los Angeles. Instead, his team has been perfecting a way to get genes into the brain hidden inside fatty spheres called liposomes.
First the team coats the liposomes with a polymer called polyethylene glycol (PEG), without which they would be purged from the blood within minutes. Next, antibodies that latch on to some of the brain-capillary receptors are tethered to a few of the PEG strands. The antibodies trick the receptors into letting the liposomes pass, where they can deliver their cargo to brain cells.
Pardridge's team has already shown that the technique works in rats, by delivering the gene for the luminescent protein luciferase (New Scientist, 10 June 2000, p 10). Now the team has tested the liposomes in rhesus monkeys, using antibodies specific to primate brain receptors. Not only did it work, but the amount of luciferase produced was 50 times greater than in rats (Molecular Therapy, vol 7, p 11).
"I haven't seen anything like this for viral or non-viral vectors," says Savio Woo, director of gene therapy at the Mount Sinai School of Medicine in New York. "To reach the central nervous system through the blood-brain barrier in a non-human primate with this kind of efficiency- that's absolutely fantastic."
The liposomes do not appear to have any toxic side effects, though they do deliver genes to other organs besides the brain. But the team has shown that by choosing the right switch to turn on the gene, the gene will be active only in the desired tissues.
Because the genes are not integrated into the genome, weekly or monthly injections would be needed for long-term treatment. But Pardridge sees this as an advantage, because there's no risk of genes lodging permanently in the wrong place and triggering cancer- a worry with some gene therapy viruses.
The method shows promise for treating Parkinson's. The team gave rats a neurotoxin that causes Parkinson's-like symptoms by cutting production of the key enzyme tyrosine hydroxylase. Four weeks later, the team injected the rats with liposomes containing a gene that boosts production of the enzyme. Three days after that, the rats' abnormal movements were reduced by 70 per cent.
The liposomes can also deliver cargoes other than genes, including drugs and "antisense" RNA. The lifespans of mice with brain tumours doubled when the liposomes were used to deliver antisense RNA to block production of a growth factor. And in studies yet to be published, the team has exploited a mechanism called RNA interference (New Scientist, 15 March, p 20), delivering fragments of double-stranded RNA that "silence" cancer genes.
Anil Ananthaswamy, San Francisco
New Scientist issue: 22nd March 2003
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