Tuesday, October 18

7:30-8:30 Registration and Morning Coffee

8:30-8:40 Chairperson's Opening Remarks
Frank Sams-Dodd, Ph.D., Head of Psychopharmacology, CNS Research, Boehringer Ingelheim Pharma GmbH & Co. 

8:40-9:10 Target Validation in Disease Models: How Valid Are The Disease Models?
Frank Sams-Dodd, Ph.D.
Disease models are developed to reproduce as accurately as possible a human disease state in a system that can be used for research and drug discovery. In most companies these models are used for target identification and validation, but in spite of their significance to the drug discovery process there does not exist a consistent system for evaluating and comparing the validity of disease models. The presentation discusses the components of a disease model and develops a system for comparing the validity of different disease models within a given therapeutic area.

Mouse and Rat Disease Models for Target Discovery and Validation

9:10-9:40 Comprehensive Phenotyping of Genetically Modified Mice to Identify New Target Disease Indications
Rosalba Sacca, Ph.D., Associate Director, Genetic Technologies/EMS, Pfizer Global Research & Development
The use of genetically modified mice to establish gene function has been well documented in literature and their role in drug discovery has been proven to be extremely valuable. This presentation will discuss the generation of the Phenotype Pfinder platform by which KO mice for specific genes of interest are characterized, using a panel of assays to identify new functions for that gene as well as potential detrimental effects. A number of examples will be highlighted to show the ability of this platform to identify new and unexpected phenotypes.

9:40-10:10 Identification of Novel Targets to Stimulate Repair of the Brain
Dr. Heather A. Arnett, Scientist, Department of Inflammation, Amgen, Inc.
Tight regulation in the intestine is necessary to balance responses that are as divergent as tolerance and active immunity. Over the past decade there have been many animal models developed which, collectively, have revealed that a loss of tolerance in the gut can lead to immune dysregulation which can manifest as IBD. Use of a diverse set of animal models of IBD permits: investigation of the preclinical events leading to IBD; analysis of early immune events following gut damage; study of enterocyte damage and regeneration; examination of the factors that perpetuate inflammation; discovery of new targets involved in the inflammatory process and testing efficacy of potential therapeutics during different stages of disease. This presentation will review the relative merits of some of these models.

10:10-10:30 Coffee Break

10:30-11:00 Rapid Target Identification Using Rat Genomics Sequencing 
Howard Jacob, Ph.D., Founder, Physio Genix, Inc. & Director, Human & Molecular Genetics Center, Medical College of Wisconsin
Combinatorial breeding and chromosome substitution strains create new models for human disease. The models offer more genetic diversity for both efficacy and safety testing. When combined with the genomic sequence, this tool set offers new and powerful strategies for rapid target identification.

11:00-11:30 Humanized Mouse Models for Inflammatory Skin Disease
Frederik H. Igney, Ph.D., Leader, "Humanized Mouse Models," Center for Specialized Skin Inflammation Models, CRBA Dermatology, Schering, AG
In drug discovery, humanized mouse models for inflammatory skin diseases are particularly useful for target validation in complex diseases that are only incompletely represented in conventional animal models, and for proof of concept with agents such as antibodies against human antigens. Moreover, because they promise better correlation with clinical outcome than classical models, they are a valuable intermediate step between preclinical research and clinical development. However, they are not appropriate for high-throughput screening.

11:30-11:55 Discovery of the Wnt Signaling Factor Dickkopf-1 as a Target for Treatment of Neurodegenerative Disorders
Georg C. Terstappen, Ph.D., VP, Discovery Research, Sienabiotech SpA
The Wnt signaling pathway is important for neuronal function and survival and accumulating evidence points to inhibition of Wnt signaling as a likely component of neurodegeneration associated with Alzheimer's disease (AD). Dickkopf (DKK)-1 is a secreted inhibitor of the canonical Wnt signaling pathway. In a rat neuronal cell culture model initially employed for target validation, DKK-1 expression was increased by exposure to the amyloid-ß (Aß) peptide and its inhibition by antisense oligonucleotides protected neurons against Aß-mediated toxicity. Further validation was obtained from analysis of postmortem tissue of AD patients where DKK-1 was overexpressed and colocalized with neurofibrillary tangles and dystrophic neurites. For target validation in vivo, recombinant DKK-1 protein was injected into the rat CA1 of hippocampus and nucleus basalis magnocellularis (NBM) where it caused severe neuronal loss and astrocytosis. Thus, in a series of target validation models of increasing relevance for neurodegeneration, DKK-1 was shown to be a potent neurotoxic factor, consistent with its proposed function as one of the mediators of Aß-mediated neurotoxicity. 

