Outlook for RNAi 2007
siRNA and miRNA in biology, diagnostics and therapeutics
| Price: £1,480.00 Approx $2,874.16 (USD) €2,210.54 (EUR) |
|
|---|---|
| Overview: | |
| RNAi-based screens have provided new opportunities for the discovery and validation of novel therapeutic targets in areas such as cancer and infectious diseases. Since 2005, enormous strides have also been made in the development of RNAi-based therapeutic products, bringing them significantly closer to the market. ‘Outlook for RNAi 2007’ is a new report which provides a detailed insight into the most effective use of this novel technology in the drug discovery and development process. It puts into context where RNAi technology is being used as a tool of choice within academia and the pharma industry for functional genomic studies, drug target discovery and mechanism of action studies. The development status RNAi based therapeutics is covered in detail, highlighting the key companies in the field, outlining their pipelines and describing the results of completed clinical trials. Understand how RNAi technology is being used to improve drug attrition rates and develop new therapeutic agents, and ensure that you are up-to-date with developments in this advancing field. |
|
| Keywords: The RNAi market is a relatively immature with global sales of approximately $447 million in 2006. It is projected to reach $0.9 billion by 2010, a compound annual growth rate (CAGR) of 19% between | |
|
This paper is available from one of our partner sites.
Click here for details and to download it. |
|
By Dr Cheryl Lee Barton / Publication Date: 1st June 2007
Contents:
Table of Contents
Outlook for RNAi
Executive Summary 12
Introduction 12
Design and Production of RNAi effectors 13
RNAi Research and Applications 14
Delivering RNAi therapeutics 15
RNAi Therapeutics: Progress and the Future 16
miRNA: diagnostics and therapeutics 17
Regulatory issues and patents 18
RNAi markets and trends 19
Chapter 1 Introduction 22
Summary 22
Introduction 23
DNA to RNA to protein – a primer 23
Antisense technologies 24
RNA interference 28
Overview and significance 28
RNAi’s mechanism 31
Post-transcriptional gene silencing (PGTS) by siRNA 31
miRNA pathways 32
Transcriptional gene silencing (TGS) by siRNA 34
Other non-coding RNAs 34
Advantages and disadvantages of RNAi 36
Report Outline 37
Chapter 2 Design and Production of RNAi
effectors 40
Summary 40
Introduction 41
Design of RNAi effectors 41
iv
siRNA design algorithms 42
Building silencing efficiency 45
Avoiding off-target effects 48
Chemical modification 49
Avoiding immunostimulation 50
Finding the right target sites 52
miRNA mimics 52
Production of RNAi effectors 53
Chemical Synthesis 55
siRNA pools 58
Dicer-substrate siRNAs (DsiRNAs) 60
Expression vectors 60
Plasmid expression vectors 62
Expression from a PCR product 64
Viral expression vectors 65
Conclusions 67
Chapter 3 RNAi Research and Applications 70
Summary 70
Introduction 71
Elucidating gene function 71
High throughput loss-of-function screening with RNAi 72
Choice of species and cell-line 73
RNAi reagents 74
Delivery method 80
Screening paradigm and format 81
Read-out methods 82
Building pathways 83
Investigating gene function in vivo 84
Applications of RNAi in drug discovery and development 88
Target discovery and validation 88
Optimization of drug therapy and development of personalized
medicine 90
miRNA Research 91
miRNA Databases and Algorithms 92
Identifying miRNAs, their targets and function 93
Isolation and enrichment of miRNA 94
Detection and quantification of miRNA 94
Functional analysis 98
Conclusions 100
v
Chapter 4 Delivering RNAi therapeutics 104
Summary 104
Introduction 105
Direct organ delivery 106
Stabilization of siRNAs 107
Non-viral delivery methods 111
Cholesterol and peptide conjugation 112
Liposomal delivery 113
Conjugation with cell penetrating peptides 116
Atelocollagen 118
Targeted polymeric delivery 118
Aptamer-siRNA complexes 120
FAb-siRNA complexes 122
MAb-siRNA complexes 123
Targeted nanoparticle delivery methods 123
Targeting with transferrin 123
