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RNAi - Technologies, Markets and Companies
Jain PharmaBiotech, Nov 2009, Pages: 451
Executive Summary
1. Technologies for suppressing gene function
Introduction
DNA transcription
RNA
Non-coding RNA
RNA research and potential applications
Role of RNA in regulation of the dihydrofolate reductase gene
Gene regulation
Post-transcriptional regulation of gene expression
Alternative RNA splicing
Technologies for gene suppression
Antisense oligonucleotides
Transcription factor decoys
Aptamers
Ribozymes
Aptazymes
RNA aptamers vs allosteric ribozymes
RNA Lasso
Peptide nucleic acid
PNA-DNA chimeras
Locked nucleic acid
Gene silencing
Post-transcriptional gene silencing
TargeTronÔ technology for gene knockout
Definitions and terminology of RNAi
RNAi mechanisms
Non-promoter-associated small RNAs
Piwi-interacting RNAs in germ cell development
Relation of RNAi to junk DNA
RNA editing and RNAi
Historical landmarks in the development of RNAi
2. RNAi Technologies
Introduction
Comparison of antisense and RNAi
Advantages of antisense over siRNAs
Advantages of siRNAs over antisense
RNA aptamers vs siRNA
RNA Lassos versus siRNA
Concluding remarks on antisense vs RNAi
Antisense vs DNP-ssRNA and DNP-siRNA
LNA and RNAi
LNA for gene suppression
Comparison of LNA and RNAi
Use of siLNA to improve siRNA
RNAi versus small molecules
RNAi in vivo
Cre-regulated RNAi in vivo
RNAi kits
ShortCut™ RNAi Kit
HiScribe™ RNAi Transcription Kit
pSUPER RNAi system
Si2 Silencing Duplex
Techniques for measuring RNAi-induced gene silencing
Application of PCR in RNAi
Real-time quantitative PCR
Assessment of the silencing effect of siRNA by RT-PCR
Bioinformatics tools for design of siRNAs
Random siRNA design
Rational siRNA design
The concept of pooling siRNAs
Criteria for rational siRNA design
BLOCK-iT RNAi Designer
QIAGEN's 2-for-Silencing siRNA Duplexes
Designing vector-based siRNA
iRNAChek for designing siRNA
TROD: T7 RNAi Oligo Designer
siDirect: siRNA design software
Prediction of efficacy of siRNAs
Algorithms for prediction of siRNA efficacy
siRNA databases
Production of siRNAs
Chemical synthesis of short oligonucleotides
In vitro transcription
Generation of siRNA in vivo
siRNA:DNA hybrid molecules
Chemical modifications of siRNAs
Sugar modifications of siRNA
Phosphate linkage modifications of siRNA
Modifications to the siRNA overhangs
Modifications to the duplex architecture
Applications of chemical modification of siRNAs
Synthetic RNAs vs siRNAs
Specificity of siRNAs
Asymmetric interfering RNA
Genome-wide data sets for the production of esiRNAs
ddRNAi for inducing RNAi
ddRNAi technology
Advantages of ddRNAi over siRNA
Short hairpin RNAs
siRNA versus shRNA
Expressed interfering RNA
RNA-induced transcriptional silencing complex
Inhibition of gene expression by antigene RNA
RNAi vs mRNA modulation by small molecular weight compounds
3. MicroRNA
Introduction
miRNA and RISC
Role of the microprocessor complex in miRNA
miRNAs compared to siRNAs
miRNA and stem cells
Influence of miRNA on stem cell formation and maintenance
Role of miRNAs in gene regulation during stem cell differentiation
miRNA databases
Sanger miRBase miRNA sequence database
Mapping miRNA genes
A database of ultraconserved sequences and miRNA function
A database for miRNA deregulation in human disease
An database of miRNA-target interactions
Role of miRNA in gene regulation
Control of gene expression by miRNA
miRNA-mediated translational repression involving Piwi
Transcriptional regulators of ESCs control of miRNA gene expression
Mechanism of miRNAs-induced silencing of gene expression
miRNA diagnostics
Biochemical approach to identification of miRNA
Computational approaches for the identification of miRNAs
LNA probes for exploring miRNA
Microarrays for analysis of miRNA gene expression
Microarrays vs quantitative PCR for measuring miRNAs
