Strategic Research Institute, The Hyatt Regency Hotel- Princeton, NJ
April 18-9, 2005
Monday, April 18, 2005 (Day 1)
7:15 - 8:15
Registration, Networking & Exhibits
8:15 - 8:30
Chairpersons’ Opening Remarks
Garth Ringheim, Ph.D.
Principal Scientist, Internal Medicine
SANOFI AVENTIS Paul Jackson, Ph.D.
Team Leader, Neurological Disorders
JOHNSON & JOHNSON Menelas N. Pangalos, Ph.D.
Vice President Neuroscience Research
WYETH RESEARCH ADVANCES FOR THE TREATMENT OF MEMORY DEFICIT
8:30 - 9:10
Emerging Therapies for Alzheimer’s Disease: Drugs Such as MEM 1003 that Both Improve Cognition and Protect Against Neurodegeneration
Treatments for Alzheimer’s disease, as well as other memory-related disorders, are generally classified as either symptomatic or disease modifying. An ideal drug for such disorders would provide both symptomatic relief and disease modifying properties. Symptomatic drugs developed for Alzheimer’s disease, such as the cholinesterase inhibitors, are effective in restoring cognitive deficits but do not seem to alter the progression of Alzheimer’s disease. Disease modifying compounds are designed to reduce the production of beta-amyloid or to reduce the inflammatory effects of beta-amyloid in the CNS. Many pharmaceutical companies are engaged in extensive efforts in this area; these drugs hold the promise of arresting the progression of Alzheimer’s disease, but will not necessarily restore cognitive deficits that have already occurred. A combined approach, being taken by Memory Pharmaceuticals, is to develop drugs based on tractable molecular targets emanating from research on mechanisms of memory mechanisms and circuitry. Examples of drugs that could provide both symptomatic and disease modifying properties include Ca2+ channel blockers, cAMP elevating agents and nicotinic agonists. MEM 1003, a Ca2+ channel blocker in development by Memory Pharmaceuticals, is able to improve cognitive performance in preclinical models by increasing the excitability of hippocampal neurons. In addition, by reducing Ca2+ entry over an extended period of time, a Ca2+ channel blocker should protect neurons from increased neuropathology associated with excessive Ca2+ entry. Drugs like MEM1003, either alone or in combination with other symptomatic or neuroprotective drugs, would greatly increase the available options to neurologists. David Lowe, Ph.D.
Chief Scientific Officer
MEMORY PHARMACEUTICALS
9:10 - 9:40
Preclinical Pharmacology of Selective and Nonselective Cholinesterase Inhibitors: Implications for Clinical Use in Alzheimer's Disease
AChE inhibitors are widely used therapeutics for AD. Some are potent inhibitors of both AChE and butyrylcholinesterase (BuChE); others (e.g., donepezil) are highly selective for AChE. Our preclinical studies revealed that central cholinergic effects (brain ACh elevation, tremors) resulted from inhibition of AChE, whereas peripheral signs (salivation) were more pronounced when both AChE and BuChE were inhibited. The improved therapeutic index observed in rodents with a highly selective AChE inhibitor may underlie the favorable tolerability profile of donepezil in AD patients. Dane Liston, Ph.D.
CNS Discovery
PFIZER GLOBAL R&D - GROTON LABORATORIES ANTI-AMYLOID APPROACHES IN ALZHEIMER’S DISEASE
9:40 - 10:10
Gene Delivery of Human Apolipoprotein E Alters Brain Aβ Burden in a Mouse Model of Alzheimer Disease
Apolipoprotein E (apoE) alleles are important genetic risk factors for Alzheimer disease (AD), with the ε4 allele increasing and the ε2 allele decreasing risk for developing AD. ApoE has been previously shown to influence brain amyloid-β peptide (Aβ) and amyloid burden, both in humans and in transgenic mice. Direct intracerebral administration of lentiviral vectors expressing the three common human apoE isoforms differentially alters hippocampal Aβ and amyloid burden in the PDAPP mouse model of AD. Expression of apoE4 in the absence of mouse apoE increases hippocampal Aβ1-42 levels and amyloid burden. By contrast, expression of apoE2, even in the presence of mouse apoE, markedly reduces hippocampal Aβ burden. Our data demonstrate rapid apoE isoform-dependent effects on brain Aβ burden in a mouse model of AD. Gene delivery of apoE2 may prevent or reduce brain Aβ burden and the subsequent development of neuritic plaques. Jean-Cosme Dodart, Ph.D.