11:55-12:15 Validating Targets in a Disease State
Paul Rounding, Ph.D., Managing Director, Artemis Pharmaceuticals GmbH
Increasingly it is becoming apparent that drug discovery programs require early, detailed in vivo functional data on targets of interest. Artemis has developed a number of methods to allow the rapid and efficient generation of conditional gene alterations in the mouse, by both conventional gene targeting as well as by RNA knockdown. Together with the use of innovative disease models, we believe this platform will allow the testing of the "therapeutic" effects of gene deletion and knockdown in vivo. This will make an important contribution towards increasing the quality of target identification and validation and thereby the overall efficiency of drug discovery.

12:30-1:45 Lunch and Learn Workshop Using High Quality Gene Expression Data to Drive the Discovery, Characterization and Validation of Novel Drug Targets and Biomarkers Within Key Therapeutic Areas Sponsored by 
Introducing Gene Logic s ASCENTA® System Version 2.0 
Philip Musk, Ph.D, Product Manager, R&D & Product Management, Gene Logic, Inc.
The ASCENTA® System is an intuitive web-based application that grants access to nearly 9000 human, rat, and mouse samples organized into more than 1600 expertly curated sample sets covering both normal tissues, and a wide range of diseased tissues within five key therapeutic areas. An innovative suite of tools in ASCENTA® System Version 2.0 allows users to profile target gene expression across panels of normal and diseased tissues, to profile differential gene expression of target genes, and to explore relationships between co-regulated genes. The new PathwayPrioritizer Tool quickly analyzes which pathways are most significantly altered across multiple biological states, and the new Marker/X Tool quickly identifies and sorts which genes are most highly and/or uniquely expressed within a sample set of interest. 

Model Organisms for Target Discovery and Validation

1:45-1:50 Chairperson's Remarks

1:50-2:20 Drosophila as a Model for Neurodegenerative Disease
Dan Garza, Ph.D., Executive Director, Genome and Proteome Sciences, Novartis Institutes for Biomedical Research
We have developed a Drosophila model for Alzheimer's Disease and have used this system to identify mutations and compounds that modify phenotypes that result from overexpression of the Abeta42 protein in the adult CNS. We will present how such disease models in a genetically tractable organism can be used to identify therapeutic targets and to identify pathways and processes involved in neurodegeneration.

2:20-2:50 The Zebrafish-Disruptive Technology for Drug Discovery
Randall Peterson, Ph.D., Assistant Professor, Medicine, Massachusetts General Hospital 
High-throughput chemical screens can be performed on intact zebrafish, making it possible to assess the effects of small molecules rapidly, inexpensively, and on a miniaturized scale. By combining the scale and throughput of in vitro screens with the physiological complexity of traditional animal 
studies, the zebrafish is enabling numerous disruptive applications in the drug discovery process, including target validation, disease modeling, lead compound discovery, and toxicology.

2:50-3:10 Zebrafish Disease Models for Target Validation
Amy Rubinstein, Ph.D., Director of Research, Zygogen
Zebrafish combine the complexity of a vertebrate model system with the advantages of rapid target validation. Fluorescent zebrafish assays that model aspects of human disease have been developed. Examples include a transgenic zebrafish with fluorescent blood vessels to evaluate anti-angiogenic compounds, a fish with fluorescent platelets to test genes and compounds involved in thrombosis, and an assay that utilizes fluorescent lipids to monitor lipid metabolism in vivo. In addition, a transgenic fish with a fluorescent heart can be used to monitor heart rate, which can be used to predict QT prolongation in humans.