miRNAs as biomarkers of hepatotoxicity
Modification of in situ hybridization for detection of miRNAs
Nuclease Protection Assay to measure miRNA expression
Real-time PCR for expression profiling of miRNAs
Targeting of miRNAs with antisense oligonucleotides
Silencing miRNAs by antagomirs
miRNA-regulated lentiviral vectors
miRNAs as drug targets
miRNAs as targets for antisense drugs
Challenges facing use of miRNAs as drug targets
Target specificity of miRNAs
Prediction of miRNA targets
Role of miRNA in human health and disease
Role of miRNAs in regulation of hematopoiesis
Role of miRNA depletion in tissue regeneration
Role of miRNA in regulation of aging
Role of miRNA in inflammation
Role of miRNAs in regulation of immune system
Role of miRNA in the cardiovascular system
Role of miRNAs in development of the cardiovascular system
Role of miRNAs in angiogenesis
Role of miRNAs in cardiac hypertrophy and failure
Role of miRNAs in conduction and rhythm disorders of the heart
miRNA-based approach for reduction of hypercholesterolemia
miRNA-based approach for restenosis following angioplasty
miRNAs as therapeutic targets for cardiovascular diseases
Concluding remarks and future prospects of miRNA in the cardiovascular system
Role of miRNAs in the nervous system
miRNAs as biomarkers of Alzheimer’s disease
miRNA and schizophrenia
miRNAs and retinal neurodegenerative disorders
Role of miRNA in viral infections
Role of miRNA in HSV-1 latency
miRNA and autoimmune disorders
miRNA in systemic lupus erythematosus
miRNA and skin disorders
Role of miRNA in inflammatory skin disorders
Role of miRNAs in cancer
Linking miRNA sequences to cancer using RNA samples
Role of miRNAs in viral oncogenesis
miRNA genes in cancer
miRNAs, embryonic stem cells and cancer
miRNAs and cancer metastases
Role of miRNAs in cancer diagnosis
Cancer miRNA signature
miRNA biomarkers in cancer
Diagnostic value of miRNA in cancer
miRNAs as basis of cancer therapeutics
Antisense oligonucleotides targeted to miRNA
Role of miRNAs in adoptive immunotherapy of cancer
Restoration of tumor suppressor miRNA may inhibit cancer
Role of miRNAs in various cancers
miRNA and brain cancer
miRNA and breast cancer
miRNA and colorectal cancer
miRNA and hematological malignancies
miRNA and hepatocellular carcinoma
miRNA and lung cancer
miRNA and nasopharyngeal carcinoma
miRNA and ovarian cancer
miRNA and pancreatic cancer
miRNA and prostatic cancer
miRNA and thyroid cancer
Future prospects of miRNA
Companies involved in miRNA
4. Methods of delivery in RNAi
Introduction
Methods of delivery of oligonucleotides
Oral and rectal administration
Pulmonary administration
Targeted delivery to the CNS
High flow microinfusion into the brain parenchyma
Intracellular guidance by special techniques
Biochemical microinjection
Liposomes-mediated oligonucleotide delivery
Polyethylenimine-mediated oligonucleotide delivery
Delivery of TF Decoys
Biodegradable microparticles
Microparticles
Nanoparticles
siRNA delivery technologies
Local delivery of siRNA
In vivo delivery of siRNAs by synthetic vectors
Intracellular delivery of siRNAs
Protamine-antibody fusion proteins for delivery of siRNA to cells
Protein transduction domains
MPG-based delivery of siRNA
Delivery of siRNAs with aptamer-siRNA chimeras
Phosphorothioate stimulated cellular delivery of siRNA
Targeted delivery of siRNAs by lipid-based technologies
Systemic in vivo delivery of lipophilic siRNAs
NeoLipid™ technology
siFECTamineÔ
Delivery of siRNA-lipoplexes
Lipidoids for delivery of siRNAs
Electroporation
Nucleofactor technology
Intravascular delivery of siRNA
27mer siRNA duplexes for improved delivery and potency
TransIT-TKOÒ
DNA-based plasmids for delivery of siRNA
Convergent transcription
PCR cassettes expressing siRNAs
Genetically engineered bacteria for delivery of shRNA
Viral vectors for delivery of siRNA
Adenoviral vectors