Neuroscience Discovery Research
ELI LILLY & COMPANY
10:10 - 10:40
Refreshments
10:40 - 11:10
Gamma-Secretase Inhibitors: Balancing Toxicity and Efficacy In Vivo
Donna Barten, Ph.D.
Principal Scientist
BRISTOL-MYERS SQUIBB
11:10 - 11:40
The Role of Insulin Resistance in Alzheimer’s Disease Neuropathology
In ongoing studies in our lab we found that diet-induced dietary condition resulting in insulin resistance in Tg2576 mice coincided with a promotion of Alzheimer’s disease (AD)-type amyloid pathology and impaired cognitive functioning relative to normoglycemic Tg2576 mice (Ho et al., 2004). Most interestingly, we recently found that administration of a traditional herbal anti-diabetic agent for 6 months decreased β-amyloid (Aβ)1-40 and Aβ1-42 peptide content in the cerebral cortex and hippocampal formations of insulin resistant Tg2576 mice. This reduction in Aβ1-40 and Aβ1-42 peptide content coincided with 1) inhibition of γ-secretase activity without influencing generation of the Notch cleavage product Notch-1, and 2) improved cognitive functioning at 12 months of age. The studies provide impetus for the use of natural anti-diabetic agents as a potential novel therapeutic agent in AD. Supported by DANA Alliance for Brain Initiatives to GMP. Giulio Maria Pasinetti, M.D., Ph.D.
Professor, Psychiatry, Neuroscience, Geriatrics and Adult Development
MOUNT SINAI SCHOOL OF MEDICINE
11:40 - 12:10
Anti-Amyloid Approaches for the Treatment of Alzheimer's Disease
Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder that is associated with the gradual loss of cognition in the elderly population. It is believed to be the result of altered neuronal function and neuronal loss associated with amyloid plaques. Based on the current understanding of underlying mechanism(s) accounting for neuronal loss, current efforts are focused on ß-amyloid peptide (Aβ) as playing a central role in the origin of AD pathology. Aβ is a highly insoluble, hydrophobic, 40-42 amino acid peptide which is derived from the larger β-amyloid precursor protein (APP) following sequential enzymatic cleavage by β-secretase (BACE) and γ-secretase. Several strategies, based on the cascade of Aβ-dependent events leading to AD, have been exploited to identify therapeutic agents that block disease progression. The inhibition of proteolytic events leading to Aß formation and immunotherapeutic strategies facilitating the clearance of Aß will be discussed. By blocking the formation of Aβ with BACE or γ-secretase inhibitors, or by enhancing Aβ;/plaque clearance, our goal is to improve cognition and to prevent neuronal loss associated with AD. Steve Jacobsen, Ph.D.
Neuroscience Research Group Leader
WYETH RESEARCH
12:10 - 1:15
Luncheon
1:15 - 1:45
PGE2 Receptors Modulate The β-Amyloid Toxicity in Neurons
Prostaglandin E2 (PGE2) is a metabolite of arachidonic acid from the the combined actions of cyclooxygenase and PGE synthase enzymes. We and others have observed protective and potentially synergistic actions of PGE2 on β-amyloid (Aβ)toxicity. Considering, the controversial results reported with the use of different PGs, we are postulating that diverse PGE2 actions can be explained through stimulation of different PGE2 prostanoid receptors (EP1 to EP4). We hypothesized that PGE2 acting on EP receptors that increase cAMP promotes neuroprotection, whereas EP receptors that decrease cAMP, or elevate calcium would increase vulnerability to Aβ. We tested the susceptibility to different concentrations of Aβ1-42; on postnatal primary neuronal and neuron/glia mixed cultures obtained from cortex of neonatal mice incubated with different EP receptor agonists and/or/antagonists. We observed a significant decrease in neuron viability (50%) by treatment with Aβ peptide at concentrations as low as 1μM or some EP receptor agonist at high micromolar concentrations such as butaprost (EP2, >95% 100 μM). Aβ toxicity was further emphasized by EP receptor agonists such as EP3/EP4 (hydroxy PGE1 >60%). Notably, pre-treatment of the postnatal cultures with nanomolar concentrations of PGE2 for neuronal and in mixed neuron/glia cultures (or with PGE2 metabolites, such as PGA2) revealed neuroprotection. All together, these results suggest that PGE2 acting on specific EP receptors modulate Aβ actions in neurons. Understanding the role of these EP receptors and other inflammatory mediators in AD neuropathology and aged related vascular dementia may provide important criterion for the design of effective clinical trials with goals to limit neuroinflammation (supported by AHAF and NIH-RO1). Sylvain Doré, Ph.D.
