Appropriate Translational Models
for Complex Diseases

8:30 Chairperson’s Remarks
Mark A. Varney, Ph.D., Chief Operating Officer and Chief Scientific Officer, Cortex Pharmaceuticals, Inc.

8:40 Animal Models in CNS Drug Discovery
Mark Varney, Ph.D.
There are no animal models that represent all components of a given human CNS disorder. However, it is clear that different animal models have both strengths and limitations which need to be recognized so that they can be used effectively in CNS drug discovery. Because of this, it is essential to establish multiple animal models for each CNS disorder to investigate the various aspects of the disease and to provide validation of the findings. In drug discovery, the most relevant facet of the model is that it provides predictive validity. That is, the animal model accurately predicts activity of a new molecule in the human disease. As a result, it is critical to define the aspects of the disease that the drug development program is focused against. The process of developing, validating and refining animal models should therefore be iterative with the process of identifying reliable measures and unmet needs in the human disease. Several examples of CNS drug discovery and development will be discussed; including preclinical data on a series of molecules termed AMPAKINES that allosterically modulate AMPA-type glutamate receptors. AMPAKINES prolong the opening and/or slow the closing of the AMPA receptor channel, thereby enhancing the inward flow of sodium ions into the neuron, facilitating LTP (Long-Term Potentiation) and improving rodent and non-human primate performance in cognitive tasks. In addition to these effects, the high-impact AMPAKINES increase gene expression for neurotrophic factors such as BDNF that may confer disease modifying activity. 

9:10 Integrated Use of Preclinical Pain Models to Improve Clinical
Predictability
Jeffrey D. Kennedy, Ph.D., Associate Director, Pain Molecular Neurobiology, Neuroscience, Discovery, Wyeth Research 

9:40 TBA 

10:10 Networking Coffee Break 

10:30 Effective Asthma Targeting via Inhibiting Type I Hypersensitivity/IgE/Mast Cells or by Immune Deviation with Th2 Cells as Targets
Henry Hess, Ph.D., Leader and Senior Scientist, Immunopharmacology Department, Biogen Idec, Inc.

11:00 Human IL-17E Transgenic Mice as a Model for Asthma
Alison Budelsky, Ph.D., Senior Scientist, Inflammation Research, Amgen Inc.
Transgenic mice overexpressing human IL-17E (hIL-17E) exhibit a general Th2-skewed phenotype including blood eosinophilia, splenomegaly, lymphoadenopathy, and elevated serum IgE and IgG1 levels. We have recently worked to fully characterize the pulmonary phenotype of these mice in both a naïve state and in an OVA asthma model. Naïve hIL-17E transgenic mice exhibited a mild pulmonary inflammation with features similar to those exhibited by wild type mice in an OVA asthma model. This intrinsic pulmonary inflammation of hIL-17E transgenic mice was exacerbated after sensitization and challenge with OVA beyond that seen in OVA sensitized and challenged wild type littermates. These data suggest that elevated IL-17E levels can exacerbate a Th2-type inflammatory response.

11:30 Technology Watch (Sponsorship Available)

11:45 Computational Review 
Improving Clinical Translation, Through Computational Modeling 
Lisl Shoda, Ph.D., Scientist, Immunology, In Silico Research and Development, Entelos, Inc.
Dr. Shoda will review a hand-picked selection of the most recent publications from the past year highlighting improvements in clinical translation through computational modeling. Each publication will be reviewed and findings summarized in a Powerpoint presentation. A copy of this review will be 
available on the conference CD. 

2:00 Chairperson’s Remarks

2:05 Validation of a DIO Model for Obesity
Karin Conde-Knape, Ph.D., Principal Scientist, In Vivo Leader, F. Hoffmann-La Roche Ltd. 
Identifying an appropriate animal model is a challenge that every disease area in drug discovery has to face. I will describe the validation of a diet induced obese rodent as a model for obesity and the Metabolic syndrome. This model is useful for drug discovery as well as target validation.

