RNAi - Technologies, Markets and Companies

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Feb 01, 2012, 05:42 ET

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RNAi - technologies, markets and companies

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RNA interference (RNAi) or gene silencing involves the use of double stranded RNA (dsRNA). Once inside the cell, this material is processed into short 21-23 nucleotide RNAs termed siRNAs that are used in a sequence-specific manner to recognize and destroy complementary RNA. The report compares RNAi with other antisense approaches using oligonucleotides, aptamers, ribozymes, peptide nucleic acid and locked nucleic acid.

Various RNAi technologies are described, along with design and methods of manufacture of siRNA reagents. These include chemical synthesis by in vitro transcription and use of plasmid or viral vectors. Other approaches to RNAi include DNA-directed RNAi (ddRNAi) that is used to produce dsRNA inside the cell, which is cleaved into siRNA by the action of Dicer, a specific type of RNAse III. MicroRNAs are derived by processing of short hairpins that can inhibit the mRNAs. Expressed interfering RNA (eiRNA) is used to express dsRNA intracellularly from DNA plasmids.

Delivery of therapeutics to the target tissues is an important consideration. siRNAs can be delivered to cells in culture by electroporation or by transfection using plasmid or viral vectors. In vivo delivery of siRNAs can be carried out by injection into tissues or blood vessels or use of synthetic and viral vectors.

Because of its ability to silence any gene once the sequence is known, RNAi has been adopted as the research tool to discriminate gene function. After the genome of an organism is sequenced, RNAi can be designed to target every gene in the genome and target for specific phenotypes. Several methods of gene expression analysis are available and there is still need for sensitive methods of detection of gene expression as a baseline and measurement after gene silencing. RNAi microarray has been devised and can be tailored to meet the needs for high throughput screens for identifying appropriate RNAi probes. RNAi is an important method for analyzing gene function and identifying new drug targets that uses double-stranded RNA to knock down or silence specific genes. With the advent of vector-mediated siRNA delivery methods it is now possible to make transgenic animals that can silence gene expression stably. These technologies point to the usefulness of RNAi for drug discovery.

RNAi can be rationally designed to block the expression of any target gene, including genes for which traditional small molecule inhibitors cannot be found. Areas of therapeutic applications include virus infections, cancer, genetic disorders and neurological diseases. Research at academic centers that is relevant to RNAi-based therapeutics is mentioned.

Regulatory, safety and patent issues are discussed. Side effects can result from unintended interaction between an siRNA compound and an unrelated host gene. If RNAi compounds are designed poorly, there is an increased chance for non-specific interaction with host genes that may cause adverse effects in the host. However, there are no major safety concerns and regulations are in preliminary stages as the clinical trials are still ongoing and there are no marketed products. Many of the patents are still pending.

The markets for RNAi are difficult to define as no RNAi-based product is approved yet but several are in clinical trials. The major use of RNAi reagents is in research but it partially overlaps that of drug discovery and therapeutic development. Various markets relevant to RNAi are analyzed from 2011 to 2021. Markets are also analyzed according to breakdown of technologies and use of siRNAs, miRNAs, etc.

Profiles of 161 companies involved in developing RNAi technologies are presented along with 218 collaborations. They are a mix of companies that supply reagents and technologies (nearly half of all) and companies that use the technologies for drug discovery. Out of these, 33 are developing RNAi-based therapeutics and 30 are involved in microRNAs. The bibliography contains selected 600 publications that are cited in the report. The text is supplemented with 35 tables and 10 figures.

