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The Outlook For RNAi: Accelerating Drug Discovery And The Development Of RNAi TherapeuticsPublished by: Business Insights Published: May. 1, 2005 - 205 Pages Table of ContentsTable of Contents The Outlook for RNAi Executive Summary 12 Current RNA technologies 12 Design, production and delivery of RNAi 13 The future of RNAi in research and drug discovery 14 The future of RNAi drug therapies 15 Emerging RNA technologies and future trends 16 Patents and strategic alliances in RNAi technology 17 RNAi markets and trends 18 Chapter 1 Current RNA technologies 20 Summary 20 Introduction 21 History of RNAi 21 From DNA to RNA to proteins 22 mRNA regulation 23 Gene expression 24 Antisense technology 25 Oligonucleotides (OGNs) 26 Peptide nuclei acids (PNAs) 28 Locked nucleic acids (LNA) 28 Triple helix DNA or triple helix-forming oligonucleotides (TFOs) 30 Ribozymes 31 DNAzymes 32 Aptamers 33 RNA interference 33 siRNAs versus dsRNA 36 siRNAs versus shRNA 36 Conclusions 38 iv Chapter 2 Design, production and delivery of RNAi 42 Summary 42 Introduction 43 Cost-effective RNA design 43 Cost-effective synthesis of siRNA 45 Chemical synthesis 47 Conclusions 49 In vitro transcription 50 DICER reaction 51 Expression vectors 52 DNA-directed RNAi (ddRNAi) 53 Expressed interfering RNA (eiRNA) 55 Conclusions 56 Improvements in siRNA stability 57 Chemical modifications 57 Formulation modifications 59 Small molecule conjugation 59 Synthetic vector systems 61 Conclusion 62 RNAi delivery options 63 Viral vectors 65 Conclusions 66 Chapter 3 The future of RNAi in research and drug discovery 70 Summary 70 Introduction 71 Applications of RNAi in research 72 Functional genomics 72 Signaling pathways 75 Applications of RNAi in drug discovery 76 Gene expressions studies 76 Target validation 81 Toxicogenomics 83 Applications of RNAi in drug development 85 Transgenics 86 The impact of RNAi in R&D 92 v Chapter 4 The future of RNAi drug therapies 96 Summary 96 Introduction 97 Shift from antisense to RNAi 98 Ocular diseases 101 Age-related Macular Degeneration (AMD) 101 Key RNAi players 103 Diabetic Retinopathy (DR) 106 Key RNAi players 106 Conclusions 107 Infectious diseases 107 Hepatitis C virus (HCV) 108 Key RNAi players 109 HIV 111 CMV (cytomegalovirus) 112 Key RNAi players 113 Conclusions 113 Respiratory 114 Respiratory Syncytial Virus (RSV) 114 Key RNAi players 114 Asthma 115 Key RNAi players 116 Cystic fibrosis 116 Key RNAi players 116 Conclusions 117 Neurological diseases 118 Huntingdon’s disease (HD) 119 Key RNAi players 120 Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's disease) 120 Key RNAi players 122 Spinal Cord Injury (SCI) 122 Key RNAi players 123 Parkinson's disease (PD) 123 Alzheimer's disease (AD) 124 Pain 125 Conclusions 126 Oncology 127 Angiogenesis 128 Key RNAi players 128 Oncogenes 129 Key RNAi players 129 Drug resistance and enhancement 131 Key RNAi players 132 Conclusions on RNAi in oncology 132 Cardiovascular diseases 132 vi Key RNAi players 133 Conclusions 134 Metabolic disorders 134 Diabetes 134 Key RNAi players 135 The future role of RNAi-based therapeutics 138 Chapter 5 Emerging RNA technologies and future trends 140 Summary 140 Introduction 140 Second generation siRNAs 142 Multifunctional siRNAs 143 Hyperfunctional or superactive siRNAs 143 No-ribose small inhibitory nucleic