Targeting with apatmers 124
Targeting with RGD peptide 125
Delivering RNAi via Plasmid DNA 126
Virosomes 126
Viral delivery methods 127
Conclusions 129
Chapter 5 RNAi Therapeutics: Progress and
the Future 132
Summary 132
Introduction 133
siRNA Therapeutics: Analysis by Therapeutic Area 134
Ocular Diseases 136
Age-related Macular Degeneration (AMD) 136
Key RNAi players 138
Diabetic Retinopathy 143
Viral diseases 144
Respiratory Syncytial Virus (RSV) 145
Key RNAi Players 146
HIV 147
Key RNAi players 148
Hepatitis C Virus (HCV) 148
Key RNAi players 149
Hepatitis B Virus (HBV) 152
Key RNAi players 152
Pandemic Flu 153
Key RNAi players 154
vi
SARS 155
Key RNAi players 156
Herpes Simplex Virus (HSV) 156
Other viral diseases 157
Respiratory diseases 157
Asthma and Chronic Obstructive Pulmonary Disease (COPD) 157
Key RNAi Players 158
Cystic fibrosis (CF) 158
Key RNAi players 159
Neurological diseases 159
Oncology 163
Angiogenesis 164
Key RNAi players 164
Oncogenes 166
Key RNAi players 166
Cardiovascular disease 168
Key RNAi players 169
Metabolic disorders 170
Diabetes and Obesity 170
Key RNAi players 170
Dermatology 172
Hair Removal 172
Key RNAi players 172
Pachyonychia congenita and related disorders 173
Key RNAi Players 173
Acute renal failure 174
Key RNAi players 174
Acute hearing loss/ pressure sores ototoxicity 175
Key RNAi players 175
Inflammatory Diseases 176
Key RNAi players 176
Conclusions 177
Chapter 6 miRNA: diagnostics and
therapeutics 180
Summary 180
Introduction 181
miRNA as a diagnostic tool 182
Companies developing miRNA-based diagnostics 183
Rosetta Genomics 183
Cepheid 186
Stratagene 187
vii
miRNA-based therapeutics 187
Companies developing miRNA-based therapeutics 189
Alnylam Pharmaceuticals 189
Asuragen Inc 189
Santaris 191
Sirna 191
Conclusions 192
Chapter 7 Regulatory issues and patents 194
Summary 194
Introduction 195
Patents in RNAi 196
Seminal patents in RNAi 196
Alnylam 199
Sirna 201
Chemical modifications 201
DNA directed RNAi 202
Patents for specific RNAi targets 204
The future – more patent litigation? 205
MicroRNA 205
Tuschl III patents 206
Zamore and other patents 206
Regulatory considerations for RNAi therapies 207
Conclusions 207
Chapter 8 RNAi markets and trends 210
Summary 210
Introduction 211
The RNAi market 213
Market size and future trends 218
RNAi suppliers: synthesis and reagents 219
Alliances with big pharma for RNAi in R&D 222
Delivery of RNAi therapeutics 224
RNAi-based therapeutics 225
Big pharma alliances for RNAi-based therapeutics 229
miRNA-based diagnostics 230
Conclusion 231
viii
List of Tables:
List of Figures
Figure 1.1: Summary of antisense technologies other than RNAi 25
Figure 1.2: Timeline of RNAi discoveries 29
Figure 1.3: Significance of RNAi 30
Figure 1.4: Mechanism of post-transcriptional gene silencing by siRNA 32
Figure 1.5: Mechanism of miRNA mediated translational repression 33
Figure 2.1: Types of RNAi effector 42
Figure 2.2: Points of the RNAi pathway involved in determining silencing efficiency 47
Figure 2.3: Influence of guide RNA structure on siRNA efficiency 48
Figure 2.4: siRNA design that avoids off-target effects 49
Figure 2.5: Mechansims of immunostimulation with siRNA 50
Figure 2.6: Advantages and disadvantages of siRNA synthesis methods 55
Figure 2.7: Mechanism of ddRNAi compared to RNAi triggered by an siRNA 61
Figure 2.8: Nucleonics multi-targeting Anti-HBV drug 64
Figure 3.1: Considerations for a HT RNAi screen 73
Figure 3.2: Structures of silencing reagents for RNAi screening 75
Figure 3.3: Read-out methods for high throughput screens 82
Figure 3.4: Method of ArteMiceTM RNAi development 85
Figure 3.5: Peer reviewed miRNA publications (2001-2006) 92
Figure 3.6: Comparison of Mirus’ LabelIT and enzymatically labelled samples 97
Figure 3.7: Inser Comparison of effectiveness of different knockdown methods t figuretitlehere,
with date where appropriate 100
Figure 4.1: Chemical modifications of siRNAs increase stability and PK 108
Figure 4.2: Ribo-T siRNAs from Nastech Pharmaceuticals 111
Figure 4.3: Structure of a SNALP 114
