Author: Allan B. Haberman, Ph.D.
CHAPTER
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)
REFERENCES
COMPANY INDEX WITH WEB ADDRESSES