Associate Professor, Dept. Critical Care Medicine SOM
JOHNS HOPKINS UNIVERSITY
1:45 - 2:15
Novel GPCR Modulators of Beta-Amyloid Secretion
Disease-modifying Alzheimer’s therapies currently focus on a limited number of drug targets involved in modulating brain beta-amyloid levels. To identify alternative disease-modifying targets we investigated the involvement of GPCRs in beta-amyloid production. Adenoviral knock-in or knock-down libraries were functionally screened and a number of known and novel GPCRs were identified. Agonists and antagonists targeting these GPCRs affected beta-amyloid levels in vitro, underscoring the possible therapeutic use of these targets. In addition, a constitutively active GPCR with a very favourable expression pattern was identified. In conclusion, these GPCRs are potential drug targets that represent an excellent opportunity to tackle Alzheimer’s disease. Pascal Merchiers, Ph.D.
Team Leader, Alzheimer’s Disease
GALAPAGOS GENOMICS NV, BELGIUM
2:15 - 2:45
Autoimmunity in Alzheimer¡¦s Disease: Increased Levels of Circulating IgGs Binding Aβ and RAGE Peptides
Plasma samples derived from 33 AD and 42 control participants were subjected to several steps to purify specific anti-(amyloid)Aβ IgGs. Affinity-purified IgGs binding the peptide Aβ1-42, a neurotoxic sequence derived from the trans-membrane amyloid precursor protein, exhibited nearly 4 fold higher titers in AD patients compared with their control non-AD cohort. Affinity-purified IgGs binding a fragment of the receptor for advanced glycation end products (RAGE) likewise were increased nearly 3 fold in AD individuals. Aβ and RAGE IgG titers were negatively correlated with cognitive status, i.e., the more cognitively impaired individuals tended to exhibit higher IgG titers. Freshly prepared leukocyte preparations were subjected to flow cytometric analysis. AD individuals exhibited significantly increased populations of cells expressing binding sites for monoclonal antibodies directed against Aβ (5.5 fold), βAPP (3.5 fold), and RAGE (2.6 fold) relative to the control group. These findings confirm the presence of circulating IgGs specifically directed at proteins implicated in immunological processes linked to AD. The close relationship between titers for Aβ and RAGE IgGs suggests the possibility that the antibodies are being produced in response to a common mechanism or protein complex (with the respective epitopes) linked to the disease. Jerry J. Buccafusco, Ph.D.
Director, Alzheimer¡¦s Research Center
MEDICAL COLLEGE OF GEORGIA
2:45 - 3:25
Networking, Refreshments & Exhibits
3:25 - 4:45
PANEL: Neuroscience Licensing: What's Different?
Neuroscience therapeutics, with $73 billion (WW, 2003) are second only to CV drugs in sales. Only oncology comes close to neuroscience, in terms of the number of new products in development. Given the potential rewards and R&D activity, neuroscience would seem to be a fertile area for deal making. But is it really different than other therapeutic areas, in this regard? What, if anything, is different about the world of neuroscience licensing? What are the trends, and where is neuroscience deal-making going? What's hot, and what's not? This interactive panel discussion will review the buzz of deals upcoming and deals in the making. MODERATOR: John Reid, Ph.D.
Director of Knowledge Management
ASTRAZENECA PHARMACEUTICALS PANELISTS: Robert Bagdorf, M.D.
Senior Director, Licensing & Development
PFIZER INC. Paul Leijten, M.D.
Director, Neuroscience Licensing
BRISTOL-MYERS SQUIBB Alejandro Donoso, Ph.D.
Director, Technology Licensing & Alliances
SANOFI AVENTIS Michael G. Palfreyman, Ph.D., D.Sc.
Principal
NOVACE CORPORATION Gardiner Smith
Vice President, Business Development
MEMORY PHARMACEUTICALS Thomas C. Seoh
Senior Vice President, Corporate and Commercial Development
GUILFORD PHARMACEUTICALS
4:45 - 5:15
The Current Status of Alzheimer’s Disease Genetics Research
Alzheimer’s disease (AD) is a genetically complex and heterogenous disorder. To date, mutations in three genes (APP, PSEN1, PSEN2) are known that lead to early-onset autosomal dominant forms of AD. Late-onset AD, which represents the majority of all cases, is likely governed by susceptibility genes that increase disease risk and/or lower onset age. Currently, only one such risk-factor has been established for late-onset AD, the å4-allele of the apolipoprotein E locus (APOE) on chromosome 19. Several lines of evidence indicate that other late-onset – and possibly also early-onset – AD genes remain to be identified. In this presentation I will talk about the latest findings of our laboratory attempting to pinpoint these still elusive AD genes, with a special focus on chromosomes 9, 10 and 12. In addition, I will introduce a new database (“Alzgene”; URL: www.alzgene.org) that was developed by our group to collect, summarize, and meta-analyze all peer-reviewed and published genetic association studies in the field of AD. Lars Bertram, M.D.
