Summary of the 10th International
Conference on Alzheimer’s Drug Discovery
hosted by the Alzheimer’s Drug Discovery Foundation
By Diana Shineman, PhD, Alzheimer’s Drug Discovery
Foundation
Alzheimer’s disease (AD) is as complex molecularly
as it is devastating emotionally to the patients and
their families that suffer from the disease. It is
becoming increasing clear that many different
approaches, used in combination or in tandem, will
be critical to significantly impact disease
progression. At the 10th anniversary of
the International Conference on Alzheimer’s Drug
Discovery, hosted by the Alzheimer’s Drug
Discovery Foundation (ADDF) on September 14-15,
2009 in Jersey City, NJ, attendees were treated not
only to the breathtaking skyline view of New York
City, but also to two days of exciting and diverse
research aimed at Alzheimer’s disease intervention.
The majority of speakers were funded by the ADDF to
seed their research programs, often considered too
risky or early-stage by other funding sources.
An introduction by ADDF’s executive director, Howard
Fillit MD, set the stage for the conference by
emphasizing the challenges CNS drug discovery
researchers face and that more work is needed to
increase “shots on goal”, bringing new ideas and
novel targets into the pipeline to develop
treatments for AD.
Day 1 Plenary:
Bridging Neurocognitive Aging and
Disease Modification: Targeting Functional
Mechanisms of Impairment
Michela
Gallagher, PhD (Johns Hopkins University)
kicked off the conference with the first plenary
session, reminding us that Alzheimer’s disease is a
disease of neuronal systems, underlined by synaptic
failure that begins very early on in the disease
process. Gallagher showed evidence that
hyperactivity in the CA3 region of the hippocampus,
the region critical for proper memory function,
precedes memory deficits in animal models as well as
in the human disease. Perhaps inhibiting this
hyperactivity could prevent the downstream synaptic
degeneration, memory loss and pathology seen in
later stages of AD? Could this therapeutic strategy
preserve individuals at a point before Alzheimer’s
takes its devastating toll? This is what Gallagher
and her team seek to find out.
Session I: Neuroprotection Strategies
Strategies targeting neuroprotection, or
strengthening neuronal defenses against the toxic
insults of Alzheimer’s, were highlighted in the
first session of the conference.
Dr.
Frank Longo, MD PhD (Stanford University)
chaired the session and also spoke about his work on
developing BDNF small molecule mimetics that
specifically activate the TrkB receptor for the
treatment of AD. These mimetics have shown
beneficial effects in preventing dendritic spine
loss and cell death in response to Aβ in cellular
models and show exciting promise in initial animal
testing.
Moving from mice to man,
Karin Yurko-Mauro,
PhD (Martek Biosciences) presented
clinical data on the health benefits of DHA, the
main component of omega-3 fatty acids. DHA
supplementation resulted in a cardiovascular benefit
(decreased heart rate, blood pressure and
triglycerides) and also showed some cognitive
benefit in older individuals with memory complaints,
specifically in the paired associated learning
test. Further studies are needed to determine if
DHA substantially impacts Alzheimer’s disease
progression.
Jerry Colca, PhD
(Metabolic Solutions Development Company)
drew on the parallels many have seen between
diabetes and Alzheimer’s disease – could the
mitochondria be the ultimate target for both
diseases? Colca presented work suggesting that
studies of thizolidinediones (TZDs) may have been
misled by its focus on PPARγ for the treatment of
diabetes and potentially Alzheimer’s. His
hypothesis is that the target responsible for the
beneficial effects of TZDs is actually the
mitochondria, while PPARγ is actually responsible
for the negative side effects seen with treatment.
Metabolic Solution’s lead compound, Mitoglitazone,
specifically targets the mitochondria and not PPARγ
and is in Phase II clinical trials for diabetes (so
far working as predicted). Colca is now moving his
testing into Alzheimer’s mouse models, as
mitochondria are gaining more notoriety as an
important target for AD. Initial results look
promising, but more testing is necessary to
determine if Mitoglitazone can move forward
clinically as an AD therapeutic.
Asa Abeliovich, MD
PhD (Columbia University) discussed
the utility of micro RNAs (miRNAs) and induced
pluripotent stem cells (iPS cells) for developing
novel therapies for neurodegenerative diseases.
miRNAs, endogenous non-coding RNAs that regulate
gene expression and are functionally very specific,
could be extremely important in disease by
regulating neural stem cell differentiation. miRNAs
could also be used in differentiating patient
derived iPS cells (stem cells derived from patient
skin cells) into neural cells that could be used for
disease modeling and/or therapeutic purposes. The
technology is still early, but the possibilities
quite exciting.