3:10-3:30 Disease Models: Target and Pathway Discovery and Validation
Catherine Willett, Ph.D., Senior Scientist, Assay Development, Phylonix Pharmaceuticals, Inc.
The zebrafish embryo has become a widely used model organism for the study of vertebrate development. As a free-living, rapidly developing and transparent embryo, it is also uniquely suitable for high throughput drug screening and target validation. Using RNA interference by morpholino injection, we have examined the function of several genes involved in angiogenesis and showed that in many cases, zebrafish display phenotypes that are similar to mouse knock-out mutants. In addition, knockdown of the Ang-2 gene in zebrafish causes neovascularization throughout the eye that can be completely suppressed by a known inhibitor of angiogenesis in mammals. We present supporting evidence that the Ang-2 knockdown fish can serve as a model of eye neovascularization and can be used to screen for modulators of this debilitating condition.

3:30-4:00 Refreshment Break

Imaging Tools for Target Selection

4:00-4:20 Development of Optical Imaging Biomarkers of Tumor Growth for Preclinical Drug Testing and Target Validation.
Bohumil Bednar, Ph.D., Senior Investigator, Imaging, Merck & Co.
Effective development of new compounds and biologics for the treatment of cancer depends on the optimization of preclinical animal models with well defined biomarkers. Of the in vivo molecular imaging modalities currently available, the development of optical imaging and its use in small animal cancer models provides significant opportunity to refine oncology drug discovery research. While xenograft tumor models focus on the use of cancer cell lines expressing fluorophores such as green (GFP) and red (DsRed) fluorescent proteins and different forms of luciferase, new so-called “smart” probes release contrast fluorophores to report tumor-specific physiology. We have developed optical imaging biomarkers for target validation in oncology drug discovery that use both optical imaging technologies. The xenograft tumor models in nu/nu mice using rat MATBIII adenocarcinoma cells constitutively expressing GFP and DsRed fluorescent proteins or firefly luciferase have been established. Two metastatic animal models have also been developed and validated. In the first model, metastases were detected in lungs and lymph nodes after tail vein injection of bioluminescent tumor cells. In the second model, orthotopic implantation in mammary glands resulted, after removal of the primary tumor, in metastasis to the lungs, mammary glands, and lymph nodes. We have implemented and validated a protease sensing probe ProSenseTM and blood-pooling probe for detection of tumor vasculature AngioSenseTM (VisEn Medical). Optical imaging is an effective way of validating drug discovery targets in oncology

Virtual Modeling - The Human Disease Model

4:20-4:40 Next-Generation Disease Models: Target Validation in Virtual Patients
Ton Rullmann, Ph.D., Senior Research Scientist, N.V. Organon 
Using the Entelos(r) Rheumatoid Arthritis (RA) PhysioLab(r) Platform 30 potential RA targets were evaluated in human RA patient phenotypes. Biosimulation within the Entelos RA PhysioLab Platform provides a unique in vivo human context that delineates the target's mechanism of action by identifying the main pathways driving the impact of target modulation on clinical outcome, such as synovial tissue hyperplasia and cartilage degradation. From this analysis, the 30 targets are prioritized by their predicted efficacy, and validation screens are proposed. Both the general approach to target validation and target identification, and a detailed example focusing on Lck, will be presented.

4:40-5:00 A Statistical Approach to Comparing Model Systems
Hugh Salamon, Ph.D., Senior Scientist, Computational Biology, Berlex Biosciences
Typical bioinformatic workflows leave the scientist with a plethora of data to digest and compare, even after data reduction steps to identify functions or pathways. In order to use global profiling platforms, such as transcript expression profiling, to compare how clinical, in vitro, and disease models respond to drugs or other perturbations, we desire simple, statistically valid scientific statements. A case study on treatment response is presented demonstrating the utility of a new statistical method. It is argued that the way is thus paved to a better understanding of whether different models and clinical systems are employing the same cellular and physiological components. We should now strive to judge in a systematic fashion whether or not target modulation in a specific model system perturbs the cellular or physiologic functions we expect to modify in humans.

5:30-7:00 Happy Hour with the Exhibitors and Poster Viewing

Wednesday, October 19
Shared Day with RNAi