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Alzheimer's - and the
Pharmaceutical industry
Future Developments
Research scientists are investigating many new approaches
to Alzheimer's treatment. Of note are potential medicines
that mimic the activity of nerve growth factor, a natural
substance that helps neurons survive or regenerate, and others
that stop the formation of neurofibrillary tangles or amyloid
plaques. Such studies have been aided by advances in genetic
engineering. In particular, it has proved possible to insert
genes into cancerous nerve cells from a tumour called a neuroblastoma
so that they will grow in cell culture outside the body.
Here they will respond to nerve growth factor-like substances
or produce the amyloid precursor protein (APP) when growing.
Such cells can be used as test systems for new potential medicines.
Promoting neuron survival
It seems likely that the maintenance of health of nerve cells
in the brain depends on small natural proteins such as nerve
growth factor (NGF). Degenerative illnesses such as Alzheimer's
may be associated with either a lack of NGF or some defect
in its action. This idea is supported by the discovery that
NGF itself promotes the survival of neurons in culture.
Treatment of Alzheimer's with NGF itself produced uncertain
results and there were some concerns about its action. However,
Ebewe Pharmaceuticals is testing a enzyme digest of brain
proteins called cerebrolysin which has NGF-like activity in
experimental systems. They believe that it may stimulate nerve
growth and protect existing neurons from damage. Phase 2 and
3 clinical trials suggest that cerebrolysin improved thought
processes and overall function in people with mild to moderate
Alzheimer's. At least one trial also suggested that the benefits
of a four-week course were still present at re-assessment
at six months. If so, repeat treatments may help maintain
function over the long-term. Sanofi-Synthélabo has
also developed an NGF-like molecule, xaliproden, which has
reached phase 3 trials, while NeoTherapeutics has a molecule
(lateprinim, AIT-082) that triggers the synthesis in neurons
of molecules that benefit nerve growth. In a Phase 2 study,
it improved thought processes and memory on the ADAS-COG scale,
and is now progressing into further trials.
Several other approaches are aimed at preventing existing
neurons from damage or death. In one, Novartis, in co-operation
with Neurocrine Biosciences, is exploring the possible role
of DHEA (dihydroepiandrosterone) as a nerve protectant. This
is based on the finding that there are changes in people with
Alzheimer's in some of the hormones produced by the brain.
In model systems, DHEA reduced nerve injury and, in small
pilot studies, favourably modified the hormone balance in
elderly individuals.
A different hormone-based approach has arisen from a series
of structures related to a thyroid hormone called TRH. One
of these, posatirelin (Dainippon Pharma) has been shown to
improve the levels of acetylcholine-processing enzymes in
damaged areas of the brain and to prevent neurons and their
connections within the brain from premature death. The compound
showed improvements in several performance scales, including
intellectual and emotional impairment, orientation, activities
of daily living, attention and motivation.
Another molecule designed to prevent neuron loss is the compound
CEP-1347 (Cephalon), now in Phase 1 trials. This is the latest
in a series which can promote the survival of neurons in culture
outside the body. Unfortunately, most of the compounds also
block the receptors for some important cellular messengers
and this is likely to cause unwanted side effects. However,
CEP-1347 does not seem to have these unwanted properties.
The compound has been shown to preserve the levels of choline
acetyltransferase (the enzyme that makes acetylcholine) and
protect damaged nerves that link to the forebrain. It was
also able to significantly improve performance in a number
of tests of learning and attention. The compound has not yet
entered the clinic, but has interesting potential.
On a related theme, a novel brain hormone called galanin
was discovered in the 1990s. Raised levels of galanin are
found in people with Alzheimer's, and it has been shown that
it has at least three receptors with different functions.
One of these relates to nerve growth and regeneration, which
is clearly relevant to Alzheimer's. These studies may provide
new targets for medicines design.
Preventing neurofibrillary tangle and
plaque formation
Plaques and tau tangles are central to the efforts
to find medicines that might 'cure' Alzheimer's. In particular,
knowledge of the way in which these structures form and what
they are made of has been a great stimulus to pharmaceutical
companies.
The role of tau tangles is not entirely clear, because
although their density is related to the severity of dementia
in Alzheimer's, they are also found in some other conditions
in which dementia is absent. Nevertheless, the enzymes that
add phosphate to tau have been studied in detail and are a
potential target for the development of inhibitors, though
none has yet entered clinical trials.
A role for amyloid plaque seems more certain and it was explained
earlier how ßAPP (beta-amyloid precursor protein) is
cut by enzymes called
secretases into small pieces, one of which, BAP42,is a major
component of plaques. An important advance was the identification
of the beta-secretase enzyme by GlaxoSmithKline, Amgen and
others. Armed with this information, companies could design
specific inhibitors of beta-secretase as well as the associated
gamma-secretase.