Instructor in Neurology
HARVARD MEDICAL SCHOOL
Assistant, Genetics & Aging Research Unit
MASSACHUSETTS GENERAL HOSPITAL
5:15 - 6:45
Networking Reception
Tuesday, April 19, 2005 (Day 2)
7:45 - 8:45
Breakfast, Networking & Exhibits
8:45 - 9:00
Chairs’ Recap of Day One
9:00 - 9:45
Impact of Phosphorylation and Kinase Modulation in AD and Tauopathies
More than 20 human dementias, including Alzheimer's disease, are characterized by the formation of neurofibrillary tangles composed of abnormally phosphorylated, aggregated tau. We are interested in the impact of abnormal phosphorylation on tangle pathogenesis and have shown that cdk5 can enhance tangle phenotype (Noble et al. Neuron 2003), We have also shown that inhibition of GSK-3 can reduce tangle pathogenesis and reduce neurodegeneration in vivo. We have also shown that cdk5 can modulate the amyloid phenotype through effects on APP processing. These, and other results will be discussed. Karen Duff, Ph.D.
Professor, Departments of Psychiatry, Physiology & Neuroscience
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
Director, Center for Dementia Research
NATHAN KLINE INSTITUTE NEW TARGETS & MECHANISMS FOR NEURODEGENERATION
9:45 - 10:15
Evidence that Immunoglobulin-Positive Neurons in Alzheimer Disease are Dying via the Classical, Antibody-Dependent, Complement Pathway
Previously, we had provided evidence that immunoglobulins (Igs) are not only present in Alzheimer's disease (AD) brains but are immunohistochemically detected in and/or on a particular population of pyramidal neurons that appeared morphologically degenerative, in contrast to neighboring normally appearing Ig-negative neurons. Subsequent findings showed that the Ig-positive neurons displayed complement C1q and C5b-9 protein immunoreactivity. Furthermore, HLA-DR-positive fibers of reactive microglia were spatially closer (p<0.001) and often in contact with the Ig-positive neurons than the Ig-negative neurons. Collectively, these data suggest that the Ig-positive neurons detected in AD brains may be dying from the processes of the antibody-induced classical complement pathway. Michael R. D'Andrea, Ph.D.
Team Leader, Target Validation Team
JOHNSON & JOHNSON PHARMACEUTICAL R&D
10:15 - 11:00
Networking, Refreshments & Exhibits
11:00 - 11:30
Statin Regulation Of Microglia Function And Gene Expression: Implications For The Treatment Of Neurodegenerative Disorders
The application of statins in the treatment of neurodegenerative disorders has been proposed for multiple sclerosis, a disease associated with the adaptive immune response, and Alzheimer’s disease, a disease associated with an overactive innate immune response. Much of the focus on the effects of statins in the brain has centered on cholesterol-mediated processes, but evidence shows that on a cellular level, statins have profound effects on chemokine and cytokine production in the brain. We have found that statins have differential effects on the expression of cytokines, chemokines, and their receptors in activated microglia as well as changes in cellular functional responses, leading us to the hypothesis that these cells comprise a major CNS target for this class of compounds. These changes in microglia function and gene expression will be discussed in context with the potential benefits and drawbacks to the use of statins in current AD and MS clinical trials. Garth Ringheim, Ph.D.
Principal Scientist, Principal Scientist, Internal Medicine
SANOFI AVENTIS
11:30 - 12:00
Disuse Modifying Therapeutic Strategies in Alzheimer's Disease: Targeting the Amyloid Cascade
Alzheimer's Disease (AD) is a progressive and devastating neurodegenerative disorder affecting the brain. It is the most common form of late-life dementia and is one of the leading causes of death in the developed world. Due to the ageing population and improvement in diagnosis it is expected that the number of diagnosed AD patients will increase from the current level of 5 million to 22 million by 2025. Dr. Adessi will present on emerging approaches for the treatment of AD, targeting the amyloid release. Céline Adessi, Ph.D.