Adeno-associated virus vectors for shRNA expression
Baculovirus vector
Lentiviral vectors
Retroviral delivery of siRNA
Transkingdom RNAi delivery by genetically engineered bacteria
Delivery of siRNA without a vector
Cell-penetrating peptides for delivery of siRNAs
Role of nanobiotechnology in siRNA delivery
Chitosan-coated nanoparticles for siRNA delivery
Delivery of gold nanorod-siRNA nanoplex to dopaminergic neurons
Lipidic aminoglycoside as siRNA nanocarrier
Lipid nanoparticles-mediated siRNA delivery
Nanosize liposomes for delivery of siRNA
PAMAM dendrimers for siRNA delivery
Polyethylenimine nanoparticles for siRNA delivery
Polycation-based nanoparticles for siRNA delivery
Quantum dots to monitor siRNA delivery
Targeted delivery of siRNAs to specific organs
siRNA delivery to the CNS
siRNA delivery to the liver
siRNAdelivery to the lungs
Control of RNAi and siRNA levels
siRNA pharmacokinetics in mammalian cells
Mathematical modeling for determining the dosing schedule of siRNA
Assessing siRNA pharmacodynamics in animal models
Research on siRNA delivery funded by the NIH
Companies involved in delivery technologies for siRNA
5. RNAi in Research
Introduction
Basic RNAi research
Genes and lifespan
Antiviral role of RNAi in animal cells
Silencing snoRNA genes
Profiling small RNAs
Study of signaling pathways
RNAi for research in neuroscience
Use of RNAi to study insulin action
Detection of cancer mutations
Loss-of-function genetic screens
Inducible and reversible RNAi
Combination of siRNA with green fluorescent protein
RNAi and environmental research
Applied RNAi research
RNAi for gene expression studies
Microarrays for measuring gene expression in RNAi
RNAi for functional genomic analysis
RNAi studies on C. elegans
RNAi studies on Drosophila
RNAi in planaria
Testing the specificity of RNAi
Tissue-specific RNAi
siRNA-mediated gene silencing
RNAi libraries
Universal plasmid siRNA library
pDual library using plasmid vector
pHippy plasmid vector library
siRNA libary including miRNAs
siRNA libraries using pRetroSuper vector
siRNA produced by enzymatic engineering of DNA
shRNA libraries
Enzymatic production of RNAi library
RNAi and alternative splicing
RNAi in animal development
RNAi for creating transgenic animals
RNAi for creating models of neurological disorders
Research support for RNAi in US
RNAi for toxicogenomics
Role of RNAi in the US biodefense research
The RNAi Consortium
Research support for RNAi in Europe
European Union for RNA Interference Technology
Research support of RNAi
Role of RNAi in MitoCheck project
Genome-Wide RNAi Global Initiative
6. RNAi in drug discovery
Basis of RNAi for drug discovery
Use of siRNA libraries to identify genes as therapeutic targets
Role of siRNAs in drug target identification
Use of a genome-wide, siRNA library for drug discovery
Use of arrayed adenoviral siRNA libraries for drug discovery
RNAi as a tool for assay development
Targeting human kinases with an siRNAi library
Challenges of drug discovery with RNAi
Express TrackSM siRNA Drug Discovery Program
Genome-wide siRNA screens in mammalian cells
Natural antisense and ncRNA as drug targets
RNAi for target validation
Delivering siRNA for target validation in vivo
Off-target effects of siRNA-mediated gene silencing
Bioinformatic approach to off-target effects
Validation of oncology targets discovered through RNAi screens
Selection of siRNA versus shRNA for target validation
Application of RNAi to the druggable genome
Application of siRNA during preclinical drug development
siRNAs vs small molecules as drugs
siRNAs vs antisense drugs
RNAi technology in plants for drug discovery and development
Application of RNAi to poppy plant as source of new drugs
7. Therapeutic applications of RNAi
Introduction
Potential of RNAi-based therapies
In vitro applications of siRNA
In vivo applications of RNAi
RNAi and cell therapy
Gene inactivation to study hESCs