TABLE OF CONTENTS

1. Technologies for suppressing gene function 17

Introduction 17

DNA transcription 17

RNA 17

Non-coding RNA 17

RNA research and potential applications 18

Role of RNA in regulation of the dihydrofolate reductase gene 19

Gene regulation 19

Post-transcriptional regulation of gene expression 20

Alternative RNA splicing 21

Technologies for gene suppression 21

Antisense oligonucleotides 21

Transcription factor decoys 22

Aptamers 22

Ribozymes 23

Aptazymes 23

RNA aptamers vs allosteric ribozymes 24

RNA Lasso 24

Peptide nucleic acid 24

PNA-DNA chimeras 25

Locked nucleic acid 25

Gene silencing 25

Post-transcriptional gene silencing 26

TargeTron? technology for gene knockout 26

Definitions and terminology of RNAi 26

RNAi mechanisms 27

Non-promoter-associated small RNAs 29

Piwi-interacting RNAs in germ cell development 30

Relation of RNAi to junk DNA 30

RNA editing and RNAi 31

Historical landmarks in the development of RNAi 31

2. RNAi Technologies 33

Introduction 33

Comparison of antisense and RNAi 33

Advantages of antisense over siRNAs 33

Advantages of siRNAs over antisense 34

RNA aptamers vs siRNA 34

RNA Lassos versus siRNA 34

Concluding remarks on antisense vs RNAi 35

ssRNAi 35

Antisense vs DNP-ssRNA and DNP-siRNA 35

LNA and RNAi 36

LNA for gene suppression 36

Comparison of LNA and RNAi 37

Use of siLNA to improve siRNA 37

RNAi versus small molecules 37

RNAi in vivo 37

Cre-regulated RNAi in vivo 38

RNAi kits 38

ShortCut™ RNAi Kit 38

HiScribe™ RNAi Transcription Kit 39

pSUPER RNAi system 39

Si2 Silencing Duplex 40

Techniques for measuring RNAi-induced gene silencing 40

Application of PCR in RNAi 40

Real-time quantitative PCR 41

Assessment of the silencing effect of siRNA by RT-PCR 41

Fluorescence resonance energy transfer probe for RNA interactions 42

Bioinformatics tools for design of siRNAs 42

Random siRNA design 42

Rational siRNA design 43

The concept of pooling siRNAs 44

Criteria for rational siRNA design 44

BLOCK-iT RNAi Designer 44

QIAGEN's 2-for-Silencing siRNA Duplexes 45

Designing vector-based siRNA 45

iRNAChek for designing siRNA 45

TROD: T7 RNAi Oligo Designer 45

siDirect: siRNA design software 46

Prediction of efficacy of siRNAs 46

Algorithms for prediction of siRNA efficacy 46

siRNA databases 46

Production of siRNAs 47

Chemical synthesis of short oligonucleotides 47

In vitro transcription 47

Generation of siRNAs in vivo 48

UsiRNAs 48

siRNA:DNA hybrid molecules 49

Chemical modifications of siRNAs 49

Sugar modifications of siRNA 49

Phosphate linkage modifications of siRNA 49

Modifications to the siRNA overhangs 50

Modifications to the duplex architecture 50

Applications of chemical modification of siRNAs 50

Synthetic RNAs vs siRNAs 51

Specificity of siRNAs 51

Asymmetric interfering RNA 52

Genome-wide data sets for the production of esiRNAs 52

ddRNAi for inducing RNAi 52

ddRNAi technology 52

Advantages of ddRNAi over siRNA 53

Short hairpin RNAs 54

siRNA versus shRNA 54

Circular interfering RNA 55

Expressed interfering RNA 56

RNA-induced transcriptional silencing complex 56

Inhibition of gene expression by antigene RNA 57

RNAi vs mRNA modulation by small molecular weight compounds 57

3. MicroRNA 59

Introduction 59

miRNA and RISC 61

Role of the microprocessor complex in miRNA 61

miRNAs compared to siRNAs 62

miRNA and stem cells 63

Influence of miRNA on stem cell formation and maintenance 63

Role of miRNAs in gene regulation during stem cell differentiation 63

miRNA databases 64

Sanger miRBase miRNA sequence database 64

Mapping miRNA genes 64

A database of ultraconserved sequences and miRNA function 65

A database for miRNA deregulation in human disease 65

An database of miRNA-target interactions 66

Role of miRNA in gene regulation 66

Control of gene expression by miRNA 67

miRNA-mediated translational repression involving Piwi 67

Transcriptional regulators of ESCs control of miRNA gene expression 67

