Innovations In Epigenetics: Advances in Technologies, Diagnostics & Therapeutics

Table of Contents
Innovations in Epigenetics
Executive summary 10
Introduction 10
Application in R&D & technological advances 10
Exploring new therapeutic targets 11
Epigenetic market, leading companies & pharmaceutical strategies 12
The future of epigenetics 13
Chapter 1 Introduction 16
What is epigenetics? 17
Epigenetics and phenotypes 19
Epigenetics a new biological paradigm 19
Epigenetics, genetics, genomics & pharmacogenomics 20
Molecular mechanisms associated with epigenetics 22
DNA methylation 22
Histone modifications 23
Nucleosome remodelling 23
Non-coding RNA 24
X chromosome inactivation 24
Gene imprinting 24
RNA interference 24
Epigenetic basis of disease 25
Epigenetic syndromes 25
Angelmann syndrome 25
Beckwith-Wiedemann syndrome 26
Prader-Willi syndrome 26
Why is epigenetics of interest to the pharmaceutical industry? 27
Biomarker discovery & diagnostics 28
Novel small molecule epigenetic therapeutics 28
Novel antisense therapeutics 28
Stem cells & regenerative medicines 29
Conclusions 29
Chapter 2 Application in R&D & technological advances 32
The application of epigenetics in drug R&D 33
DNA methylation biomarkers 34
Histone modification biomarkers 35
Technological advances in epigenetics 35
Chromatin immunoprecipitation 36
DNA methylation technologies 38
Non-coding RNA technologies 43
Bioinformatic modeling 43
Conclusions 44
Chapter 3 Exploring new therapeutic targets 48
Potential new therapeutic targets 49
Epigenetics in cancer 50
DNA methyltransferase & DNMT inhibitors 52
Case study: Vidaza (Celgene Corporation) & Dacogen (Eisai /J&J) 53
Case study: Zebularine a research tool 56
Histone acetylase (HAT) and histone deacetylase (HDAC) 59
Case study: Zolinza (Merck & Co.) 61
Case study: MGCD0103 (MethylGene/Taiho Pharmaceutical) 62
Case study: PCI-24781 (Pharmacyclics/Servier) 63
Histone demethylases and histone methyltranserases 65
Case study: PG11144 & PG11047 (Progen Pharmaceuticals) 66
Potential epigenetic based diagnostics 67
Diagnostic DNA methylation cancer biomarkers 67
Case study: Epi proColon (Epigenomics AG) 69
The next generation of epigenetic cancer biomarkers 71
Epigenetics in neurological disorders 72
Case study: EVP-0334 (EnVivo Pharmaceuticals) 73
Epigenetics in infectious diseases 75
Case study: MGCD290 (MethylGene) 75
Case study: siRNA targeting HIV-1 (Kevin Morris, Scripps, La Jolla) 76
Epigenetics in metabolic disorders 78
Epigenetics in cardiovascular disease 81
Epigenetics in ocular disorders 83
Case study: Kinase inhibitors (Otsuka Pharmaceutical/MethylGene) 84
Case study: Kinase inhibitors/S-adenosyl methionine (SAM) (Epizyme). 85
Conclusions 86
Chapter 4 Epigenetic market, leading companies & pharmaceutical strategies 90
Epigenetic market 91
Epigenetic therapeutic revenues: Now and the future 92
Leading epigenetic companies 93
4SC AG, Planegg-Martinsried, Germany 94
Celgene Corporation, Summit, New Jersey 95
Curis Inc, Cambridge, MA 96
Chroma Therapeutics Ltd, Oxon, UK 98
Constellation Pharmaceuticals, Cambridge, MA 99
EnVivo Pharmaceuticals, Watertown, MA 100
EpiTherapeutics Aps, Copenhagen, Denmark 101
Epizyme, Cambridge, MA 101
Gloucester Pharmaceuticals, Cambridge, MA 103
MethylGene, Inc. Montreal, Québec 104
Pharmacyclics, Sunnyvale, CA 106
Progen Pharmaceuticals, Brisbane, Australia 107
Repligen Corporation, Waltham, MA 108
SuperGen, Dublin, CA 109
Syndax Pharmaceuticals, Waltham, MA 112
TopoTarget, Copenhagen, Denmark 113
Summary of epigenetic-based companies 114
Recent alliances, mergers & acquisitions in epigenetics 115
Pharmaceutical strategies in epigenetics 118
GlaxoSmithKline, Middlesex, UK 118