Zhiqun Tan’s, MD PhD
(University of California Irvine)
presentation brought us all back in time with a
brief history of Chinese medicine and the advantages
of many of these compounds from a drug discovery
prospective. Tan’s work has focused on TMP (tetramethylpyrazine)
which was originally isolated from a Chinese
medicinal herb. He found that this compound
protects neurons from the insults of Aβ and
decreases the amyloid plaque pathology associated
with the disease in mouse models. Tan is working on
identifying the mechanism of this exciting compound,
which has already been in many human studies in
China, so that he can translate this compound into
clinical testing in Alzheimer’s disease patients.
Finally,
Karen Duff,
PhD (Columbia University) ended the
session with a preview of what was to come in the
neurofibrillary tangle session on Day 2. She
presented work on developing a brain slice model for
more high-throughput testing of compounds that
disrupt tau aggregation. Initial results look
promising in that some of the cyanine dye derived
compounds presented cause tau disaggregation,
unfortunately higher doses of these compounds seem
to accelerate tau aggregation. Nevertheless, these
results are exciting as modifications can be made to
these compounds to increase their potency without
the negative pro-aggregating effects.
Session II: Anti-Amyloid and Protein Misfolding
The second session of the conference focused on
targeting the amyloid pathway and protein misfolding
in neurodegenerative diseases. The session chair
and first speaker,
Michael Wolf, PhD (Harvard Medical School)
spoke about his work developing potent Notch-Sparing
γ-secretase inhibitors. Wolfe presented data on his
lead compounds that show potent selection for APP
cleavage over Notch with nanomolar potency. These
compounds are being tested for drug like properties
and further developed to meet the criteria of a
clinical candidate.
Traveling all the way from the University of
Hawaii,
Philip Williams, PhD, added a splash of
chemical space diversity to the conference with his
presentation on his work using marine derived
natural products. Williams is screening these
natural product extracts for inhibitory activity
towards BACE-1 using an innovative BACE1 inhibitor
assay and a cell-based screen “made possible from a
collaboration made [at this conference] two years
ago” said Williams. He then plans to use novel
methods he has developed to isolate the specific
active components from these extracts.
Degrading Aβ and amyloid plaques is a goal sought by
many as demonstrated in this session of the
conference. Two speakers in the session presented
very different and innovate approaches to promote Aβ
degradation.
Robert
Marr, PhD (Rosalind Franklin University
of Medicine and Science) is validating a novel
Aβ degrading enzyme with very high homology to the
well-know Aβ enzyme neprilysin (NEP). This new
enzyme, NEP2, looks to be playing a significant role
in Aβ degradation. NEP2 knockout mice have an
increase in Aβ levels across many brain regions,
even on a NEP knockout background. While there may
be other endopeptidases that play a role in Aβ
degradation and more needs to be learned about the
mechanism of Aβ degradation, NEP2 looks to be an
important and interesting target.
The approach of
Walter Schmidt, PhD
(University of
Georgia) is to enhance the activity Aβ degrading
enzyme, IDE (insulin degrading enzyme), using small
molecules. Typically quite challenging to do, the
structure of IDE makes it theoretically amenable to
activation with a directly interacting compound.
Schmidt has a number of initial hits from his screen
for IDE activators and while he wants to screen more
compounds, his initial results validate the approach
of IDE activation for further drug discovery
efforts.
Michael Sierks,
PhD (Arizona State University)
presented an approach to blocking Aβ generation
using engineered antibody fragments. One antibody
fragment (or nanobody) would inhibit BACE cleavage
by specifically binding to the β-secreatase cleavage
site on APP. This nanobody would be conjugated to a
proteolytic antibody that cleaves at the α secretase
site, drving APP processes away from pathological Aβ
generation towards the α-secretase pathway.
Somewhat off the beaten path for traditional Aβ
enthusiasts,
Sidney Strickland, PhD (Rockefeller
University) presented work on the role of Aβ’s
interaction with fibrinogen. Fibrinogen is cleaved
into fibrin – the primary component of blood clots.
Aβ interacts with fibrin and alters the clot, making
it irregular and resistant to degradation. Using
in vivo imaging techniques, Alzheimer’s mice
were found to form clots more readily and the clots
were resistant to degradation. This abnormal clot
formation could alter the blood brain barrier, cause
inflammation and neuro-vascular damage. Therefore,
Strickland and his team are screening for compounds
that disrupt the Aβ/fibrin interaction and could be
used to target this pathway in the disease.
Finally, while many groups have shied away from
targeting protein misfolding because of the
complexity of interactions involved,
Manfred Windisch
from JSW Lifesciences takes advantage of
natural differences with α and β isoforms of
synuclein to develop β-synuclein N-terminal
peptidomimetics to disrupt α-synuclein aggregation
in Parkinson’s disease (also relevant to the 60% of
Alzheimer’s patients that show some α-synuclein
pathology). These peptides are also neuroprotective
and disrupt Aβ aggregation. While issues related to
the druggability of these peptidomimetics still need
to be worked out, initial results are encouraging
and open the door for new directions of therapy.