Mechanism of miRNAs-induced silencing of gene expression 67

miRNA diagnostics 68

Biochemical approach to identification of miRNA 68

Computational approaches for the identification of miRNAs 69

LNA probes for exploring miRNA 69

Microarrays for analysis of miRNA gene expression 69

Microarrays vs quantitative PCR for measuring miRNAs 70

miRNAs as biomarkers of hepatotoxicity 70

Modification of in situ hybridization for detection of miRNAs 71

Nuclease Protection Assay to measure miRNA expression 71

Real-time PCR for expression profiling of miRNAs 71

Targeting of miRNAs with antisense oligonucleotides 72

Silencing miRNAs by antagomirs 72

New tools for miRNA silencing 72

Use of HAPIscreen for identification of aptamers against pre-miRNAs 73

miRNA-regulated lentiviral vectors 73

miRNAs as drug targets 73

miRNAs as targets for antisense drugs 74

Challenges facing use of miRNAs as drug targets 74

Target specificity of miRNAs 75

Prediction of miRNA targets 75

Role of miRNA in human health and disease 76

Role of miRNAs in regulation of hematopoiesis 76

Role of miRNA depletion in tissue regeneration 76

Role of miRNA in regulation of aging 77

Role of miRNA in inflammation 77

Role of miRNAs in regulation of immune system 77

Role of miRNA in the cardiovascular system 78

Role of miRNAs in development of the cardiovascular system 78

Role of miRNAs in angiogenesis 78

Role of miRNAs in cardiac hypertrophy and failure 78

Role of miRNAs in conduction and rhythm disorders of the heart 79

Diagnostic and prognostic value of miRNAs in acute coronary syndrome 79

miRNA-based approaches for reduction of hypercholesterolemia 80

miRNA-based approach for restenosis following angioplasty 80

miRNA gene therapy for ischemic heart disease 80

miRNAs as therapeutic targets for cardiovascular diseases 81

Concluding remarks and future prospects of miRNA in the cardiovascular system 81

Role of miRNAs in the nervous system 81

miRNAs and addiction 82

miRNAs in neurodegenerative disorders 82

miRNAs as biomarkers of Alzheimer's disease 83

miRNAs in Huntington's disease 83

miRNA malfunction in spinal motor neuron disease 83

miRNAs and retinal neurodegenerative disorders 84

miRNA and schizophrenia 84

Role of miRNA in viral infections 84

Role of miRNA in HSV-1 latency 84

miRNA and autoimmune disorders 85

miRNA in rheumatoid arthritis 85

miRNA in systemic lupus erythematosus 85

miRNAs in gastrointestinal disorders 86

miRNA-based therapies for the irritable bowel syndrome 86

miRNA and skin disorders 86

Role of miRNA in inflammatory skin disorders 86

Role of miRNAs in cancer 86

miRNAs linked to the initiation and progression of cancer 86

Oncomirs 87

Linking miRNA sequences to cancer using RNA samples 88

Role of miRNAs in viral oncogenesis 88

miRNA genes in cancer 88

miRNAs interaction with p53 89

miRNAs, embryonic stem cells and cancer 89

miRNAs and cancer metastases 90

Role of miRNAs in cancer diagnosis 91

Cancer miRNA signature 91

miRNA biomarkers in cancer 91

Diagnostic value of miRNA in cancer 92

Prognostic value of miRNA in cancer 92

miRNAs as basis of cancer therapeutics 92

Antisense oligonucleotides targeted to miRNA 92

Delivery of miRNA mimetics in Cancer 93

Role of miRNAs in adoptive immunotherapy of cancer 93

Restoration of tumor suppressor miRNA may inhibit cancer 93

Role of miRNAs in various cancers 94

miRNA and brain cancer 94

miRNA and breast cancer 95

miRNA and colorectal cancer 95

miRNA and gastrointestinal cancer 95

miRNA and hematological malignancies 96

miRNA and hepatocellular carcinoma 97

miRNA and lung cancer 97

miRNA and nasopharyngeal carcinoma 98

miRNA and ovarian cancer 99

miRNA and pancreatic cancer 99

miRNA and prostatic cancer 100

miRNA and thyroid cancer 100

Future prospects of miRNA therapeutics 101

Companies involved in miRNA 101

4. Methods of delivery in RNAi 105

Introduction 105

Methods of delivery of oligonucleotides 105

Oral and rectal administration 106

