By Chandra Shekhar

NEWS

Blood-brain barrier bypassed

Scientists use gene therapy and low-density lipoprotein receptors to deliver drugs to the mouse

brain

[Published 24th April 2007 01:42 PM GMT]

Using a combination of gene therapy and receptor targeting, scientists have successfully

enabled a protein to cross the blood-brain barrier into the central nervous system, a crucial

step in delivering drugs to diseased brains, according to a study in this week's Proceedings

of the National Academy of Sciences.

"It's a very nice demonstration of how to get proteins into the brain," David Begley of the

Blood-Brain Barrier Group at King's College in London, who was not involved in the study,

told The Scientist.

During the study, the researchers delivered the enzyme glucocerebrosidase to the brains of

adult mice. In humans, a deficiency of this enzyme causes Gaucher's disease, a genetic

disorder that is often neurodegenerative and fatal.

Made of tightly packed endothelial cells that line capillaries in the brain, the blood-brain

barrier permits only a few essential chemicals to enter the brain. The barrier makes neural

disorders such as Alzheimer's and Gaucher's diseases very hard to treat, since existing

drug-delivery techniques -- such as brain injections, implants, and nanoparticles -- can

bring only small quantities of protein into the brain. "None of these methods is capable of

continuously delivering a therapeutic protein to the central nervous system," the study's

lead author, Brian Spencer of the University of California in San Diego, told The Scientist.

To help the glucocerebrosidase enzyme get through the blood-brain barrier, Spencer and

co-author Inder Verma of the Salk Institute in San Diego exploited the low-density

lipoprotein (LDL) receptors that shuttle some large molecules such as apolipoprotein B

across the barrier. Specifically, they attached the LDL receptor-binding domain of

apolipoprotein B to the glucocerebrosidase molecule, reasoning that the LDL receptors

would then allow the enzyme to enter the brain.

The researchers' next step was to provide the brain with a continuous supply of the

modified glucocerebrosidase. To do this, they transduced adult mice with the gene for this

protein using a lentivirus, effectively turning the animals' livers and spleens into "depot"

organs for continuously manufacturing the protein. Two weeks after transduction, the

enzyme appeared not only in the animals' livers and spleens, but also in their brain tissue.

Additional tests showed that the enzyme reached therapeutic levels. "We are surprised by

the amount of protein we are able to get into the brain," Spencer said.

Though exciting from a research standpoint, Spencer and Verma's method might not have

immediate clinical utility, some experts cautioned.

Victor Shashoua of Brookline, Mass.-based BioTherapeutix, which makes an Alzheimer's

drug that crosses the blood-brain barrier using a proprietary technique, pointed out that

brain work in mice often doesn't translate to humans. He cited the example of the

Alzheimer's vaccine Aß, which showed promise in mice but provoked an adverse immune

response in humans during Phase II trials. Spencer and Verma's work "is a very fine tool to

demonstrate where specific receptors exist in brain cells and what peptides can be

transported through them," he told The Scientist. "But is this going to be useful for human

treatment?"

"[Spencer and Verma's] approach is appealing -- make the body produce its own drug, and

use receptor targeting for delivery," noted Pieter Gaillard of to-BBB, a Dutch company

which also uses receptor targeting for drug delivery to the central nervous system. "But

using gene therapy to deliver a recombinant protein to the brain may not be clinically

feasible at this point."

Begley suggested a compromise: Instead of using gene therapy, researchers could use a cell

line to make the recombinant protein, then inject Gaucher's patients with the drug, like

normal enzyme replacement therapy for this disease. "In the shorter term, this might offer

a valuable route to get the enzyme into the brain," he said.

Chandra Shekhar

Links within this article:

K.Y.Krieger, " Blood-brain barrier booming as a source of new biotechnology research

challenges," The Scientist, September 16, 1996.

B.J. Spencer and I.M. Verma, "Targeted delivery of proteins across the blood-brain barrier,"

PNAS April 24, 2007.

Blood Brain Barrier group at King's College in London

'http://www.kcl.ac.uk/depsta/biomedical/cfnr/bbb.html

Inder Verma

D. Steinberg, "Companies halt first Alzheimer vaccine trial," The Scientist, April 1, 2002.

'http://www.the-scientist.com/article/display/12959

to-BBB

A. Fischer and M. Cavazzana-Calvo, "Whither gene therapy?," The Scientist, February 1,

2006.