Oregon Health Sciences
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.
Leslie 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
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.
Edward 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
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
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, Robert 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 Michael A. Pagel, B.A., VAMC, and Robert A. Kroll, D.V.M.,
Simon Roman-Goldstein, M.D., and Russell S. Jones, B.S. all of OHSU.
The National Institutes of Health and the Veterans Administration
fund the work.