RNAi and stem cells
Cell therapy for immune disorders
RNAi gene therapy
Drug-inducible systems for control of gene expression
Potential side effects of RNAi gene therapy
Systemic delivery of siRNAs
In vivo RNAi therapeutic efficacy in animal models of human diseases
Virus infections
RNAi approaches to viral infections
Delivery of siRNAs in viral infections
RNAi applications in HIV
Anti-HIV shRNA for AIDS lymphoma
Aptamer-mediated delivery of anti-HIV siRNAs
Bispecific siRNA constructs
Role of the nef gene during HIV-1 infection and RNAi
siRNA-directed inhibition of HIV-1 infection
Synergistic effect of snRNA and siRNA
Targeting CXCR4 with siRNAs
Targeting CCR5 with siRNAs
Concluding remarks on RNAi approach to HIV/AIDS
Influenza
Inhibition of influenza virus by siRNAs
Delivery of siRNA in influenza
Challenges and future prospects of siRNAs for influenza
Respiratory syncytial and parainfluenza viruses
Coronavirus/severe acute respiratory syndrome
Herpes simplex virus 2
Hepatitis B
Hepatitis C virus
Cytomegalovirus
siRNA vs antisense oligonucleotides for viral infections
siRNA against methicillin-resistant S. aureus
RNAi-based rational approach to antimalarial drug discovery
Inhibiting the growth of malarial parasite by heme-binding DNA aptamers
siRNA-based antimalarial therapeutics
RNAi applications in oncology
Inhibition of oncogenes
RNAi approach to study TRAIL
Modification of alternative splicing in cancer
Allele-specific inhibition
siRNAs for anticancer drug discovery
siRNAs for inhibition of angiogenesis
siRNA targeting the R2 subunit of ribonucleotide reductase
siRNA for cancer chemoprevention
Onconase
Drug delivery issues in managing cancer by RNAi approach
siHybrids vs siRNAs as anticancer agents
Nanobiotechnology-based delivery of siRNAs
Lipid nanoparticle-based delivery of anticancer siRNAs
Minicells for targeted delivery of nanoscale anticancer therapeutics
Nanoimmunoliposome-based system for targeted delivery of siRNA
Polymer nanoparticles for targeted delivery of anticancer siRNA
RNA nanotechnology for delivery of cancer therapeutics
RNAi-based treatment of various cancer types
RNAi-based therapy of brain cancer
RNAi in breast cancer
Enhancing efficacy of hyperthermia/chemotherapy in cervical cancer
RNAi and colorectal cancer
RNAi and Ewing’s sarcoma
RNAi and leukemias
RNAi and lung cancer
RNAi and melanoma
RNAi and pancreatic cancer
RNAi and prostate cancer
Overcoming drug resistance in cancer
Targeting fusion proteins in cancer
Increasing chemosensitivity by RNAi
Genetic disorders
Pachyonychia congenita
Neurological disorders
RNAi for neurodegenerative disorders
Alzheimer's disease
Parkinson's disease
Amyotrophic lateral sclerosis
Prion diseases
Polyglutamine-induced neurodegeneration
Fragile X syndrome and RNAi
RNAi-based therapy for Huntington's disease
Combination of RNAi and gene therapy to prevent neurodegenerative disease
siRNA for relief of neuropathic pain
siRNA for dystonia
Role of RNAi in repair of spinal cord injury
Role of RNAi in treatment of multiple sclerosis
siRNA for Duchenne muscular dystrophy
RNAi in ophthalmology
Age related macular degeneration
Current treatment of AMD
RNAi-based treatments for AMD
Diabetic retinopathy
Retinitis pigmentosa
RNAi and metabolic disorders
RNAi and obesity
Genes and regulation of body fat
RNAi and diabetes
Use of siRNAs to study glucose transporter
Use of RNAi to study genes in animal models of diabetes
RNAi for drug discovery in diabetes
A miRNA that regulates insulin secretion
RNAi in hematology
Stem cell-based gene therapy and RNAi for sickle cell disease
RNAi and disorders of the immune system
siRNA applications in immunology
Use of RNAi in transplantation
RNAi for cardiovascular disorders
RNAi for hypercholesterolemia
siRNA targeting NADPH oxidase in cardiovascular diseases
siRNA for study and treatment of ischemia-reperfusion injury