Pulmonary administration 106

Targeted delivery to the CNS 106

High flow microinfusion into the brain parenchyma 107

Intracellular guidance by special techniques 107

Biochemical microinjection 108

Liposomes-mediated oligonucleotide delivery 108

Polyethylenimine-mediated oligonucleotide delivery 108

Delivery of TF Decoys 108

Biodegradable microparticles 109

Microparticles 109

Nanoparticles 109

Self-delivering rxRNA 109

siRNA delivery technologies 110

Local delivery of siRNA 111

In vivo delivery of siRNAs by synthetic vectors 111

Intracellular delivery of siRNAs 111

Delivery of siRNAs with aptamer-siRNA chimeras 112

MPG-based delivery of siRNA 112

Nanoparticles for intracellular delivery of siRNA 112

Protamine-antibody fusion proteins for delivery of siRNA to cells 112

Protein transduction domains 113

Phosphorothioate stimulated cellular delivery of siRNA 113

Targeted delivery of siRNAs by lipid-based technologies 113

Delivery of siRNA-lipoplexes 114

Lipidoids for delivery of siRNAs 114

NeoLipid™ technology 115

siFECTamine? 115

Systemic in vivo delivery of lipophilic siRNAs 115

Systemic delivery of siRNAi by lipid nanoparticles 115

Challenges and future prospects of lipid-based siRNA delivery 116

Electroporation 116

Nucleofactor technology 117

Visualization of electrotransfer of siRNA at single cell level 117

Intravascular delivery of siRNA 117

27mer siRNA duplexes for improved delivery and potency 118

TransIT-TKO? 118

DNA-based plasmids for delivery of siRNA 119

Convergent transcription 120

PCR cassettes expressing siRNAs 120

Genetically engineered bacteria for delivery of shRNA 120

Viral vectors for delivery of siRNA 120

Adenoviral vectors 120

Adeno-associated virus vectors for shRNA expression 121

Baculovirus vector 121

Lentiviral vectors 122

Retroviral delivery of siRNA 123

Transkingdom RNAi delivery by genetically engineered bacteria 123

Delivery of siRNA without a vector 123

Cell-penetrating peptides for delivery of siRNAs 124

Role of nanobiotechnology in siRNA delivery 124

Chitosan-coated nanoparticles for siRNA delivery 124

Cyclodextrin nanoparticles 125

Delivery of gold nanorod-siRNA nanoplex to dopaminergic neurons 125

Lipidic aminoglycoside as siRNA nanocarrier 125

Lipid nanoparticles-mediated siRNA delivery 125

Nanosize liposomes for delivery of siRNA 126

PAMAM dendrimers for siRNA delivery 126

Polyethylenimine nanoparticles for siRNA delivery 127

Polycation-based nanoparticles for siRNA delivery 127

Quantum dots to monitor siRNA delivery 128

Targeted delivery of siRNAs to specific organs 128

siRNA delivery to the CNS 128

siRNA delivery to the liver 129

siRNA delivery to the lungs 129

Control of RNAi and siRNA levels 130

siRNA pharmacokinetics in mammalian cells 130

Mathematical modeling for determining the dosing schedule of siRNA 131

Assessing siRNA pharmacodynamics in animal models 131

Research on siRNA delivery funded by the NIH 131

Companies involved in delivery technologies for siRNA 132

5. RNAi in Research 135

Introduction 135

Basic RNAi research 135

Antiviral role of RNAi in animal cells 135

Combination of siRNA with green fluorescent protein 135

Detection of cancer mutations 136

Genes and lifespan 136

Inducible and reversible RNAi 136

Loss-of-function genetic screens 136

Profiling small RNAs 137

RNAi for research in neuroscience 137

RNAi and environmental research 138

Silencing snoRNA genes 138

Study of signaling pathways 138

Transgenic RNAi 139

Use of RNAi to study insulin action 139

Applied RNAi research 139

RNAi for gene expression studies 139

Microarrays for measuring gene expression in RNAi 139

RNAi for functional genomic analysis 140

RNAi studies on C. elegans 140

RNAi studies on Drosophila 141

RNAi in planaria 142

Testing the specificity of RNAi 142

Tissue-specific RNAi 142

siRNA-mediated gene silencing 143

RNAi libraries 143

Universal plasmid siRNA library 144

pDual library using plasmid vector 144