Project Leader, Lab Head
F. HOFFMAN-LA ROCHE LTD.
12:00 - 12:30
Application of Functional Genomics to Stroke Yields a Clinical Candidate, AGY-94806 for Enhancement of Functional Recovery
AGY developed a multifaceted functional genomics approach and expanded the understanding of molecular pathways relevant to stroke pathology. Environmental enrichment induces neuroregeneration after stroke in animals. AGY identified the sigma 1 receptor as highly up-regulated by enriched environment, acting as a master switch of neuroregeneration. AGY’s clinical compound AGY-94806 is a potent and selective agonist of this receptor and displayed strong enhancement of functional recovery in animal models of stroke in an array of sensory-motor tests. AGY-94806 is entering clinical development for post-stroke recovery and represents a unique example of a CNS development program enabled by a functional genomics approach. Roman Urfer, Ph.D.
Senior Vice President Drug Discovery & Development
AGY THERAPEUTICS, INC.
12:30 - 1:45
Luncheon
1:45 - 2:15
The Development of Psoriasin as a Novel Therapeutic Agent in Alzheimer¡¦s Disease
Using surface-enhanced laser desorption ionization-mass spectrometry SELDI-(MS) proteomic technology, we identified purified and sequence identified psoriasin, a protein known to be involved in immune responses. We continued to explore the potential role of psoriasin in AD amyloidogenesis in vitro and found that psoriasin prevents the generation of β-amyloid (Aβ)1-42 and Aβ1-40 peptides, coincidental with a selective induction ADAM ¡V10. Because ADAM-10 has many properties of a physiologically relevant α-secretase, our study supports the hypothesis that induction of ADAM-10 by psoriasin may provide a novel therapeutic strategy for attenuating AD neuropathology. Giulio Maria Pasinetti, M.D., Ph.D.
Professor, Psychiatry, Neuroscience, Geriatrics and Adult Development
MOUNT SINAI SCHOOL OF MEDICINE
2:15 - 2:45
Automated Screening of Drosophila Neurodegenerative Disease Models Facilitates CNS Drug Discovery
Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease together affect tens of millions of people worldwide. However, the development of drugs that stop or slow the progression of these CNS diseases has been challenging and requires new drug discovery approaches. EnVivo Pharmaceuticals has developed an in vivo, high content screening platform using Drosophila models of human neurodegenerative diseases. Integral to EnVivo’s proprietary platform is industrialization of the production and handling of Drosophila, compound dosing, and automated phenotypic assays. One exemplary assay uses robotics and video-based motion tracking software to sensitively and rapidly measure multiple metrics of locomotor behavior. From these metrics, a Phenoprofile is generated, which reveals phenotypic impairment and improvements with drug treatment. The output of EnVivo’s discovery platform also has the potential to generate additional information on the efficacy and toxicity of a compound in an intact nervous system, thus providing the ability to select high quality hits that will more quickly advance into preclinical development. EnVivo is currently screening compound libraries in these proprietary neurodegenerative disease models and has moved hits from these screens forward in the drug discovery process. This ability of triaging compounds with a primary phenotypic screen promises to accelerate, and improve success rate of, drug discovery and development in the difficult CNS arena. Gerhard Koenig, Ph.D.
Senior Vice President of R & D
ENVIVO PHARMACEUTICALS
2:45 - 3:15
Zebrafish Models of Neurodegenerative Diseases for Drug Discovery
We are developing a zebrafish model for Alzheimer’s disease that involves overexpression of human proteins in the zebrafish brain. For example, overexpression of the human gene encoding Tau has been shown to cause neuropathology similar to tangles in the zebrafish embryonic brain (Tomasiewicz et al., 2002). To better simulate the Alzheimer’s disease condition in zebrafish, we will express both Tau and Amyloid beta in the brain. Neuronal cell death caused by overexpression of these proteins can be observed by performing experiments in a transgenic fish with fluorescent neurons. The zebrafish affords the unique opportunity to rapidly test either compounds or antisense molecules for their ability to protect neurons from damage by Alzheimer’s proteins. In earlier work, we have shown that MPTP damage of dopaminergic neurons in the zebrafish can be protected by either L-Deprenyl, a drug currently used to treat Parkinson’s disease, or antisense morpholino knockdown of the dopamine transporter gene, which is known to be required for transport of MPTP into neurons. Since zebrafish antisense experiments can be performed in less than one week, genes that may be useful targets in neurodegenerative diseases can be rapidly validated in zebrafish models of Parkinson’s disease and Alzheimer’s disease. Furthermore, these in vivo models can be used to rapidly screen compounds with neuroprotective potential. Amy L. Rubinstein, Ph.D.
Director of Research
ZYGOGEN
3:15 - 3:20
Conference Concludes
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