Figure 4.4: Mirus Bio’s Dynamic PolyConjugates™ delivery system for siRNA 119
Figure 4.5: Aptamer complexes for cell-type specific delivery of siRNAs 121
Figure 4.6: Heavy-chain antibody fragment for delivery of siRNAs to cell surface receptors 122
Figure 4.7: Targeted nanoparticles delivering siRNA 124
Figure 4.8: Aptamer directed nanoparticle formulation of docetaxel 125
Figure 4.9: Preparation of virosomes encapsulating siRNA 127
Figure 4.10: Viral delivery of shRNA 128
Figure 5.1: Development of AMD 136
Figure 5.2: siRNA targeting VEGF reduces blood vessel growth in the cornea 138
Figure 5.3: Visual Acuity data from Phase 1 studies of Sirna-027 142
Figure 5.4: Possible targets for suppressing HIV replication 147
Figure 5.5: siRNA mediated knockdown in Sirna’s primate model of HCV chimeric infection 150
Figure 5.6: Inhibition of three regions of the HCV genome by TT-033 for more than 2 months
after a single administration to mice 151
Figure 5.7: Down regulation of Hepatitis B Surface Antigen after intravenous delivery of
Nucleonic’s HBV candidate 153
Figure 6.1: Rosetta Genomics’ method for miRNA identification and validation 184
Figure 6.2: Illustration of Exiqon’s miRNA diagnostics 186
Figure 6.3: Structure of an antagomir 188
Figure 6.4: Asuragen’s development of miRNA-based therapeutics 190
Figure 6.5: let-7: tumor suppressor and future therapeutic 191
Figure 8.1: RNAi market sectors 211
Figure 8.2: Growth in the RNAi market 2006-2015 218
ix
List of Tables
Table 1.1: Failures of antisense drugs 27
Table 1.2: Highly generalized comparison of siRNAs and miRNAs 34
Table 1.3: Advantages of RNAi 36
Table 1.4: Disadvantages of RNAi 37
Table 2.1: Selection of publicly available siRNA design tools 43
Table 2.2: Commercial siRNA design services 45
Table 2.3: Suppliers of custom and predesigned siRNAs 56
Table 2.4: Suppliers of siRNA pools and kits to create them 59
Table 2.5: Comparison of plasmid-based vectors and synthetic siRNA for research purposes 62
Table 2.6: Selection of plasmid vector products for siRNA generation 63
Table 2.7: Suppliers of kits for generating siRNA expression cassettes by PCR 65
Table 2.8: Advantages and disadvantages of different viral and non-viral expression vectors 66
Table 2.9: Selection of suppliers of viral vectors for gene silencing 67
Table 3.1: Suppliers of siRNA libraries for HT screening (3.1) 76
Table 3.2: Commercial availability and coverage of shRNA libraries 78
Table 3.3: Summary of the pros and cons of the different silencing reagents for RNAi screening
80
Table 3.4: Advantages and disadvantages of RNAi knock-down in vivo 86
Table 3.5: Key databases and algorithms for miRNA target prediction 93
Table 3.6: Suppliers of miRNA mimics and inhibitors 99
Table 4.1: Non-viral methods for siRNA delivery 112
Table 5.1: RNAi therapeutics in, or close to, clinical development 135
Table 5.2: RNAi therapeutic targets in neurological disease 161
Table 5.3: Atugen’s pipeline of anticancer therapeutics 167
Table 6.1: miRNA expression profiling in human cancers 183
Table 7.1: Seminal patents in RNAi 197
Table 7.2: Issues in Tuschl I vs Tuschl II 198
Table 7.3: Licensees of Alnylam’s RNAi patents 200
Table 7.4: Chemical modifications – Sirna’s patent portfolio 202
Table 7.5: Therapeutic targets for RNAi – Sirna’s patent portfolio 204
Table 8.1: Companies involved in RNAi technologies, A-B 214
Table 8.2: Companies involved in RNAi technologies, C-G 215
Table 8.3: Companies involved in RNAi technologies, I-O 216
Table 8.4: Companies involved in RNAi technologies, P-Z 217
Table 8.5: Sales forecasts for total RNAi market, 2006-2015 218
Table 8.6: Sales forecasts for RNAi suppliers: synthesis and reagents, 2006 – 2015 222
Table 8.7: Pharma’s alliances for RNAi in R&D 223
Table 8.8: Sales forecasts for delivery of RNAi therapeutics, 2006-2015 225
Table 8.9: Costs associated with RNAi therapeutic development 226
Table 8.10: Potential value of therapy areas targeted by RNAi therapeutics, 2005 & 2010 227
Table 8.11: Sales forecasts for RNAi therapeutic drugs launched 2010-2015 229
Table 8.12: Pharma’s alliances for RNAi in R&D 230