acids (siNAs) 145 siRNAs conjugated with small molecule drugs 145 Alternative RNA based therapies: 146 Micro RNAs (miRNAs) 146 miRNA processing 147 miRNA in embryonic development 148 miRNA in neurological disorders 149 miRNA in cancer 149 Future direction of miRNA research 149 Small nucleolar RNAs (snoRNAs) 150 Aptamers 151 Chapter 6 Patents and strategic alliances in RNAi technology 154 Summary 154 Introduction 155 Patents for siRNA reagents 156 Patents for siRNA therapeutics 158 Alnylam Pharmaceuticals (Cambridge, MA, US) 160 Patent position 160 Strategic alliances, 2003-2005 161 Benitec Ltd (Queensland, Australia) 163 Patent position 163 Strategic alliances, 2003-2005 164 Sirna Therapeutics (formerly Ribozyme Pharmaceuticals) 165 Patent position 165 vii Strategic alliances, 2003-2005 168 Acuity Pharmaceuticals (Philadelphia, PA, US) 168 Patent position 168 Strategic alliances, 2003-2005 169 Atugen AG (Dresden, Germany) 169 Patent position 169 Strategic alliances, 2003-2005 169 CytRx Labs (Los Angeles, MA, USA) 170 Patent position 171 Strategic alliances, 2003-2005 171 Intradigm (Rockville, MD, USA) 172 Nucleonics Inc. (Horsham, PA, USA) 172 Future impact of IP on RNAi research 173 Chapter 7 RNAi markets and trends 176 Summary 176 Introduction 177 The RNAi market 178 Market size and future trends 180 siRNA synthesis and delivery 182 RNAi reagents 183 RNAi in drug discovery and target validation 184 RNAi therapeutics 185 Chapter 8 Appendix 190 Acknowledgements 190 Index 191 Bibliography 193 Glossary 201 References 205 viii List of Figures Figure 1.1: History of RNAi 22 Figure 1.2: Schematic of DNA, genes and proteins 23 Figure 1.3: Schematic of gene splicing 24 Figure 1.4: Major mechanisms for antisense OGN action 25 Figure 1.5: Mechanism of preventing translation using OGN technology 27 Figure 1.6: Chemical structure of PNA versus DNA 28 Figure 1.7: Chemical structure of LNA versus RNA 29 Figure 1.8: Mechanism of preventing translation using triple helix DNA technology 30 Figure 1.9: Mechanism of preventing translation using ribozymes 31 Figure 1.10: Schematic of the mechanism of gene silencing by RNAi 34 Figure 1.11: Schematic of the mechanism of shRNAs 36 Figure 2.12: Advantages and disadvantages of siRNA synthesis methods 46 Figure 2.13: In vitro transcription of siRNAs 50 Figure 2.14: DICER digestion of dsRNAs 52 Figure 2.15: psiRNA plasmid vector system 53 Figure 2.16: Mechanism of ddRNAi 54 Figure 2.17: Chemical modifications of siRNAs increase stability and PK 57 Figure 2.18: Chol- siRNAs improve tissue uptake and PK 60 Figure 2.19: Intradigm's nano-delivery technology TargeTran 61 Figure 2.20: Summary of viral vector advantages and disadvantages 65 Figure 3.21: The application of TCA in gene expression 77 Figure 3.22: Optimization of lead compounds with siRNAs 82 Figure 3.23: Comparison of gene expression profiles to optimize lead compounds 83 Figure 3.24: Investigation of the intracellular mechanism of Endothelin A receptor 85 Figure 3.25: Schematic of knock-out and knock-down transgenics 87 Figure 3.26: Heritable suppression of Neil-1 in mouse model 88 Figure 3.27: ArteMiceTM RNAi in vivo in 4 months 89 Figure 3.28: Artemis Pharmaceutical timelines for transgenic animals 89 Figure 3.29: Status leptinR knockdown using shRNAs 91 Figure 3.30: Impact of RNAi in R&D 92 Figure 4.31: Antisense drugs currently in clinical