Neurodegenerative Diseases Drug Discovery

Day 1 - Thursday, October 9, 2008

7:00

Registration & Breakfast

7:55

Welcome and Opening Remarks

[KEYNOTE PRESENTATION]

TBA

Session I - Pathogenesis of Neural Degenerative Disorders

  8:45

Aberrant Phosphorylation as a Pathogenic Mechanism and Drug
Target in Alzhiemers Disease

Karen E. Duff, Professor, Taub Institute for Alzheimer's Disease Research, Columbia University

Alzheimer’s disease is characterized by the presence in the brain of Ab containing plaques, and tangles containing filamentous, hyperphosphorylated tau. Hyperphosphorylation has been cited as a pathogenic mechanism in the production of pathogenic tau and tangle formation, and we have shown that kinases cdk5 and GSK3 can impact this process (Noble et al, Neuron 2003, PNAS 2005). These kinases are also implicated in Ab production, and our recent work has shown that Ab levels are increased in mice overexpressing the cdk5 activator p25. Enhanced cdk5 activity in these mice, and in cell culture models correlates with increased levels of APP metabolites including the amyloidogenic Ab peptides. The APP processing enzyme BACE1, is also increased in response to elevated p25, and it accumulates in early endosome compartments which are known to favor APP processing. Analyses show that upregulation of BACE through transcriptional control ( via STAT3) leads to increased Ab levels, which may be relevant for AD pathogenesis. Of interest, inhibiton of cdk5 leads to decreased Ab levels suggesting cdk5 inhibitors may act as BACE attenuators.
We have also shown that GSK activity is decreased in transgenic mice with increased cdk5 activity. The proposed inhibitory pathway involves neuregulin and Akt signaling. Discussion will be presented regarding the relative impact of cdk5 and GSK3 (and inhibitors of these kinases) on tau phosphorylation and APP processing. Lastly, we have data showing that hyperphosphorylation of tau does not impact its normal function with regard to microtubule (MT) stabilization .in normal mice, however, it hyperphosphorylation does decrease MT stability in mice with tauopathy. As hyperphosphorylation of tau occurs during anesthesia, the significance of anesthesia in elderly patients as a risk factor for AD will be discussed.
1) Addresses whether aberrant phosphorylation is a pathological event in neurodegenerative disease
2) Examines whether hyperphosphorylation of tau has functional consequences that are of relevance to pathogenesis.
3) Tests if cdk5 or GSK is a better target for therapeutic intervention in AD models
4) Identifies BACE as a target of cdk5 and suggests cdk5 inhibitors can act as BACE attenuators.
5) Examines whether anesthesia occurring during surgery is a risk factor for AD due to induced tau hyperphosphorylation and altered APP processing.

  9:15

Huntington’s Disease: Target Validation and Therapeutics

Lisa M. Ellerby, Associate Professor, Buck Institute for Age Research

Huntington’s disease (HD) is caused by an expansion of the poly-Q encoding CAG tract in exon 1 of the human HD gene. Mutant huntingtin protein (Htt) has been shown to exert a range of toxic effects on multiple cellular processes; however it is currently unclear what the key therapeutic targets are in this disease. In order to mount a comprehensive search for HD targets, we screened a collection of 7,300 siRNA pools (comprised of genes annotated as being druggable) to identify genes that when inhibited could suppress mutant Htt-mediated apoptosis. HEK293T cells transiently transfected with a construct encoding an amino-terminal fragment of mutant Htt containing 141Q (1-552)-GFP and each siRNA pool. Çaspase -3/7 activity was used as an endpoint for the screen. From the primary screen, 53 confirmed hits were identified that had less than 70% of the caspase 3/7 activity of the control cells. The 53 hits were validated in a secondary screen using the STHdh^Q111 mouse striatal cell line expressing full-length mutant Htt. This screen has identified several key pathways involving multiple cellular processes as potential drug targets. Several genes of interest, particularly protease targets, are being further investigated using small molecule inhibitors and show promise for development as therapeutic targets for HD.

