Animal Models for Therapeutic Strategies

Animal Models for Therapeutic Strategies published by Insight Pharma Reports in March, 2010. This report price starts from US $ 3195.

Introduction

Abstract

The use of animal models in development of novel therapeutic strategies is the main emphasis of this report. Creation of new animal models is an important part of this research. Discussed in this publication:

• Case studies of the use of established animal models in developing novel therapeutic strategies
• Emerging animal models for use in drug discovery and the development of new therapeutic strategies
• Development of animal models that are more predictive of drug efficacy
• Technological developments in progress
• Use of computer models and translational biomarkers to move more effectively from preclinical animal studies to the clinic
• Thought-leader interviews and a user survey are also included

Although animal models based on mammalian species have been long employed, more recently the pharmaceutical/biotechnology industry has also adopted several invertebrate and lower vertebrate animal models. The aim of using animal models to develop novel therapeutic strategies is to achieve knowledge of pathways and targets that leads to new paradigms for drug discovery and development.

Chapters 2, 3, 4, and 6 focus on the nematode Caenorhabditis elegans, the fruit fly Drosophila, the zebrafish, and the mouse, respectively. Each chapter includes cases studies of the use of each of these established animal models in developing novel therapeutic strategies for human disease. Chapters 5 and 7 focus on emerging animal models, the African clawed toad Xenopus tropicalis and emerging mammalian animal models. Each of these chapters focuses on technological developments in progress to develop tractable animal models based on these organisms. Chapter 7 also includes a discussion of the rat as an animal model, which is "reemerging" as the result of new technologies and collaborations.

Chapter 8 discusses the use of computer models and translational biomarkers in helping researchers move more effectively from preclinical animal studies to human clinical trials. Pharmaceutical and biotechnology company researchers have been increasingly applying pharmacokinetic/pharmacodynamic modeling to all stages of drug development. These models, as well as biophysical models such as those developed by Novartis and physiological models such as those developed by Entelos, can help researchers more effectively use animal model data in the design of clinical trials. In particular, they can help researchers reduce drug attrition in clinical trials due to suboptimal dosing.

Chapter 6, which focuses on the mouse, concludes with a discussion of the issue of developing more predictive animal models of drug efficacy, specifically more predictive mammalian models. One main reason for researchers' difficulties in producing predictive mouse models is major unknown factors in disease biology. Although these factors make developing predictive animal models difficult, researchers can use animal models to learn about unknown or poorly understood areas of disease biology. This is expected to lead to the development of improved animal models as well as the development of new therapeutic strategies and drugs.

Developing animal models that are more predictive of efficacy is an iterative process. But progress is being made, as researchers apply new knowledge and experimental approaches in elucidating the biology of particular diseases to creation of animal models.

Table of Contents

CHAPTER 1 INTRODUCTION

• 1.1. Uses of Model Organisms
  • Basic Research
  • Developing Therapeutic Strategies
  • Target Evaluation
  • Preclinical Studies
• 1.2. Why Do We Need New Animal Models?
  • Animal Models Used in Drug Discovery and Preclinical Studies Need to be More Predictive of Clinical Results
  • Can animal models be replaced with human cellular models in drug discovery?
  • New Animal Models to Aid Researchers in Understanding Disease Biology and Developing New Therapeutic Strategies
• 1.3. The Issue of Animal Welfare and Its Effects on Animal Research in Drug Discovery and Preclinical Studies
  • The 3Rs
  • The Effects of Public Perception and Behavioral Research on Support of Animal Research

CHAPTER 2 THE NEMATODE CAENORHABDITIS ELEGANS AS A MODEL SYSTEM

• 2.1. Introduction
• 2.2. A C. elegans Model of Parkinson' s Disease
• 2.3. Using C. elegans as a Platform for Drug Discovery and Target Identification via Chemical Genetics Studies
• 2.4. A C. elegans Model of Spinal Muscle Atrophy
• 2.5. Conclusions

CHAPTER 3 THE FRUIT FLY DROSOPHILA MELANOGASTER AS A MODEL SYSTEM

• 3.1. Introduction
• 3.2. Use of RNAi Screens to Identify Drug Targets in Drosophila Cells and a Novel Approach to Cancer Therapy
• 3.3. A Drosophila Model for Human Glioma
• 3.4. Conclusions

CHAPTER 4 THE ZEBRAFISH DANIO RERIO AS A MODEL SYSTEM

• 4.1. Introduction
• 4.2. Use of Forward Genetic Screens in Target Identification in Zebrafish: The Case of Polycystic Kidney Disease (PKD)
• 4.3. Zebrafish Models of Melanoma
  • The Relationship between Melanocyte Development and Metastatic Melanoma
  • Using Melanoma Genetics to Design Zebrafish Models of Melanoma
  • Genes Involved in Melanocyte Development Can Synergize with Oncogenes to Produce Metastatic Melanoma
  • Design of Zebrafish Model Systems for Use in Developing Further Understanding of Melanoma Pathobiology
• 4.4. The Japanese Medaka (Oryzias latipes): An Emerging Fish Model
• 4.5. Zebrafish Companies
  • Phylonix
  • Znomics
  • Evotec' s Zebrafish Technology Platform
  • The Future of Zebrafish Platform Companies
• 4.6. Conclusions