pHippy plasmid vector library 145

siRNA libary including miRNAs 145

siRNA libraries using pRetroSuper vector 145

siRNA produced by enzymatic engineering of DNA 145

shRNA libraries 146

Enzymatic production of RNAi library 147

RNAi and alternative splicing 147

RNAi in animal development 147

RNAi for creating transgenic animals 148

RNAi for creating models of neurological disorders 148

Research support for RNAi in US 149

RNAi for toxicogenomics 149

Role of RNAi in the US biodefense research 149

The RNAi Consortium 149

Research support for RNAi in Europe 150

European Union for RNA Interference Technology 150

Research support of RNAi 151

Role of RNAi in MitoCheck project 151

RNAi Global Initiative 152

SIROCCO project 153

6. RNAi in drug discovery 155

Basis of RNAi for drug discovery 155

RNAi for identification of genes as therapeutic targets 155

Role of siRNAs in drug target identification 156

Use of a genome-wide, siRNA library for drug discovery 156

Use of arrayed adenoviral siRNA libraries for drug discovery 156

RNAi as a tool for assay development 157

Targeting human kinases with an siRNAi library 157

Challenges of drug discovery with RNAi 157

Express TrackSM siRNA Drug Discovery Program 158

Genome-wide siRNA screens in mammalian cells 158

PhenomicID™ 158

Natural antisense and ncRNA as drug targets 159

RNAi for target validation 159

Delivering siRNA for target validation in vivo 159

Off-target effects of siRNA-mediated gene silencing 161

Bioinformatic approach to off-target effects 162

Validation of oncology targets discovered through RNAi screens 162

Selection of siRNA versus shRNA for target validation 163

Application of RNAi to the druggable genome 163

Application of siRNA during preclinical drug development 163

siRNAs vs small molecules as drugs 164

siRNAs vs antisense drugs 164

RNAi technology in plants for drug discovery and development 165

Application of RNAi to poppy plant as source of new drugs 165

7. Therapeutic applications of RNAi 167

Introduction 167

Potential of RNAi-based therapies 168

In vitro applications of siRNA 168

In vivo applications of RNAi 169

RNAi and cell therapy 169

Gene inactivation to study hESCs 170

RNAi and stem cells 170

Cell therapy for immune disorders 171

RNAi gene therapy 171

Drug-inducible systems for control of gene expression 171

Potential side effects of RNAi gene therapy 172

Systemic delivery of siRNAs 172

In vivo RNAi therapeutic efficacy in animal models of human diseases 173

Virus infections 173

RNAi approaches to viral infections 174

Delivery of siRNAs in viral infections 175

RNAi applications in HIV 175

A multiple shRNA approach for silencing of HIV-1 176

Anti-HIV shRNA for AIDS lymphoma 176

Aptamer-mediated delivery of anti-HIV siRNAs 176

Bispecific siRNA constructs 176

Role of the nef gene during HIV-1 infection and RNAi 177

siRNA-directed inhibition of HIV-1 infection 177

Synergistic effect of snRNA and siRNA 178

Targeting CXCR4 with siRNAs 178

Targeting CCR5 with siRNAs 178

Concluding remarks on RNAi approach to HIV/AIDS 179

Influenza 179

Inhibition of influenza virus by siRNAs 180

Delivery of siRNA in influenza 181

Challenges and future prospects of siRNAs for influenza 181

Respiratory syncytial and parainfluenza viruses 182

Coronavirus/severe acute respiratory syndrome 183

Herpes simplex virus 2 183

Hepatitis B 183

Hepatitis C virus 184

Cytomegalovirus 186

Ebola virus 186

siRNA vs antisense oligonucleotides for viral infections 186

siRNA against methicillin-resistant S. aureus 187

RNAi-based rational approach to antimalarial drug discovery 187

Inhibiting the growth of malarial parasite by heme-binding DNA aptamers 187

siRNA-based antimalarial therapeutics 188

RNAi applications in oncology 188

Allele-specific inhibition 189

Drug delivery issues in managing cancer by RNAi approach 189

Inhibition of oncogenes 190

Modification of alternative splicing in cancer 191

Onconase 191