  9:45

Refreshment Break and Networking

  10:15

Cell Therapy for Stroke

Klaudyne Hong, Ph.D., Team Leader & Principal Scientist, Johnson & Johnson Ethicon, Inc.

  10:45

Lipoxygenases as Novel Enzymatic Pathways in AD Pathogenesis

Domenico Pratico, Associate Professor, Pharmacology, Temple University

Alzheimer’s disease (AD) is a neurodegenerative disorder that causes progressive loss of cognitive function and dementia. The pathological hallmarks in the AD brains are amyloid plaques in the extracellular parenchyma consisting mainly of Amyloid-b (Ab) peptides, and intra-neuronal tangles made of abnormally phosphorylated microtubule-associated tau protein. Increasing evidence suggests that inflammation is an important player in the pathogenesis of AD. Eicosanoids, including prostaglandins and leukotrienes, derive from arachidonic acid by the action of cyclooxygenases and lipoxygenases (12/15 lipoxygenase (12/15LO) and 5-lipoxygenase (5LO)) enzymes.
5-Lipoxygenase (5LO), by producing leukotrienes, is a pro-inflammatory enzyme and there is evidence suggesting that it is up-regulated with aging and may be involved in AD. In this paper, we studied the effect of 5LO targeted gene disruption on the amyloid phenotype of a transgenic mouse model of AD, the Tg2576. Ab deposition in the brains of Tg2576 mice lacking 5LO was reduced by 64%-80% compared with Tg2576 controls. This reduction was associated with a similar significant decrease in Ab levels measured by sandwich ELISA. Absence of 5LO did not induce any significant change in amyloid-b precursor protein (APP) levels and processing, or Ab catabolic pathways. Furthermore, in vitro studies showed that 5LO activation or 5LO metabolites increase, whereas 5LO inhibition decreases Ab formation, which were secondary to correspondent changes in g-secretase activity. These data establish a novel functional role for 5LO in the pathogenesis of AD-like amyloidosis, whereby modulating g-secretase activity. Pharmacological inhibition of 5LO could provide a novel therapeutic tool for AD.

Session II - Preclinical Models & Clinical Overview

  11:15

Preclinical Models of Parkinson's Disease: Pros, Cons and Limitations in the Search for Disease Modifying Drugs

Michael J. O'Neill, Ph.D., Research Advisor - Neurodegenerative Diseases Drug Hunting Team, Eli Lilly & Co. Ltd.

Parkinson’s disease (PD) is a progressive, neurodegenerative disorder of the basal ganglia. Clinical symptoms include tremor at rest, muscular rigidity and bradykinesia and while the available pharmacotherapies are effective at reducing symptom severity they do not affect the course of the disease. Therefore, to maintain an acceptable quality of life for PD patients, therapies that slow disease progression are greatly needed.
In the search for disease modifying agents it is important to have animal models to assess the efficacy of novel compounds. The 6-OHDA and MPTP neurotoxin models have been widely used to explore transplantation, growth factors and certain small molecules as potential neuroprotectants. I will present some data from the well-established 6-OHDA and MPTP toxin models that illustrate the molecular differences between these models and how they vary in their sensitivity to various classes of pharmacological intervention.
In an attempt to more closely reproduce the pathological processes occurring in human PD a variety of newer toxin-based models (rotenone and proteasome inhibition) have been reported in the literature. However, these models also have limitations and need further refinement and development. In the last few years several genes (a-synuclein, parkin, DJ-1, PINK-1, dardarin/LRRK2) have been linked to to PD. Based on these genetic findings a number of transgenic mice and viral vector rat models has been created and are under investigation. These genetic leads and the study of early pathological events are helping our understanding of PD and this should allow us to select better molecular targets that may ultimately lead to a disease modifying therapy.
Benefits of the talk:
- The talk will up-date on our current understanding of the molecular pathophysiology of PD.
- The talk will introduce the current models used in PD research and the benefits and deficits of these models for drug discovery.
- The talk will summarize the various disease modifying approaches taken in academia and industry and highlight data form some recent trials.
- The talk will review the newer models of PD that have reported in the literature and the pro’s and con’s of these models.
- The talk will conclude with some future directions in PD research.