CHAPTER 5 XENOPUS TROPICALIS: AN EMERGING MODEL SYSTEM

• 5.1. Introduction
• 5.2. Developing Genetic and Genomic Tools for X. tropicalis
• 5.3. Studies with X. tropicalis with Relevance to Human Disease
• 5.4. Conclusions

CHAPTER 6 MOUSE MODEL SYSTEMS

• 6.1. Introduction
• 6.2. Background: Complex Diseases Are Difficult to Model
• 6.3. Comprehensive Strategies to Improve Mouse Models
  • Gene Disruption Technologies, Functional Genomics, and Target Validation
  • Natural Variation and Quantitative Trait Loci
  • Chemical Mutagenesis to Create Point Mutations
  • Modeling of Polygenic Traits to Improve the Predictiveness of Mouse Model Studies
  • Modeling of Copy Number Variation
  • Humanized Mouse Models
• 6.4. Other Strategies for Improving Mouse Model Studies: Phenotyping and Modeling Environmental Factors
  • Phenotyping 74
  • Modeling Environmental Factors
• 6.5. Case Study: A Mouse Model of Autism Based on Copy Number Variation
• 6.6. Case Study: A Difference between the Mouse and Humans May Affect Drug Discovery in Diabetes
• 6.7. Case Study: Using an Improved Mouse Model of Pancreatic Cancer to Develop Novel Therapeutic Strategies
• 6.8. Conclusions 84

CHAPTER 7 EMERGING MAMMALIAN MODEL SYSTEMS

• 7.1. Introduction
• 7.2. The Reemergence of the Laboratory Rat
• 7.3. Site-Directed Mutagenesis in Mammalian Models Other than the Mouse
• 7.4. Zinc-Finger Nuclease Genome Editing to Produce Knockout Rats
• 7.5. Creating Knockout Mice and Rats from Cultured Spermatogonial Stem Cells
• 7.6. Production of Transgenic Marmosets That Transmit Transgenes to Their Offspring
• 7.7. Conclusions

CHAPTER 8 MOVING FROM ANIMAL MODELS TO THE CLINIC

• 8.1. Modeling and Simulation
  • Computer Modeling and Simulation is Complementary to, but Cannot Replace, Animal Studies
• 8.2. Computer Modeling and Simulation for Moving From Animal Models to the Clinic
  • Allometric Scaling: Determining the Human Equivalent Dose (HED)
  • Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling
  • Modeling and Simulation at Novartis
  • Entelos
  • Entelos/American Diabetes Association virtual NOD mouse model
• 8.3. Translational Biomarkers
• 8.4. Conclusions

CHAPTER 9 OUTLOOK

• 9.1. Animal Welfare Issues
• 9.2. "Established" and "Emerging" Animal Models
• 9.3. Advantages of Using Invertebrate Models and the Zebrafish in Drug Discovery Research
• 9.4. Animal Model Studies Help Researchers Learn About New Aspects of Disease Biology
• 9.5. Developing More Predictive Animal Models of Drug Efficacy

CHAPTER 10 THOUGHT LEADER INTERVIEWS

• 10.1. Adrian Hill, PhDAssociate DirectorEvotecAbingdon, Oxfordshire, UK
• 10.2. Davide Molho, DVMCorporate Senior Vice President Charles River Wilmington, MA
• 10.3. Brian W. Soper, PhDResearch Affiliates Program, Scientific LiaisonThe Jackson LaboratoryBar Harbor, ME
• 10.4. Ann Sluder, PhDDirector of BiochemistryScynexisResearch Triangle Park, NC

CHAPTER 11 INSIGHT PHARMA REPORTS' ANIMAL MODELS SURVEY: JANUARY 2010

• Question 1. Please classify your organization.
• Question 2. What aspect(s) of the drug development process do you work in? (You may answer more than one.)
• Question 3. What class(es) of drugs do you work on? (You may choose more than one answer.)
• Question 4. Do you work directly with animal models?
• Question 5. If you answered yes to question 4, in what aspect of drug development do you work with animal models? (You may answer more than one if applicable.)
• Question 6. What types of animal models does your company use in-house? (May answer more than one)
• Question 7. What types of animal models are used in studies that your company outsources to CROs? (May answer more than one)
• Question 8. Do you agree that poorly predictive animal models have been a major reason for the low productivity of drug development?
• Question 9. Has there been any improvement in the predictiveness of animal models for use in discovery research and in preclinical studies since the initiation of the FDA' s Critical Path Initiative in 2004?
• Question 10. Do you expect any improvements in the predictiveness of animal models for use in discovery research and in preclinical studies in the next five years?
• Question 11. Do you expect human cellular models based on induced pluripotent stem cells or similar technology to replace some uses of animals in pharmaceutical/biotechnology research over the next five years?
• Question 12. Does your company use modeling/simulation to move from animal studies in discovery and preclinical studies into human trials?
• Question 13. Do you expect computer models ("virtual animal models," "virtual human models," "virtual physiological systems," "virtual tumors," etc.) to replace some uses of animal models over the next five years?
• Question 14. Is development of computer-based animal or human models severely limited by researchers' limited knowledge of biological systems and of disease biology?
• Question 15. How do regulations designed to promote animal welfare (e.g., the Animal Welfare Act, the Public Health Services' Guide for the Care and Use of Laboratory Animals, local regulations, the 3Rs) affect your operations?
• Question 16. Does your company work with any of the following to develop novel animal models? (May choose more than one answer)

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