Strategies and Technologies for Target Validation

Published by: Datamonitor

Published: Sep. 1, 2012 - 87 Pages

Table of Contents

Executive summary
Key findings

Chapter 1 The need for target validation
Summary
Target validation and the drug development process
Target validation and R&D investment
Target validation and drug attrition
References

Chapter 2 Strategies involved in target validation
Summary
Introduction
Target identification
Target confirmation studies
Target validation strategies
Phenotypic screening models
Model organisms
Vertebrate and invertebrate models
Human cell models
Target-based drug discovery
Druggable targets
Systems biology approach
Network pharmacology approach
Target validation companies
Conclusions
References

Chapter 3 Application of new technologies in target validation
Summary
Recent technological advances
Stem cells
Case study: iPSC technology (iPierian)
Stem cell conclusions
RNA interference
In vitro applications of RNAi
Case study: CellSelect technology (BerGenBio AS)
Case study: FlexSelect and SilenceSelect technology (Galapagos)
In vivo applications of RNAi
Case study: RNAi mouse model (Taconic)
Case study: RNAi Quick Knock-in mice (genOway)
RNAi conclusions
Omic technologies
Next-generation sequencers
Chemogenomics and chemoproteomics
Metabolomics
Epigenomics
Case study: Epigenetic markers (Constellation Pharmaceuticals)
Case study: small-molecule HMT inhibitors (Epizyme)
Omic conclusions
High-content screening technology
Case study: HT/HC automated microscopy-based assays (Cenix BioSciences)
HCS conclusions
Bioinformatics
Data mining
Computer modeling
Whole animal modeling
Conclusions
Potential differences between phenotypes deriving from genetic versus small-molecule tools
References

Chapter 4 Challenges, opportunities, and future outlook in target validation
Summary
Challenges in target validation
Opportunities in target validation
The development of high-quality relevant resources
The development of more accurate processes and techniques
Exploiting existing data
Open innovation
Future outlook
References
Appendix
Scope
Methodology
Research methodology
Acknowledgements
Abbreviations

Table of figures
Figure 1: Pre-approval capitalized costs per approved new drug
Figure 2 Pre-approval out-of-pocket (cash outlay) and time costs per approved new biopharmaceuticals
Figure 3: Reasons for failure in drug development
Figure 4: Probability of success based on therapeutic category, 2004
Figure 5: Target validation process
Figure 6: Phenotypic-based drug discovery and validation
Figure 7: Target-based drug discovery and validation
Figure 8: Druggable protein targets
Figure 9: Systems biology principal approaches
Figure 10: iPierian’s iPSC technology
Figure 11: Cenix’s HT-RNAi-based target validation process
Figure 12: Cenix’s HT/HC RNAi screening technology
Figure 13: Target validation from the genome to the targetome

Table of tables
Table 1: Recent target-based alliances between industry and academia, 2008–12
Table 2: Attributes of model organisms for phenotypic screening
Table 3: Number of genetic targets with drugs
Table 4: Target validation companies
Table 5: Bioinformatic and software companies

Abstract

Target validation involves the thorough assessment of a molecular target, evaluating its physiology, pathology, and pharmacology and determining its role in altering the disease phenotype. Inadequate target validation has been attributed as a major cause of clinical-stage attrition. This report analyses the strategic and technological developments in the field.

In recent years greater emphasis has been placed on the validation of a target in human cell and animal disease models prior to screening for lead compounds. This facilitates in-depth knowledge of the underlying biology of a disease and allows investigators to evaluate the importance of upstream and downstream pathways of new targets.

RNAi-based technologies offer high throughput, a high-predictive value, relatively low cost, short experimental times, and the ability to knock down several genes in vitro and in vivo.

Improvements in molecular imaging and bioinformatics have enabled high-content screening to become more widely applied to measure phenotypic endpoints, allowing structural and biochemical changes within cells, tissues, organs, or whole organisms to be visualized in real time, leading to improvements in target validity.

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