Novartis, Basel, Switzerland 119
Merck & Co., Whitehouse, NJ 121
Eisai Corporation of North America, NJ 122
Takeda, Osaka, Japan 123
Overall conclusions 123
Chapter 5 The future of epigenetics 126
The future of epigenetics 127
Epigenetic consortia; unraveling the human epigenome 128
NIH’s Roadmap Epigenomics Program initiative 128
European Epigenome Network of Excellence 130
Human Epigenome Consortium 130
KOLs in epigenetics 131
John Mattick, Institute for Molecular Bioscience, University of Queensland,
Australia 132
Overview 132
Technology 133
Applications 133
Future 134
Kevin Morris, Scripps Institue, La Jolla, CA 134
Overview 134
Technology 135
Applications 135
Future 136
Monika Lachner, Max-Planck Institute of Immunobiology, Department of
Epigenetics, Freiburg, Germany 136
Overview 136
Technology 136
Applications 137
Future 137
Johnathan Whetstine, Department of Medicine, Massachusetts General
Hospital Cancer Center 137
Overview 138
Technology 138
Applications 138
Future 139
Peter Fraser, Head, Senior Fellow of the Medical Research Council, UK, The
Babraham Institute, Cambridge 139
Overview 139
Technology 140
Applications 140
Future 141
Summary of KOLs commentary 141
Challenges 142
Fundamental research 142
Technological demands 142
Financial constraints 143
Intellectual property 144
Opportunities 144
Biomarker discovery & diagnostics 144
Therapeutic intervention 145
Regenerative medicines 145
Conclusions 146
Chapter 6 Appendices 150
Glossary 150
Acknowledgements 156
Index 157
Index 157
Bibliography 159
Endnotes 165
List of Figures
Figure 1.1: Timeline of epigenetics study 18
Figure 1.2: Schematic of chromatin structure 22
Figure 1.3: Schematic of epigenetic mechanisms associated with health and disease 23
Figure 1.4: Epigenetic applications by the pharma industry 27
Figure 2.5: Epigenetics in the drug discovery & development process 34
Figure 2.6: Schematic of key technologies used in epigenetics 36
Figure 2.7: Schematic of ChIP technology 37
Figure 2.8: Epigenomics AG methylation specific PCR (MSP) methods 42
Figure 3.9: DNA methylation targets for epigenetic cancer therapies 51
Figure 3.10: Mechanism of action of HAT and HDAC 61
Figure 3.11: Epi proColon high throughput colorectal epigenetic test 70
Figure 3.12: Competitive pricing of Epi proColon 71
Figure 3.13: EnVivo’s HDAC project screening cascade 74
Figure 3.14: Agouti mice and epigenetic manipulation 79
Figure 3.15: Epizyme’s rational design of small molecule HMT inhibitors 85
Figure 4.16: Epigenetic therapies: product class and developmental phase 91
Figure 4.17: Epigenetic therapies: therapy target and developmental phase 92
Figure 4.18: CUDU-101 structure & design: combining multiple pharmacophores 97
List of Tables
Table 2.1: DNA methylation PCR methods 40
Table 2.2: Techniques to analyze DNA methylation 41
Table 3.3: Examples of DNMT inhibitors: potential anticancer agents targeting epigenetic pathways 54
Table 3.4: Examples of DNMT inhibitor research tools 55
Table 3.5: HDAC inhibitors: potential anticancer agents targeting epigenetic pathways 57
Table 3.6: Examples of HDAC inhibitor research tools 59
Table 3.7: Histone modification and their effect on gene expression 60
Table 3.8: Safety profiles of PCI-24781 rivals 64
Table 3.9: DNA methylation sites associated with cancers 67
Table 3.10: Validated and hypothetic miRNA targets for diabetes & obesity 81
Table 4.11: Epigenetic therapeutic revenues ($m), 2009-2020 93
Table 4.12: Preliminary clinical data for Pharmacyclics PCI-24781 106
Table 4.13: Recent alliances, acquisitions and mergers in the epigenetic arena 117
Table 5.14: NIH Epigenetic Roadmap – funded epigenetic projects 129