Several organisations are seeking inhibitors of beta-amyloid
plaque formation in preclinical research programmes. Two American
universities, the Oklahoma Medical Research Foundation and
the University of Illinois, have developed a group of inhibitors
of beta-secretase, the best of which, OM-992, has interesting
properties. It breaks down too easily to be used as a medicine,
but is serving as a good starting point for future work. Merck
Sharp & Dohme is investigating a series of potent gamma-secretase
inhibitors to try and unravel the relationship between this
enzyme and presenilins 1 and 2 (PS1 and PS2). Using a special
technique, one compound has been shown to bind to PS1 and
PS2, indicating that these proteins may in fact be the same
as the gamma-secretase enzyme. Though possibly not a medicine
in its own right, the data on it will clarify what is happening
and pave the way for the design of potential medicines. Sanofi-Synthélabo
is investigating SL-65.0102, a compound that acts on the presenilins.
Its precise mechanism of action is unknown, but it has now
entered Phase 1 clinical studies. Lilly is studying a molecule
called DAPT, which it detected in a cell culture test for
medicines that might reduce beta-amyloid formation. In mice
carrying human genes, it reduced plaque components by 30 to
50 per cent in the various brain regions examined. Amgen has
also discovered a series of gamma-secretase inhibitors called
fenchylamine sulphonamides which it considers to be useful
research leads. Several other companies have active research
going on in this area, including AstraZeneca, Bristol-Myers
Squibb, Du Pont and GlaxoSmithKline, and new inhibitors of
both beta- and gamma-secretase could soon be identified.
A more speculative approach to the prevention of plaque build-up
is based on the knowledge that Alzheimer's is worsened by
the presence of certain metals, especially copper. Groups
in Australia and the USA are currently testing the clinical
effects of a molecule called clioquinol which is able to bind
to and remove copper from the body. Their studies have received
support from observations in special strains of mice in which
beta-amyloid peptide is over-produced. The animals develop
plaques similar to those in man. When treated with clioquinol,
the amyloid deposits were reduced in most animals and disappeared
completely in some. The compound is now in Phase 2 clinical
trials.
An unusual approach is being taken by the US firm, Nymox.
In 1998, it published a controversial theory that amyloid
plaques arise from structures called spherons. These are considered
to be dense balls of protein present in the brain cells of
all people from very early childhood. Nymox suggested that
they gradually enlarge until they are too big for the nerve
cells to hold them. At this point, they burst into the spaces
between neurons to form amyloid plaques. This idea is supported
by analyses showing that spherons are made of the same materials
as amyloid plaques. Nymox is developing a new medicine, NXD
2858, which it believes will prevent spherons developing into
plaques, and has applied for permission to test it in the
USA.
Somewhat further in the future, Cambridge Antibody Technology
has forged an agreement with Wyeth to develop human monoclonal
antibody medicines that may 'neutralise' the beta-amyloid
peptide found in amyloid plaques.
No matter which of the above approaches is the most successful,
all are at last beginning to tackle the root causes of Alzheimer's,
and hold the potential to provide real treatment rather than
symptomatic relief. However, the most exciting recent development
in the anti-plaque area has been the report of a potential
vaccine based on
the toxic BAP42 fragment that arises when ßAPPis split
up by beta- and gamma-secretase.
Potential Alzheimer's vaccines
Although the concept of a vaccine for Alzheimer's may seem
surprising, scientists at Elan Pharmaceuticals believe that
an immune response mounted against the material making up
amyloid plaques may help eliminate them or prevent their formation.
The company made a vaccine based on the toxic fragment of
amyloid precursor protein, BAP42. Results published in mid-1999
suggested that in Alzheimer's models, the vaccine substantially
prevented the formation of plaques and slowed the disruption
of neurons.
At the end of 2000, simultaneous publications confirmed and
extended these observations. In a variety of different models
of short- and long-term memory in mice, the vaccine offered
some protection against particular defects in learning and
reasoning that appear as plaques arise, and prevented the
decline of learning and memory. There are two drawbacks regarding
this work. The first is the mouse model itself, which lacks
tau tangles and thus only partially resembles Alzheimer's
in humans. Secondly, the mechanism as to how the vaccine works
is not clear and producing an effective vaccine in man may
be difficult.
Phase 1 human studies have now begun in the UK using a synthetic
amyloid peptide called AN-1792. Single doses were well tolerated
and multiple dose studies are now continuing in the UK. Further
development will be conducted jointly by Elan and Wyeth. These
are very exciting results and if trials confirm the value
of the approach, it will alter the main thrust of research
in Alzheimer's throughout the world. It will also hold out
the very real prospect of a preventive strategy for those
at risk from early-onset Alzheimer's because of their genetic
make-up, as well as elderly but otherwise well people entering
the critical age group.
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