RNAi in respiratory disorders
siRNA for cystic fibrosis
siRNA for asthma
RNAi for musculoskeletal disorders
RNAi for rheumatoid arthritis
RNAi for bone disorders
Future prospects of RNAi
Clinical trials of RNAi-based therapies
Improving efficacy of siRNAs for clinical trials by improved delivery
Role of RNAi in development of personalized medicine
Challenges for the development of RNAi-based therapeutics
8. Safety, regulatory and patent issues
Introduction
Limitations and drawbacks of RNAi
Adverse effects of RNAi
Effect of siRNAs on interferon response
Detection of interferon response
Prevention of the interferon response in RNAi
Overcoming the innate immune response to siRNAs
Regulatory issues relevant to RNAi
RNAi patents
Companies with strong patent position
Alnylam
Benitec
Intradigm
Sirna Therapeutics
9. Markets for RNAi Technologies
Introduction
Current and future market potential for RNAi technologies
RNAi reagents
RNAi-based drug discovery and target validation
RNAi-based development of therapeutics
RNAi market potential according to therapeutic areas
Market for viral infections
Market for cancer
Market for age related macular degeneration
Unmet needs in RNAi
Strategies for marketing RNAi
Choosing optimal indications
Strategies according to the trends in healthcare in the next decade
Concluding remarks
10. Companies involved in RNAi Technologies
Introduction
Major players in RNAi
Profiles of companies
Collaborations
11. References
Tables
Table 1-1: Historical landmarks in the evolution of RNAi
Table 2-1: RNAi versus small molecules
Table 2-2: Providers of software for siRNA design
Table 2-3: Methods for the production of siRNAs
Table 2-4: Advantages and limitations of methods of shRNA-derived siRNA knockdown
Table 2-5: Comparison of eiRNA with siRNA
Table 3-1: Methods for miRNA target prediction
Table 3-2: Dysregulation of miRNA expression in epithelial cancers
Table 3-3: Companies involved in miRNA diagnostics and therapeutics
Table 4-1: Methods of delivery of oligonucleotides
Table 4-2: Methods of delivery of siRNA
Table 4-3: Companies developing siRNA delivery technologies
Table 5-1: RNAi libraries
Table 6-1: Delivery of siRNAs in vivo for target validation
Table 6-2: Selection of siRNA versus shRNA for target validation
Table 7-1: RNAi-based therapeutic approaches
Table 7-2: In vivo RNAi therapeutic efficacy in animal models of human diseases
Table 7-3: Inhibition of viral replication by RNAi
Table 7-4: Cancer-associated genes that can be targeted by RNAi
Table 7-5: Neurological disorders that have been studied by using RNAi
Table 7-6: Clinical trials of RNAi-based therapeutics
Table 9-1: RNAi markets according to technologies and reagents 2008-2018
Table 9-2: Markets for RNAi therapy for selected diseases: years 2008-2018
Table 10-1: RNAi reagent, technology and service companies
Table 10-2: Pharmaceutical companies using RNAi for drug discovery and development
Table 10-3: Biotechnology companies using RNAi for drug discovery and development
Table 10-4: Companies developing RNAi-based therapeutic products
Table 10-5: Major players in RNAi
Table 10-6: RNAi products of Benitec
Table 10-7: Proprietary reagents of ImuThes
Table 10-8: Product pipeline of Silence Therapeutics
Table 10-9: Collaborations in RNAi technologies
Figures
Figure 1-1: Relationship of DNA, RNA and protein in the cell
Figure 1-2: Schematic of suppression of gene expression by RNAi
Figure 2-1: Overview of ShortCut RNAi Kit
Figure 2-2: Gene silencing by RNAi induced with ddRNAi
Figure 3-1: A schematic miRNA pathway
Figure 3-2: Molecular mechanisms of miRNA generation
Figure 7-1: Targeting disease by RNAi
Figure 7-2: Role of RNAi in personalized medicine
Figure 8-1: Problems with use of synthetic siRNAs and measures to prevent them
Figure 9-1: Unmet needs in RNAi technologies
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