  11:45

TBA

Donna M. Bartin, Senior Research Investigator, Neuroscience Drug Discovery, Bristol-Myers Squibbs

Lunch

  1:45

Disease Modifying Therapies for Parkinson’s Disease: Which Animal Models, When and Why?

Jonathan Brotchie, Senior Scientist, University Health Network, Toronto Western Research Institute

Many opportunities exist to develop disease-modifying therapies for Parkinson’s disease. Prioritising targets and drug candidates, and defining the most appropriate development programme, remains a challenge. This presentation will provide a perspective and overview of the breadth of targets and the models available, and will highlight lessons learned from attempts, to date, to translate our increasing understanding of disease mechanisms in Parkinson’s disease into novel therapies.
The presentation will argue that,
1. Disease modifying therapies can be
-neuroprotective
-neurorestorative, or,
-enhance or support compensatory mechanisms
2. Available animal models are most likely valuable for developing neurorestorative or compensatory mechanisms.
3. Proof of principle pre-clinical studies should be developed to support translation to “delay of disability” Phase II clinical studies.
4. The most likely drug candidates for successful translation to the clinic are those based on
-small molecule approaches to enhancing neurotrophic factor signalling
-modulation of endogenous immune responses
-disruption of protein aggregates

  2:15

Challenges with Transgenic Models of AD in a Drug Discovery Environment

Kaitlin E. Browman, Senior Group Leader, Neuroscience, GPRD, Abbott Laboratories

  2:45

TBA

Peter H. Reinhart, Ph.D., Senior Director, Neurodegeneration, Discovery Neuroscience, Wyeth Research

  3:15

Refreshment Break and Networking

Session III - Translational Medicine & Biomarkers

  3:45

Cognition Enhancers & Disease Modifiers for Alzheimer’s Disease - Three Promising Approaches and their Current Status

Gerhard Koenig, Ph.D., Chief Scientific Officer, EnVivo Pharmaceuticals

This session is focused on Alzheimer’s disease for which EnVivo has an exciting and promising pipeline of therapeutic approaches. My talk will summarize the preclinical data package on the nicotinic a7-nAChR program and introduce the Histone de-acetylase inhibitor (HDACi) program. I will also update the audience on the status of our Gamma-secretase modulator (GSM) program.
We have developed potent, selective and highly brain penetrant small molecule α7-nAChR agonists. Our lead alpha-7 agonist, EVP-6124, is a potent enhancer of learning and memory in various animal behavioral tests. EVP-6124 has excellent pharmacokinetic and pharmaceutical properties and is currently in phase Ib studies in Schizophrenia patients and Alzheimer’s disease. EVP-6124 has completed four separate Phase 1 studies in normal volunteers where it demonstrated acceptable safety, tolerability, and had positive cognitive effects in quantitative cognitive testing.
EnVivo’s has also discovered orally bioavailable, CNS-penetrant small molecule HDAC inhibitors. In contrast to the nicotinic alpha7 receptor target which is a well accepted molecular target for cognition enhancement, this approach is a completely new approach and we believe we are leading the industry in exploring this novel mechanism of action for its potential in neurodegenerative disorders. The HDAC lead compound, EVP-0334 is scheduled to enter clinical phase to improve cognition in AD later this year. EnVivo’s disease modifying therapeutic approach is exemplified in the Gamma-secretase modulator program which aims to nominate a preclinical candidate by end of this year.

  4:15

The Value of Automated Cognitive Testing in Developing Treatments for Neurodegenerative Diseases

Keith A. Wesnes, Ph.D., Chief Executive, Cognitive Drug Research Ltd.

