New
York , NY (8/03/01)- Decades of painstaking basic research in the
laboratory into the pathogenesis of Alzheimer's disease may soon pay off in
the form of new screening methods and treatments for the devastating neurological
disorder. Recent advances include new vaccine and drug candidates, as well
as surgically based gene therapy.
| One
in 10 persons over 65 and nearly half of those over 85 have Alzheimer's
disease. Today, four million Americans have Alzheimer's disease. Unless
a cure or prevention is found, that number will jump to 14 million by
the year 2050. Worldwide, it is estimated that 22 million individuals
will develop Alzheimer's disease by the year 2025 Source: Alzheimer's
Association |
Alois
Alzheimer, the German neurologist for whom the illness is named, first noticed
the presence of tangled plaques of tissue in autopsy specimens of Alzheimer's
patients 1906. Nearly 100 years later, researchers are convinced that these
plaques do indeed lead to the development of damaged brain tissue, producing
the characteristic dementia of the disease. Many labs are investigating the
nature of this amyloid plaque and potential methods for blocking its formation.
When
research revealed that mutations in amyloid precursor protein (APP) resulted
in increased production of beta-amyloid peptide (A-beta-42) found in virtually
all amyloid plaque of Alzheimer's patients, investigators decided to make
a vaccine with a synthetic form of AB42 to see if it might confer protection
against the disease. Early animal studies suggested that the vaccine did indeed
appear to protect transgenic "Alzheimer" mice. This led the vaccine
developer, Elan Pharmaceuticals, to test the safety of the vaccine in a small,
Phase I human clinical trial. In July ('01), the company announced that the
vaccine appeared to be safe and well tolerated in humans. A phase II study
is now being prepared that will begin to determine whether the vaccine provides
any therapeutic or prophylactic effects.
Meanwhile, researchers at the
NYU School of Medicine have developed a different vaccine candidate that they
believe may be even better, at least from a safety standpoint. Reporting in
the
current issue of the American Journal of Pathology, the NYU team says they
have successfully immunized mice against Alzheimer's. The NYU vaccine, based
on a fragment of amyloid protein, reduced the amount of amyloid plaque in
the brains of mice by 89 percent. It also reduced the amount of soluble amyloid
beta in the brain by 57 percent.
"Our study clearly shows that the vaccination approach is a powerful one that
shows great promise for Alzheimer's disease. And significantly, our approach
appears to be nontoxic," says. Thomas Wisniewski, M.D., Associate Professor
of Neurology, Pathology, and Psychiatry at NYU School of Medicine.
The
NYU researchers believe that the Elan vaccine now in human trials could be
toxic to nerve cells in the brain. They believe it might trigger the formation
of fibrils of plaque-forming amyloid. And they believe their vaccine candidate
may be safer:
"We
believe that our peptide vaccine isn't toxic to nerve cells because it doesn't
aggregate into clumps; it remains in solution," said Blas Frangione, M.D.,
Ph.D., Professor of Pathology at NYU School of Medicine.
Human clinical trials with the NYU vaccine could begin within one year.
DESIGNER
PLAQUE BUSTER
Researchers
at the University of Illinois at Chicago are working on a different approach.
They have designed and synthesized a potent compound that
blocks the action of one of two proteases that play a critical role in plaque
creation. This enzyme, memapsin 2, severs a longer protein in the brain called
amyloid precursor protein, or APP, to produce beta-amyloid, the major component
of the plaques that lead to the development of Alzheimer's disease. The new
inhibitor compound attracts memapsin 2 and keeps it from cutting APP, potentially
a useful way to halt accumulation of beta-amyloid in the brain.
Left: Amyloid Plaque in
Brain of Alzheimer's Patient
"This
enzyme is probably the most exciting target for an Alzheimer's drug," said
Arun Ghosh, professor of chemistry. Ghosh led the Chicago research team in
collaboration with Jordan Tang, head of the Protein Studies department at
the Oklahoma Medical Research Foundation in Oklahoma City.
While
the finding is promising, it is only a first step towards developing a therapeutic
agent, Ghosh cautioned:
"That
was a preliminary inhibitor. It's a big one, containing eight peptides - a
size that is inconceivable to be a drug candidate. Peptide-like compounds
never make useful drugs because they're metabolically unstable, they're insoluble
and, perhaps the biggest problem in Alzheimer's patients, they're hard to
deliver in the human brain."
Nonetheless,
the new finding will guide researchers in their search for smaller, more potent
inhibitors based on the same princple.That in turn could lead to effective
treatments for Alzheimer's disease.
GENE
SCREEN
In recent years genetic researchers looking for a way to identify those at
risk for Alzheimer's disease have zeroed in on a gene called APOE4.People
with this gene are believed to be at increased risk for developing the disease.
Those with multiple copies of the gene appear to be at even greater risk.
Researchers from the University of Pittsburgh
reported recently the identification of yet another genetic
risk factor for susceptibility to Alzheimer's disease.
After following 300 first-degree relatives of 189 Alzheimer's patients for
ten years, the researchers identified a small area of chromosome 10 that,
when combined with the previously identified APOE E4 gene, appears to significantly
increase a person's risk of developing the disease. The combination of the
genes is associated with a 16-fold increase in the risk of AD among first-degree
relatives. These findings may also provide new molecular targets for therapeutic
drug development . They could also help researchers to determine which patients
might benefit the most from new treatments for the disease.
HUMAN BRAIN TRANSPLANTS
No investigators are farther out on the frontier of Alzheimer's research than
those at UC San Diego. In April of this year, a team of physicians surgically
implanted genetically modified tissue into the brain of an Alzheimer's patient.
The surgery was the beginning of an experimental gene therapy protocol.It
was the first attempt to use human gene therapy to treat a disease of the
nervous system. The gene therapy was designed to deliver nerve growth factor
(NGF) a naturally occurring protein, directly to the part of the brain affected
by the disease.
Months
before the surgery, the researchers inserted NGF genes into tissue samples
obtained from the patient. These genetically engineered cells were then cultured.
Over time, the modified cells began producing large quantities of NGF.
In
earlier animal studies, this approach produced improvements in cholinergic
function. It will be some time before the researchers know if the procedure
is beneficial in humans. The UCSD team will continue to test the procedure
in selected patients.
"NGF
gene therapy is not expected to cure Alzheimer's disease, but we hope that
it might protect and even restore certain brain cells and alleviate some symptoms,
such as short-term memory loss, for a period that could last a few years,"
noted UCSD neurologist Mark H. Tuszynski, MD, Ph.D.
References
The
NYU research appeared in the August 2, 2001 issue of the American Journal
of Pathology. The Chicago research was reported in the American Chemical
Society's Journal of Medicinal Chemistry. The Pittsburgh research was
published in Molecular Psychiatry 2001 Volume 6, number 4, pages 413-419.
The UCSD team published animal data in the Sept. 14, 1999 and February 2000
issues of the Proceedings of the National Academy of Sciences.
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Related information on the Internet (Updated: August 2003)
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