2:35 SHIP2 KO Mice Protected from Age-Onset and Diet-Induced Obesity
Dan F. Lazar, Ph.D., Principle Research Scientist, Endocrine Division, Lilly Research Laboratories
It has been reported that leptin and insulin central regulation of food intake and energy expenditure involves stimulation of the PI3K pathway, as do most of the peripheral metabolic responses to insulin. Expressed in insulin-sensitive tissues and the brain, SHIP2 is a lipid 5’-phosphatase whose catalytic activity degrades the lipid second messenger generated by PI3K activity. SHIP2 KO mice have been generated and characterized and their profound anti-obesity 
phenotype will be discussed.

3:05 Target Validation: Use of Preclinical Models and Clinical Samples
Michael R. Cancilla, Ph.D., Associate Director, Translational Medicine, Exelixis, Inc.
Target validation continues beyond the drug discovery process as measurable pharmacodynamic (PD) biomarkers and/or stratification of patients based on target profiles have the potential to expedite drug development. The development of spectrum selective kinase inhibitors (SSKI) offers many challenges and opportunities. This presentation will cover our approaches for further target validation including a comparative analysis of PD markers from preclinical models with samples collected from subjects in Phase 1 trials.

3:35 Networking Refreshment Break

4:30 Progress Review 
Model Organisms for Target Discovery & Validation 
David Joseph Milan, M.D., Co-Director, Clinical Cardiac Electrophysiology Training Program, Massachusetts General Hospital
Dr. Milan is the Co-Director, Clinical Cardiac Electrophysiology Training Program at Massachusetts General Hospital and his research focus is on cardiovascular zebrafish models. He will review a hand-picked selection of the most recent publications from the past year highlighting recent work in the model organisms for target identification and validation. Each publication will be reviewed and findings summarized in a Powerpoint presentation. 

Technology Watch 
5:15 Effective Use of In Vivo Screening in Early Stage Drug Discovery Programs
Richard Storer, Ph.D., Chief Scientific Officer, VASTox
Early in vivo evaluation is a highly desirable component of a modern drug discovery programme. Studies in zebrafish (Danio rerio) and fruitflies (Drosophila melanogaster) can provide a wealth of critical information on both mechanism of action and toxicity using microgram quantities of materials.

7:00 am Registration & Morning Coffee

KEYNOTE SESSION

8:30 Keynote Introduction 8:40 Target Discovery: Seeking Innovation and the Role of Collaboration with Biotech and Academia Jeremy Levin, D. Phil, MB. Bchir, Global Head, Business Development and Strategic Alliances, Novartis 9:10 Reducing Clinical Attrition through Efficiencies in Discovery Joseph Bolen, Ph.D., Senior Vice President, Research & Drug Discovery, Millennium Pharmaceuticals 9:40 Coffee Break in the Exhibit Hall

10:20 Introduction and Welcome to RNAi: From Target Discovery & Validation to Therapeutic Development

10:30 Cell-Type and Tissue-Specific RNAi (Genes & Development Jan. 2006)
Miles Wilkinson, Ph.D., Professor, Department of Biochemistry and Molecular Biology, MD Anderson Cancer Center
We present a simple approach to stably knockdown the expression of genes in specific cell types in vivo. The approach mimics the way naturally occurring microRNAs down regulate their targets. This microRNA-based approach can be used to determine the tissue- or cell type-specific function of genes in experimental animals or be used as a therapeutic agent to silence deleterious genes in specific target tissues or cell types in humans. 

11:00 siRNA Targeting TNF Modulates Host Resistance to Herpes Simplex Virus (Nature Protocols in press)
Edouard Cantin, Ph.D., Professor and Associate Chairman, Division of Virology, Beckman Research Institute, City of Hope Medical Center
Data on in vivo application of siRNA targeting TNF in a mouse model of HSV encephalitis will be presented. Peritoneal macrophages were efficiently transfected with 27-mer siRNAs in vivo using Mirus TransIT TKO transfection reagent and these cells migrated rapidly to the brainstem of HSV infected mice. Using this in vivo siRNA delivery system, we have been able to confirm that TNF signals independently of the known TNF receptors to mediate resistance to fatal HSV encephalitis. Additionally, we have shown trafficking of in vivo transfected macrophages into tumors, illustrating the potential utility of the procedure for targeting macrophages in diverse disease states.