The first day of the conference concluded with an
announcement of the Young Investigator Scholarship
winners by a representative from Apredica, one of
the scholarship sponsors, before the networking
reception commenced. Beautiful weather and the
gorgeous Manhattan skyline were the perfect backdrop
to reflect on the scientific discussions of the day,
touch base with old friends and meet new ones.
Day 2 Plenary:
Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration: Connecting the
Dots through TDP-43
Renewed and refreshed after a very full and exciting
first day of the conference, participants arrived at
the second day ready for more exciting scientific
discussions. The day began with a plenary talk by
Virginia Lee, PhD,
MBA (University of Pennsylvania) who
spoke about TAR DNA-binding protein (TDP-43) as a
target for neurodegenerative diseases. After having
been only recently discovered as a major disease
protein that is ubiqutinated and accumulates in
neurodegenerative diseases, most typically
frontotemporal dementias (FTD) and amyotrophic
lateral sclerosis (ALS), there has been rapid
progress in the understanding of the protein in
disease. From this understanding, we have learned
important lessons that may apply to all
neurodegenerative disease. For example, TDP-43
aggregates are not the highly ordered amyloid
aggregates seen with plaques, tangles, or Lewy
Bodies – meaning a highly ordered amyloid structure
is not necessary to cause neurodegeneration. In
addition, genetic studies have given us much insight
into polymorphisms associated with disease. While
it is still early days, some of these initial
discoveries about disease mechanisms are already
being translated into drug discovery programs.
Session III: Anti-Tangles and Frontotemporal
Dementia
The third session of the conference focused on
approaches to target neurofibrillary tangles in
Alzheimer’s disease and other tauopathies. The idea
that tau pathology could be propogated throughout
the brain either through cell-cell transmission of
pathological tau or through extracellular tau
propagation is new and exciting hypothesis in the
field and resonated in many of the talks in this
session.
Jeff
Kuret, PhD (Ohio State University College
of Medicine) chaired the session and also gave
the first talk on developing imaging agents that
would specifically bind to tangles and not other
amyloid aggregates, like amyloid plaques. Such an
agent could be used for early diagnosis and to
monitor changes in disease progression, since
tangles are more closely associated with disease
progression than amyloid plaques. Achieving this
specificity is quite challenging, as is developing
agents that are able to enter the cell to bind
tangles. Through the use of pharmacokinetic
modeling methods, Kuret has been able to develop
agents that specifically bind tangles over α-synuclein
deposits, but has yet to develop agents with
specificity over Aβ deposits.
Gabriela Chiosis,
PhD (Memorial Sloan-Kettering Cancer
Center) is taking a direct approach to
disrupting neurofibrillary tangle formation by
developing inhibitors of a chaperone protein,
HSP90. Inhibiting HSP90 blocks pathological
aggregation of tau by inhibiting tau phosphorylation
and upregulating Hsp70, which is protective by
preventing aggregate formation and toxicity.
Chiosis has been focused on developing HSP90
inhibitors that are safe and can enter the brain.
Using medicinal chemistry around the lead scaffold,
her team has made over 80 derivatives, many of which
have increased brain affinity and efficacy.
Chemistry is still ongoing, but Chiosis is moving
forward with an IND filing for these compounds.
Taking another approach to clear pathological tau
species,
Einar
Sigurdsson, PhD (New York University
School of Medicine) discussed his work on
immunotherapy to clear pathological tau species from
the brain. The rational is that this approach may
be more appropriate for later stage disease than Aβ
immunotherapy. Sigurdsson presented data showing
that active tau immunotherapy targeted to
phosporylated tau residues, reduced brain tau
aggregates and improved function in tau transgenic
mice. Results with passive tau immunotherapy look
promising as well. The mechanism of how these
intracellular aggregates are removed is still
unclear, but the fact that it works may help
validate the role for extracellular tau and tau
pathology propagation in the disease process.
James Moe, PhD MBA (Oligomerix,
Inc.) next presented his work on targeting tau
oligomers which have been hypothesized to be the key
pathological species involved in disease
propagation. Moe spoke about Oligomerix’s work to
characterize the effects of extracellular tau on
memory as well as methods to develop assays for
oligomer detection to screen for inhibitors that
disrupt their formation.