development 98 Figure 4.32: RNAi drugs currently in clinical development 100 Figure 4.33: Development of AMD 102 Figure 4.34: siRNA targeting VEGF reduces blood vessel growth in the cornea 103 Figure 4.35: Lead siRNA candidates block HCV replication 109 Figure 4.36: HCV target destruction in mouse liver 110 Figure 4.37: Efficacy of HIV drug in vitro 112 Figure 4.38: In vivo efficacy of direct RNAi for RSV 115 Figure 4.39: Systemic siRNA leads to significant reduction in apolipoproteins 134 Figure 5.40: Conventional RISC silencing pathways and RISC pathway using “On-Target” siRNA reagents 144 Figure 5.41: siRNA RISC process using “On-Target plus” siRNA Reagents 145 Figure 5.42: Schematic representation of aptazyme development 152 Figure 6.43: Key RNA-based companies targeting RNAi reagents 157 Figure 6.44: Key RNA-based companies targeting therapeutic agents 159 Figure 6.45: Sirna Therapeutics’ IP portfolio and therapeutic areas 167 ix Figure 7.46: RNAi market segments, 2004 181 Figure 7.47: Growth in the RNAi market 2004-2010 181 Figure 7.48: Alliances in RNAi R&D 184 Figure 7.49: Potential value of therapy areas targeted by RNAi therapeutics, 2004 & 2010 186 List of Tables Table 1.1: Advantages and disadvantages of OGN technology 26 Table 1.2: Advantages and disadvantages of modified OGNs 29 Table 1.3: Advantages and disadvantages of TFOs 31 Table 1.4: Advantages and disadvantages of ribozymes 32 Table 1.5: Advantages and disadvantages of DNAzymes 32 Table 1.6: Advantages and disadvantages of aptamers 33 Table 1.7: Genes crucial for RNAi in model organisms 35 Table 1.8: Advantages of RNAi 37 Table 1.9: Disadvantages of RNAi 38 Table 2.10: Algorithms available for designing siRNAs 44 Table 2.11: Class of functional RNA molecule 45 Table 2.12: Companies offering siRNA synthesis 48 Table 2.13: Advantages of ddRNAi versus siRNA 55 Table 2.14: Advantages of eiRNA versus siRNAs 56 Table 3.15: Commercial siRNA libraries 79 Table 4.16: Antiviral siRNA targets 108 Table 4.17: RNAi-based targeted therapies 119 Table 4.18: Examples of RNAi targets for neuronal pain 125 Table 4.19: Chemotherapeutic siRNA targets 128 Table 5.20: Animal miRNA genes with genetically assigned functions 147 Table 6.21: RNA patents registered worldwide up to March 2005 155 Table 7.22: Companies involved in RNAi technologies, A-M 179 Table 7.23: Companies involved in RNAi technologies, N-Z 180 Table 7.24: Sales forecasts for total RNAi market, 2004-2015 182 Table 7.25: Sales forecasts for siRNA synthesis and delivery, 2004-2015 183 Table 7.26: Sales forecasts for RNAi reagents, 2004-2015 183 Table 7.27: Sales forecasts for RNAi in drug discovery & target validation, 2004-2015 185 Table 7.28: Sales forecasts for RNAi therapeutics, 2004-2015 187 Table 7.29: Sales forecasts for RNAi therapeutic drugs launched 2010-2015 188 AbstractWhile the human genome project has provided vast amounts of sequence information, the in vivo functional analysis of thousands of genes has presented a significant challenge to researchers and to pharmaceutical companies in the discovery of new drug targets. However, RNAi-based screens have provided new opportunities for the discovery and validation of novel therapeutic targets in several disease areas such as cancer and infectious diseases.Get Full Details About This Report >> |
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