11:30 Genetic Analysis of Autoimmunity by RNA Interference (Nature Genetics April 2006)
Stephan Kissler, Ph.D., Research Scientist, Center for Cancer Research, Massachusetts Institute of Technology
One of the challenges in identifying susceptibility genes in multigenic diseases is the validation of individual candidate loci by experimentation. We have made use of lentiviral RNA intereference by transgenesis to test a candidate gene, Nramp1, in the type 1 diabetes-prone NOD mouse strain. We found that Nramp1 silencing reduced disease frequency and confirmed this gene's involvement in disease, making this approach a feasible strategy for the identification of susceptibility genes in this and other complex diseases.

11:45 Reproducible and Inducible Knockdown of Gene Expression in Mice (Genesis May 2006)
Jing Yu, Ph.D., Research Scientist, Andrew McMahon Laboratory, Harvard University
In mammalian cells, vector-based expression of small hairpin RNAs (shRNA) produces potent and stable gene knockdown effects. An inducible RNAi system with reproducible levels of siRNA expression will extend the usefulness of this methodology to the identification of gene functions within the developing or adult mouse. We present evidence that an RNA polymerase III driven U6 promoter with stuffer sequences flanked by loxP sites inserted at three different sites within the promoter drives shRNA expression in a Cre recombinase-dependent manner. We have utilized this approach to develop a generic strategy for the reproducible knockdown of gene expression in mice by placing the inducible shRNA cassette into the ROSA26 locus of the mouse. This approach circumvents the pre-screening of random integration in ES clones and further enables conditional gene knockdown with temporal and/or tissue specificity. This methodology should expedite large-scale functional studies.

12:30 Lunch in the Exhibit Hall

3:30 Refreshment Break in the Exhibit Hall

Six or more companies will present their solutions to in vivo delivery and stability in a series of concise presentations. Questions from potential technology end-users from both larger pharma and biotech companies and academic labs will be answered following each talk. Discussions will follow.

4:00 Company One: Alnylam Pharmaceuticals Inc.
         Delivery Technology: siRNA design, modifications of siRNA for improved stability, systemic delivery, anti-viral applications
Presenter: Tracy Stage Zimmermann, Ph.D., Senior Scientist, Alnylam Pharmaceuticals Inc.

4:20 Company Two: Nastech Pharmaceutical Company Inc. 
          Delivery Technology: siRNA delivery via intra-nasal, intra-pulmonary and systemic routes, peptide and lipid based delivery, anti-viral 
        applications
Presenter: Paul H. Johnson, Ph. D., Senior Vice President of Research and Development, Chief Scientific Officer, Nastech Pharmaceutical Company Inc.

4:40 Company Three: Atugen AG 
       Delivery Technology: siRNA design, modifications of siRNA for improved stability, oncology applications
Presenter: Klaus Giese, Ph.D., Chief Scientific Officer, Atugen AG

5:00 Company Four: Artemis Pharmaceuticals GmbH 
         Delivery Technology: RNAi transgenics (constitutive and inducible)
Presenter: Holger Kissel, PhD., Senior Manager, Scientific Project Management, Artemis Pharmaceuticals-an Exelixis Company

5:20 Company Five: Protiva Biotherapeutics Inc.
       Delivery Technology: siRNA Design, Modifications of siRNA for Improved Stability, SNALP Based Delivery
Presenter: Ian Maclachlan, Ph.D., Chief Scientific Officer, Protiva Biotherapeutics Inc.

5:40 Company Six: Sirna Therapeutics, Inc. 
         Delivery Technology: siRNA design, modifications of siRNA for improved stability, anti-viral (HCV/HBV), dermal applications
Presenter: Barry Polisky, Senior Vice President & CSO, Sirna Therapeutics, Inc.

6:30 In Vivo Networking Reception (Sponsorship Available)

End of Preclinical Disease Models

*Apple is not a sponsor or participant of this program. 

For more information, please contact:
Edel O'Regan, Senior Conference Director, Cambridge Healthtech Institute
Phone: 617-630-6323 E-mail: eoregan@healthtech.com

For exhibits and sponsorship information, please contact:
David Karp at 781-972-5483 or dkarp@healthtech.com