Overcoming drug resistance in cancer 192

Targeting fusion proteins in cancer 193

Increasing chemosensitivity by RNAi 193

RNAi approach to study TRAIL 193

RNAi-based logic circuit for identification of specific cancer cells 194

siRNAs for anticancer drug discovery 194

siRNAs for inducing cancer immunity 195

siRNAs for inhibition of angiogenesis 195

siRNA targeting the R2 subunit of ribonucleotide reductase 196

siRNA for cancer chemoprevention 196

siHybrids vs siRNAs as anticancer agents 196

Nanobiotechnology-based delivery of siRNAs 197

Lipid nanoparticle-based delivery of anticancer siRNAs 197

Minicells for targeted delivery of nanoscale anticancer therapeutics 197

Nanoimmunoliposome-based system for targeted delivery of siRNA 198

Polymer nanoparticles for targeted delivery of anticancer siRNA 198

RNA nanotechnology for delivery of cancer therapeutics 199

Targeted delivery of a nanoparticle-siRNA complex in cancer patients 199

RNAi-based treatment of various cancer types 200

RNAi-based therapy of brain cancer 200

RNAi in breast cancer 201

RNAi for enhancing hyperthermia/chemotherapy in cervical cancer 202

RNAi and colorectal cancer 202

RNAi and Ewing's sarcoma 203

RNAi and leukemias 203

RNAi and lung cancer 204

RNAi and melanoma 204

RNAi and pancreatic cancer 205

RNAi and prostate cancer 205

Genetic disorders 205

RNAi for skin disorders 206

Experimental studies for RNAi applications in skin disorders 206

Clinical applications of RNAi in skin disorders 207

Pachyonychia congenita 207

Neurological disorders 207

RNAi for neurodegenerative disorders 208

Alzheimer's disease 209

Parkinson's disease 209

Amyotrophic lateral sclerosis 210

Prion diseases 211

Polyglutamine-induced neurodegeneration 211

Fragile X syndrome and RNAi 212

RNAi-based therapy for Huntington's disease 212

Combination of RNAi and gene therapy to prevent neurodegenerative disease 213

Role of RNAi in pain therapy 214

Role of RNAi in repair of spinal cord injury 214

Role of RNAi in treatment of multiple sclerosis 215

siRNA for Duchenne muscular dystrophy 215

siRNA for dystonia 215

RNAi in ophthalmology 216

Age related macular degeneration 216

Current treatment of AMD 216

RNAi-based treatments for AMD 217

Diabetic retinopathy 218

Retinitis pigmentosa 219

RNAi and metabolic disorders 219

RNAi and obesity 220

Genes and regulation of body fat 220

RNAi and diabetes 220

Regulation of insulin secretion by a miRNA 220

RNAi for study of genes in animal models of diabetes 221

RNAi for drug discovery in diabetes 221

RNAi for treating liver dysfunction in diabetes 222

siRNAs for study of glucose transporter 222

siRNAs for targeting adipose inflammation in diabetes and obesity 223

RNAi in hematology 223

Stem cell-based gene therapy and RNAi for sickle cell disease 223

RNAi and disorders of the immune system 224

siRNA applications in immunology 224

Use of RNAi in transplantation 225

RNAi for cardiovascular disorders 225

RNAi for hypercholesterolemia 226

siRNA targeting NADPH oxidase in cardiovascular diseases 226

siRNA for study and treatment of ischemia-reperfusion injury 227

RNAi in respiratory disorders 227

siRNA for cystic fibrosis 227

siRNA for asthma 228

RNAi for musculoskeletal disorders 228

RNAi for rheumatoid arthritis 228

RNAi for bone disorders 229

RNAi for treatment of osteoporosis 229

Research relevant to RNAi-based therapies at academic institutes 230

Laboratory of RNA Molecular Biology, The Rockefeller University 230

RNAi Center, La Jolla Institute for Allergy & Immunology 230

Clinical trials of RNAi-based therapies 231

Improving efficacy of siRNAs for clinical trials by improved delivery 232

Role of RNAi in development of personalized medicine 232

Future prospects of RNAi 233

Challenges for the development of RNAi-based therapeutics 233

8. Safety, regulatory and patent issues 235

Introduction 235

Limitations and drawbacks of RNAi 235

Adverse effects of RNAi 235

Effect of siRNAs on interferon response 236