Session IV: Alternative Strategies: New Targets for
AD Therapy
Finally the last session of the conference was
chaired by
Diana Shineman, PhD
(ADDF) and
emphasized alternative “outside-of-the box”
approaches to targeting Alzheimer’s disease. This
session, new this year, was developed to reflect
progression in the field in reference to Aβ. Given
that most clinical trials for AD are focused on Aβ
mechanisms, the need for complementary approaches is
critical whether or not the on-going clinical trials
are successful.
Rebecca Evans, MD MSc (Pfizer) started the
session with an update on the status of Pfizer’s
PDE9 program for Alzheimer’s disease. The
hypothesis behind targeting PDE9 is that enhancing
this physiological cascade underlying synaptic
plasticity will boost synaptic transmission and
improve cognition. Preliminary data to support this
hypothesis is compelling and Pfizer is enthusiastic
about transitioning PDE9 inhibitors into man. Phase
I data showed safety and tolerability and their
inhibitor is now in Phase II. Stay tuned.
Tae-Wan Kim, PhD (Columbia University) next
presented his work on phospholipids that regulate
cell signaling and membrane dynamics. His work has
focused on small molecule modulators of the PIP2
pathway. This pathway may be involved in the
biogenesis and synaptic action of Aβ and may play
other roles in the disease process. Specifically,
Kim is targeting the enzyme, PI4KIIα, which could
mediate an Aβ lowering effect by segregating with γ-secretase
components and affecting the membrane localization,
ultimately influencing Aβ secretion.
The role of membrane dynamics came up again in
James Bamburg’s, PhD (Colorado State University)
talk on a relatively new pathology associated with
AD, cofilin pathology. Cofilin is a major regulator
of actin dynamics and plays an important role in
cell division, chromatin structure, transcription
and membrane lipid metabolism. Cofilin can bundle
with actin forming abnormal actin/cofilin rods which
accumulate in processes. These rods are found in AD
brain and could block axonal transport of valuable
cargo. It’s possible that these rods could alter
microtubule function and be the first step in the
tau pathogenic cascade. Bamburg is working to
develop ways to block this cofilin/actin rod
formation through the use of peptides and
peptidomimetic compounds.
Echoing the sentiments in first plenary talk of the
conference,
James Malter, MD (University of
Wisconsin) also looks as AD as a systems based
disease. His work has focused on the Fragile X
Mental Retardation Protein (FMRP) which he has
recently shown to regulate the dendritic translation
of APP downstream of mGluR5 activation. mGluR5
antagonists can increase APP translational and
reduce Aβ 40 in brain lysate. Work is ongoing to
expand on these exciting findings.
Graham Jones, PhD (Northeastern University)
presented work on developing new methods for
producing radiolabelled drugs for SPECT and PET
imaging of AD. These new techniques allow for much
easier production of these agents. The agents can
be radiolabelled in house and on the order of days
(rather than months at a separate facility) using
microwave energy and modern catalysts to accelerate
synthesis. These new methods create new agents for
practical use of PET imaging, while also reducing
time and cost. These techniques can be applied to
many compounds and could, for example, allow for
monitoring of drug distribution in the brain and be
used for diagnostic purposes. Jones also noted that
that the Center of Molecular Imaging where he is
located has a radiomedicinal chemistry training
program that will educate new investigators on
developing and applying these novel techniques.
Closing the session was
Lawrence Wennogle, PhD (Intra-Cellular
Therapies) who spoke about developing cognitive
enhancing agents that inhibit phosphodiesterase 1
(PDE1). PDE1 is highly abundant in dopamine
receptors, hypo-function of which can lead to
cognitive dysfunction. The investigators have
developed a series of compounds that potently and
selectively inhibit PDE1 and have good drug-like
properties. Their lead compound improves cognitive
performance in rodent models and increases
wakefulness. The most advanced candidate in this
class is undergoing pre-clinical development and
Wennogle expects their lead to be in clinical trials
by next year.
In summary, this conference highlighted the
diversity and the complexity of on-going drug
discovery research for Alzheimer’s disease. The
theme of new directions was prevalent as
participates were hungry for novel ideas and fresh
discussion. This year’s higher proportion of
industry attendants compared to previous years
allowed for increased networking between industry
and academia scientists. Finally, this event would
not have been possible without the generous support
from our sponsors. The 10th International Conference
on Alzheimer’s Drug Discovery was sponsored by
Pfizer Inc.; Elan Pharmaceuticals; Martek
Biosciences Corporation; Schering-Plough; Allon
Therapeutics, Inc.; JSW Lifesciences; Abbott; The
American Journal of Geriatric Pharmacotherapy;
Apredica; Intra-Cellular Therapies, Inc.; and
Rhenovia Pharma.
We hope you will join ADDF for our next conference–
The 4th Drug Discovery for
Neurodegeneration Conference. This conference will
take place on February 1-2, 2010 in Houston, Texas.
For more information on this conference, please view
the
conference web site.