Many neurodegenerative diseases have as a core symptom impairments to cognitive function. The profile of impairments to major aspects of cognitive function varies widely between conditions, most involve disruptions to various aspects of memory, but for many such diseases these are not the major disruptions, and evidence is accumulating that severe disruptions to attention and information processing are central to many disorders. This talk will stress the need for precise, reliable, repeatable and sensitive assessments of core aspects of cognitive function in neurodegenerative disorders, and will make the case for the widespread utilization of automated techniques. Case studies of the benefits of properly developed and validated computerized systems will be made using clinical trial experience from the Cognitive Drug Research computerized assessment system. Data will be presented for various disorders including Alzheimer’s, Parkinson’s, Huntington’s and Lewy Body dementia plus multiple sclerosis and narcolepsy. The central theme will be that once sensitive and appropriate assessments are widely introduced into these disorders, the full profiles of the impairments can be established and the ongoing deterioration and also the response to therapy can be properly evaluated.
1. Obtain a better understanding of the precise cognitive deficits in various neurodegenerative disorders
2. Learn of the greater precision and sensitivity which automated assessments can bring to the field.
3. Evaluate the value of automated techniques in translational medicine, from Phase I onwards.
4. Become better informed of the alternatives available in evaluating the benefits of cognitive therapies in this field.

  4:45

Histone Deacetylases: Inhibitors or Promoters of Neurodegeneration

Santosh R. D'Mello, .D., Professor of Molecular and Cell Biology, University of Texas - Dallas

Apoptosis, an essential aspect of normal neurodevelopment, is also responsible for the pathological loss of neurons in a variety of neurodegenerative conditions. Among the molecules implicated in the regulation of neuronal apoptosis are the histone deacetylases (HDACs). Indeed, pharmacological inhibitors of HDACs protect against neurodegeneration in some in vitro and in vivo experimental paradigms, but actively promote neuronal death in other paradigms. A major drawback of the currently available HDAC inhibitors is that they inhibit all members of the HDAC family efficiently. The role of individual HDAC proteins in the regulation of neuronal survival or death has thus been difficult to ascertain using these inhibitors. We have focused on individual HDAC proteins. We find that in cultured neurons, the overexpression of either one of two different HDAC proteins, HDRP (a spliced form of HDAC9) or HDAC4, protects against neuronal death. We will present data demonstrating that despite their extensive similarity in primary sequence, HDRP and HDAC4 exert their neuroprotective action by distinct mechanisms.

  5:15

Abeta Immunotherapy: Translation of Preclinical Biomarkers into the Clinic

Ronald B. DeMattos, Ph.D., Research Advisor, Neuroscience Division, Lilly Research Laboratories

  5:45

Networking Reception and Poster Session

Day 2 - Tuesday, October 10, 2008

Top of Page

7:30

Continental Breakfast

[KEYNOTE PRESENTATION]

Progress with LY450139, a Functional Gamma Secretase Inhibitor in Phase 3 Trials for Alzheimer’s Disease
 

The preclinical research on LY450139 commenced well before the molecular nature of the gamma secretase complex had been elucidated. LY450139 has been demonstrated to reduce A-beta production in transgenic APPV717F mice. Using inhibition of plasma A-beta as a biomarker to bridge from preclinical studies, LY450139 has entered Phase 3 trials for Alzheimer’s disease.
Benefits:
- Participants will learn about the development of the most clinically advanced gamma secretase inhibitor.
- Participants will learn about the nature of the gamma secretase complex
- Participants will gain an overview of current drug development for Alzheimer’s disease.

[KEYNOTE PRESENTATION]

TBA
 

  9:30

Refreshment Break and Networking

Session IV - Novel Technologies in Drug Delivery & Distribution

Eric Karran
Chief Scientific Officer
Neurodegenerative Diseases Drug Hunting Team
Eli Lilly & Co.

 William Z. Potter M.D., Ph.D.
Vice President, Translational Neuroscience
Merck & Co.

Register by August 9 for a 20% Discount.