Detection of interferon response 236

Prevention of the interferon response in RNAi 237

Overcoming the innate immune response to siRNAs 237

Toxicity associated with RNAi 238

Selection of siRNAs to improve specificity and efficacy 238

Regulatory issues relevant to RNAi 238

RNAi patents 239

Companies with strong patent position 239

Alnylam 239

Benitec 242

Intradigm 242

Quark Pharmaceuticals 242

Sirna Therapeutics 243

9. Markets for RNAi Technologies 245

Introduction 245

Current and future market potential for RNAi technologies 245

RNAi reagents 246

siRNA markets 246

RNAi-based drug discovery and target validation 246

RNAi-based development of therapeutics 246

RNAi market potential according to therapeutic areas 247

Market for viral infections 247

Market for cancer 248

Market for age related macular degeneration 248

Unmet needs in RNAi 248

Strategies for marketing RNAi 249

Choosing optimal indications 249

Strategies according to the trends in healthcare in the next decade 250

Concluding remarks 251

10. Companies involved in RNAi Technologies 253

Introduction 253

Major players in RNAi 256

Profiles of companies 257

Collaborations 445

11. References 453

List of Tables

Table 1 1: Classification of small RNA molecules 27Table 1 2: Mechanisms of small RNAs involved in gene silencing 28Table 1 3: Historical landmarks in the evolution of RNAi 31Table 2 1: RNAi versus small molecules 37Table 2 2: Providers of software for siRNA design 43Table 2 3: Methods for the production of siRNAs 47Table 2 4: Advantages and limitations of methods of shRNA-derived siRNA knockdown 55Table 2 5: Comparison of eiRNA with siRNA 56Table 3 1: Methods for miRNA target prediction 75Table 3 2: miRNA expression in neurodegenerative diseases 82Table 3 3: Dysregulation of miRNA expression in epithelial cancers 87Table 3 4: Companies involved in miRNA diagnostics and therapeutics 101Table 4 1: Methods of delivery of oligonucleotides 105Table 4 2: Methods of delivery of siRNA 110Table 4 3: Companies developing siRNA delivery technologies 133Table 5 1: RNAi libraries 143Table 6 1: Delivery of siRNAs in vivo for target validation 160Table 6 2: Selection of siRNA versus shRNA for target validation 163Table 7 1: RNAi-based therapeutic approaches 168Table 7 2: In vivo RNAi therapeutic efficacy in animal models of human diseases 173Table 7 3: Inhibition of viral replication by RNAi 174Table 7 4: Cancer-associated genes that can be targeted by RNAi 190Table 7 5: Neurological disorders that have been studied by using RNAi 208Table 7 6: Clinical trials of RNAi-based therapeutics 231Table 9 1: RNAi markets according to technologies and reagents 2011-2021 245Table 9 2: Markets for RNAi therapy for selected diseases: years 2011-2021 247Table 10 1: RNAi reagent, technology and service companies 253Table 10 2: Pharmaceutical companies using RNAi for drug discovery and development 254Table 10 3: Biotechnology companies using RNAi for drug discovery and development 255Table 10 4: Companies developing RNAi-based therapeutic products 256Table 10 5: Major players in RNAi 256Table 10 6: RNAi products of Benitec 277Table 10 7: Proprietary reagents of ImuThes 332Table 10 8: Product pipeline of Silence Therapeutics 414Table 10 9: Collaborations in RNAi technologies 445

List of Figures

Figure 1 1: Relationship of DNA, RNA and protein in the cell 20

Figure 1 2: Schematic of suppression of gene expression by RNAi 28

Figure 2 1: Overview of ShortCut RNAi Kit 39

Figure 2 2: Gene silencing by RNAi induced with ddRNAi 53

Figure 3 1: A schematic miRNA pathway 59

Figure 3 2: Molecular mechanisms of miRNA generation 60

Figure 7 1: Targeting disease by RNAi 167

Figure 7 2: Role of RNAi in personalized medicine 233

Figure 8 1: Problems with use of synthetic siRNAs and measures to prevent them 236

Figure 9 1: Unmet needs in RNAi technologies 249

To order this report:Biological Therapy Industry: RNAi - technologies, markets and companies