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In October 1999, Amgen identified an enzyme that may be
involved in the build-up of the beta-amyloid plaques in
Alzheimer's disease. Known as BACE, or beta-site amyloid
precursor protein cleaving enzyme, it may have potential
for treating the disease.
The plaques that are a feature of Alzheimer's disease are
dependent on the cleavage of amyloid precursor protein by
the protease enzymes beta-secretase and gamma-secretase.
BACE is believed to be beta-secretase, although validation
of this hypothesis is still to be tested in a transgenic
mouse model. The exact role of beta-secretases in Alzheimer's
is also unclear.
Both beta- and gamma-secretase have been targets for drug
therapy of Alzheimer's for some time without true knowledge
of the enzymes. Other companies have candidates for the
two enzymes, including Elan, which has a patent on a beta-secretase
candidate. In addition, SmithKline Beecham, Bristol-Myers
Squibb and Scios are all working in the area.
Other recent developments include:
- Researchers at the Oklahoma Medical Research Foundation
have designed an inhibitor for memapsin 2 (beta-secretase).
Beta- and gamma-secretase produce beta-amyloid, so over-activity
is associated with the development of Alzheimer's, and
an inhibitor is the first step towards the design of
an effective drug. The OMRF is holding discussions with
pharmaceutical companies to take the research further.
- Scientists from the NIH National Institute on Ageing
described a series of inhibitors of another Alzheimer's-associated
enzyme, butyrylcholinesterase, in April. These inhibitors
are thought to represent a promising new strategy for
Alzheimer's therapy. Axonyx is developing a series of
selective butyrylcholinesterase inhibitors, which reduce
the production of toxic (beta)-amyloid precursor protein
and (beta)-amyloid peptide.
Axonyx is also collaborating with Ares-Serono on the
development of its "beta-(b)-sheet breaker" compounds
for the inhibition and dissolution of amyloid deposits.
- Swiss researchers led by the University of Lausanne
have suggested that apolipoprotein (a), or apo(a), is
associated with Alzheimer's. It is involved in the transport
of lipids in the body, and elevated blood levels appear
to increase the risk of Alzheimer's in some individuals,
but lower the risk in others. The variation was dependent
on age and a gene already linked with the disease, apoE4.
60% of Alzheimer's sufferers had apoE4, compared to
25% without the disease. Apo(a) may thus amplify the
effect of apoE4 - impacting diagnosis and treatment.
- At the beginning of March, Eli Lilly and its collaborators
from the Washington University School of Medicine released
their research into the role of apolipoprotein E in
the formation of beta-amyloid plaque-forming deposits.
Noting that apoE2 was protective, Lilly's Dr Steven
M Paul said people with two copies of apoE4 (i.e. one
from each parent) had a 10-fold greater risk of developing
Alzheimer's. 50% of such individuals will develop the
disorder by the age of 65, and 80% by age 85. 10%, however,
will never develop Alzheimer's, suggesting that another
factor is also involved. ApoE4 seems to encourage more
amyloid deposition and the formation of nerve tangles
and plaques in brain areas involved in learning and
memory. Modification of apoE levels or interactions
with beta-amyloid may lead to innovative strategies
for the treatment or prevention of Alzheimer's.
Dr Paul commented, "If we could find a way to reduce
apoE expression, since we know what cells make it in
the brain, we think we could come up with a drug that
might prevent plaque deposition." He cautioned that
such a drug is some years away from the market.
- Three weeks later, scientists at the University of
California-San Francisco published their findings on
apoE3 in Nature. This gene may actually prevent the
onset of some Alzheimer's symptoms. Mice carrying human
apoE3 performed better in maze-solving tests than those
with apoE4, even though they had similar levels of beta-amyloid.
Work is now focusing on the development of drugs that
mimic the effect of apoE3 on the brain.
- Apolipoprotein is not the only protein linked to Alzheimer's.
US and Italian teams have discovered that genes for
interleukin-1 can also be a factor. There are alpha
(IL-1A) and beta (IL-1B) versions. Having two copies
of the specific variation IL-1A2 leads to a three-fold
increase in the risk of developing Alzheimer's. This
plus IL-1B2 is linked to a ten-fold increase in risk.
A variation in IL-1A is also associated with developing
the disease at an earlier age. The research could help
explain why some anti-inflammatory drugs appear to delay
the onset of Alzheimer's (hence the COX-2 inhibitor
trials).
- In April, American Home Products and Elan announced
that they would collaborate on the development of a
vaccine for the treatment of mild to moderate Alzheimer's
disease, and possibly its prevention. Known as AN-1792,
Elan's vaccine has been shown to reduce and prevent
the development of amyloid plaque in transgenic mice.
It is now in Phase I trials in the UK and US.
Any vaccine would arrive at an opportune time. Maureen
Reagan, daughter of ex-US President and Alzheimer's sufferer
Ronald Reagan, told a Senate sub-committee in March that
an extra $100 million was needed to prevent an 'epidemic'
of Alzheimer's disease that could bankrupt the country's
Medicare system. The US Alzheimer's Association says the
incidence of the disease will rise 350% by the middle
of the century. Analysts predict that the US Alzheimer's
market alone will be worth $2.3 billion by 2003.
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