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Trojan Horse Delivers Drugs Across the Blood-Brain Barrier
By Nancy Touchette

A marker gene delivered to an adult rhesus monkey using a molecular Trojan horse reaches all areas of the brain (blue).

The vast majority of drugs designed to treat brain disease never make it to the brain.

That’s because the blood vessels to the brain are made of tightly packed cells that form a physical barrier, allowing very few molecules to slip through.

For the most part, the so-called blood-brain barrier is a good thing. It protects the brain from potentially damaging toxins in the bloodstream. But it also keeps out 98 percent of small-molecule drugs and all drugs made of large molecules, including new drugs designed to treat a variety of brain disorders such as cancer, Alzheimer’s, stroke, and spinal cord injury.

Now researchers have designed an ingenious strategy dubbed a “molecular Trojan horse” for ferrying molecules across the blood-brain barrier. They deliver specific substances to the brain by attaching them to a protein that is normally able to cross the barrier.

Once a drug has crossed the blood-brain barrier, it can travel the extensive network of blood vessels that nourish the brain, thereby reaching virtually every neuron in the brain.

Researchers have been trying for decades to deliver drugs across the blood-brain barrier. The new results, presented last month by William Pardridge of the University of California in Los Angeles at the fourth Annual Conference on Regenerative Medicine in Washington, D.C., represents the first time such as system works in animals.

Pardridge bases the approach on the fact that while most molecules are excluded from the brain, some are allowed to enter. Molecules that are either very small or fat-soluble, such as aspirin, can penetrate the blood-brain barrier. Larger molecules must attach to a special protein called a transporter that takes them across.

Pardridge has developed a system that uses the transporter protein to allow several types of molecules into the brains of mice, rats and monkeys. For example, he has delivered molecules that protect neurons, a feat that could pave the way for their use in patients with stroke or spinal cord injury.

Pardridge and his colleagues have also figured out a way to deliver genes into the brain. For instance, they have introduced a gene that blocks a cancer protein in mice with brain tumors. Mice that receive the gene live twice as long as those who don’t.

So far, Pardridge has been successful in delivering genes that remain active for a month or so before they naturally die off. In a clinical setting, patients being treated for chronic disease would still have to receive monthly injections.

Pardridge says few drug companies have shown an interest in his work. He has formed his own company and has received funding from the U.S. National Institutes of Health to try to develop and test an effective way to deliver drugs to patients who have had a stroke. He is preparing a proposal for a clinical trial in humans.

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Pardridge, W.M. Drug and gene targeting to the brain with molecular Trojan horses. Nature Reviews 1, 131-139 (2002).


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