Blood Brain Barrier

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Oregon Scientists Discover A Second

Blood-Brain Barrier; Important Finding

For Patients With Brain Cancers And

Neurological Disorders

Scientists at Oregon Health Sciences University and

the Portland Veterans

Affairs Medical Center have observed a second barrier

that apparently

prevents passage of agents from the blood to the

brain. The primary barrier is

a good thing in a healthy person, but this barrier

also keeps drugs such as

cancer-fighting chemotherapy from reaching the brain

in patients undergoing

treatment for brain tumors and other brain

malignancies.

L. Muldoon, Ph.D., assistant professor of

neurology, and cell biology

and developmental biology, and her colleagues in the

Blood-Brain Barrier

Program at OHSU report their finding in the February

1999 issue of the

American Journal of Neuroradiology (which comes out

in March). The group

has 20 years of experience with a technique that

opens the first blood-brain

barrier - an anatomic structure composed of tight

junctions in endothelial cells

-- to deliver cancer-fighting drugs. But some agents

that pass through the first

barrier apparently get caught on the second barrier

-- called the basement

membrane -- and never reach the brain.

The Oregon group is able to get certain therapeutic

agents inside the brain

with a barrier disruption technique that involves

injecting patients with a sugar

solution. This solution causes the tight endothelial

junctions to shrink and open

temporarily. With the barrier down, physicians can

get cancer-fighting drugs

across the barrier and into the brain - a place drugs

don't permeate well with

conventional chemotherapy.

More recently, the group has been experimenting on

ways to deliver genes

across the blood-brain barrier in rodents. The genes

are loaded onto altered

viral vectors, such as the herpesvirus vector or the

adenovirus vector.

(Scientists are able to inactivate the dangerous

parts of the virus and then use

recombinant techniques to load genes onto the virus.

These recombinant viral

vectors can then safely ferry therapeutic genes to

their target tissues.) Using

iron particles the same size as viruses, the Oregon

researchers noticed that

some agents crossed the endothelial junctions only to

get stuck just beyond

them. The authors inferred the existence of a

secondary blood-brain barrier at

the level of the basement membrane. The basement

membrane is a protein

layer surrounding capillaries.

A. Neuwelt, M.D., professor of neurology at

OHSU and the

VAMC, describes the second barrier as a " spider web "

because it seems to

trap some viral particles, while others slip through.

The agents that make it

through he calls " stealth " and those that don't he

terms " non-stealth. "

Although their studies suggest the presence of a

second barrier, the

researchers don't yet fully understand how it works.

If not an actual anatomic

structure, it may be an electrically charged barrier

like the one that exists in the

kidney. In either case, Neuwelt says the group's next

challenges are to find

ways to defeat the second barrier and to learn more

about the properties that

allow the stealth agents to pass through both

barriers.

The work with viral vectors is important because

toxic genes can be targeted

at tumor cells for killing. Researchers have been

using a herpes virus gene to

" infect " tumor cells, rendering them susceptible to

the antiviral drug acyclovir

or ganciclovir. This gene has been approved for

clinical trials, and Phase I

trials are under way at a few institutions by direct

injection into the tumor.

Oregon researchers hope to improve delivery by

delivering these vectors from

blood to brain.

Researchers also hope to use viral vectors to carry

replacement genes into the

brains of people with neurodegenerative disease

caused by the absence of a

single gene or by a defective gene. In Parkinson's

disease, for example, it may

be possible to deliver a functional gene to alleviate

symptoms of the disease.

The research findings in the neuroradiology journal

also point to problems with

current magnetic resonance imaging. Blood-brain

barrier disruption relies on

MR imaging to assess the distribution of iron

particles throughout the brain

hemisphere. However, MR images cannot show

incorporation of these agents

at the cellular level. In other words, the MR image

machines in clinical use

today only show delivery across the first barrier,

but not whether the agents

have actually crossed the basement membrane, or

second barrier. Clinicians

may incorrectly assume that a drug is reaching its

target in the brain when in

fact it is being stopped at the second barrier.

With viral particles, which are much larger than

chemotherapeutic molecules,

it's important for clinicians to know whether a

specific viral vector can pass

through the secondary barrier. In an editorial in the

same issue, M.

Quencer, M.D., editor of the American Journal of

Neuroradiology, calls this

" a distinct challenge for highly detailed MR

imaging. " He suggests the use of

stronger magnets in MR imaging to provide adequate

spatial resolution. The

Oregon team has approval to assess the distribution

of these viral-sized iron

particles in patients with brain tumors to determine

the feasibility of gene

therapy.

In addition to Muldoon and Neuwelt, authors include

A. Pagel, B.A.,

VAMC, and A. Kroll, D.V.M., Simon

Roman-Goldstein, M.D., and

S. , B.S. all of OHSU. The National

Institutes of Health and the

Veterans Administration fund the work.