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New Hope for Alzheimer’s Treatment
By Boris Predovich, Covance Research Products
There
is now widespread agreement among research scientists and medical
professionals that Alzheimer’s Disease (AD) is a problem quickly growing
to vast proportions. As the life expectancy of Americans continues to
rise, increasing the percentage of the population over 65 years of age,
so does the number of Alzheimer’s cases.
It is currently
estimated that people over 65 years of age have a 10% chance of
developing Alzheimer’s, while those over 85 have a 50% likelihood of
developing AD, making it the leading cause of dementia among older
people. Though the disease is associated primarily with memory loss, its
effects also comprise a number of other severe disabilities, including
changes in personality, disorientation, difficulty with speech and
comprehension, and a lack of ability to move normally.
Consequently,
most Alzheimer’s patients require a great deal of care, costing society
close to $100 billion annually. According to Christian Fritze, Ph.D.,
Director of the Antibody Products Division at Covance Research Products,
"The impact of Alzheimer's Disease on our society will only increase as
our population ages. The prevalence of the disease and disabling
effects on the patient are significant by themselves. In addition we are
becoming increasingly aware of the far-reaching effects on families,
care-giver networks and the economics of our health care system. The
drive for progress towards effective treatments by the research and drug
development community is growing stronger every day."
A New Consensus
But
recent developments in the medical research community do provide some
hope. During the last two years, there has been a growing consensus
among Alzheimer researchers about the cause of Alzheimer’s disease,
providing focus for scientists exploring the new treatment options.
The
focus is on amyloid beta oligomers, a new wrinkle on an older
hypothesis called the “amyloid cascade hypothesis”. Widespread
acceptance of this new conclusion is something of a milestone in the
history of Alzheimer’s research. As Dr. Fritze says, "The decades old
quest for the causative agent in Alzheimer's Disease has recently
focused on the precursors of amyloid plaques. These precursors are part
of a bewildering array of processed (APP) Amyloid Precursor Protein)
variants, Tau isoforms and secretase components that play a role in
neuronal cytotoxicity and subsequent brain dysfunction.”
Amyloid
plaques are sticky protein deposits in the brain containing amyloid beta
peptide. Researchers have associated the buildup of this plaque with
Alzheimer’s disease since its discovery in 1907. But despite the clear
correlation, scientists were not sure what, exactly, spurred the onset
of Alzheimer’s Disease.
The hypothesis that amyloid beta
accumulation in the brain is the major cause of Alzheimer’s Disease1 has
been the focus of much attention over the past decade. Although this
hypothesis was the leading explanation for the cause of AD, it had
several weaknesses. The most obvious problem with the theory was the
fact that the buildup of amyloid beta peptides did not necessarily
correspond with the severity of Alzheimer’s symptoms.
However,
in 19982 and in 20023, researchers proposed that it was not the amyloid
beta plaques themselves that were neurotoxic – and therefore the cause
of Alzheimer’s – but rather precursors to amyloid beta plaques formed by
smaller aggregates of amyloid beta. These new ideas are gaining
widespread acceptance among the Alzheimer’s research community, creating
a consensus that had not existed before.
This new focus
provides one more spur to action for Alzheimer’s researchers, and
underscores the need for further advancement. “The AD field demands
sophisticated, highly-sensitive research tools to track these components
and quantitate the existence of monomeric, oligomeric and fibrillar
amyloid forms present in the progression of Alzheimer's disease,” says
Dr. Fritze.
Antibody Treatment
Two new studies, both
released in October 20044, suggest that new treatment options may be on
the horizon. The studies are the modification of one of two previous
attempts using amyloid beta (Aβ) antibodies in the treatment of
Alzheimer’s Disease. The previous attempts, though not successful, did
at least suggest new courses of action in Alzheimer’s research and
provided invaluable information for researchers.
In the first of
the two previous attempts, researchers injected the antigen itself –
pieces of the beta amyloid protein that makes up amyloid plaque – into
mice, in the hopes that the injections would generate an immune
(antibody) response against amyloid. Results were initially positive.
The injected antigen produced Aβ antibodies and slowed the onset of the
disease by decreasing Aβ levels. However, when tried on humans, the
procedure led to meningoencephalitis (an inflammation of tissue around
the brain) in some patients, and was therefore halted.
In the
second attempt, a passive immunity therapy was tried in which antibodies
to amyloid beta (not amyloid protein) were injected into mice, but
hemorrhaging and inflammation ensued due to the high antibody doses
required to be effective.
New Hope
But now there appears
to be new hope for the use of antibodies as therapeutic agents for the
treatment of Alzheimer’s patients. In the first of the two new studies
that appeared in October conducted by the National Institute for
Longevity Sciences, NCGG, and the Center for Neurological Diseases,
Brigham & Women’s College, Harvard Institute of Medicine,
researchers modified the first procedure. Concluding that the
meningoenchaphalitis which occurred in some patients was caused by
autoimmune T-cell activation, the researchers hoped to develop a vaccine
that could minimize this T-cell activation while retaining the
production of Aß antibodies. To accomplish this they created an oral
vaccine that attached Aß DNA to an adeno-associated virus vector, which
served to mitigate T-cell activation. Thus they were able to decrease Aß
levels in the brains of the mice and yet not activate T-cells to the
degree they had before, greatly reducing the risk of
meningoencephalitis.
In the other new study, conducted at the
University of Illinois at Chicago, researchers succeeded in making the
passive immunity protocol much safer. This they accomplished by changing
the point of entry for the Aß antibodies. Rather than injecting the
antibodies into the body of the mice, as was done previously, antibody
was injected directly into the brain of the mice. Because the antibodies
were injected directly into the brain, smaller doses were needed, and
side effects were minimized.
The results of the above studies,
and the potential for further optimized immunization strategies may
prove to be watershed events in the history of Alzheimer’s treatment.
Covance
is a leading provider of innovative antibody products and custom
antibody development services to the research community for Alzheimer’s
disease. Visit www.Covance.com for
more in-depth information and to view the suite of products for
Alzheimer’s disease. Boris Predovich is Vice President of Immunology and
Surgical Services at Covance Research Products.
Notes
1.J.A. Hardy, G.A. Higgins (1992), Science, 256:184-5.
2.M.P. Lambert et al (1998), Proc Natl Acad Sci, 95:6448-53.
3.D.M. Walsh et al (2002), Nature, 416:535-9.
4.Neelima B. Chauhan et al (2004), Journal of Neuroscience Research, 78, 5:732-741.
Hideo Hara et al (2004), Journal of Alzheimer’s Disease, 6, 5:483-488.
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