Printer Friendly Printed from http://www.researchandmarkets.com/reports/323964 The Outlook For RNAi: Accelerating Drug Discovery and the Development of RNAi Therapeutics Description: While 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. The RNAi market achieved global sales of just over $1bn in 2004 and is projected to reach $2.5bn by 2010, a compound annual growth rate (CAGR) 2004-2010 of 14%. "The Outlook for RNAi: Accelerating Drug Discovery and the Development of RNAi Therapeutics" is a new management report which analyzes the latest trends in the RNAi market, allowing pharmaceutical companies to decide which areas of RNAi technologies to invest in, to improve drug attrition rates and develop new therapeutic agents. RNAi therapeutics are forecast to generate sales of around $1bn by 2015 and this market has significant potential, should companies be able to overcome delivery constraints. This report analyzes future trends of RNAi and provides detailed insight into the most effective use of this novel technology in the drug discovery process. This report details recent alliances and acquisitions being made by big pharmaceutical companies, allowing you to assess their investment in this new and rapidly advancing field. Key Features: - Value and breakdown of sub-sector performances of the RNAi market 2004-2015 - In-depth examination of key companies involved in the development of RNAi therapeutics, key therapy areas, the phase of clinical development, potential drug sales and patent position - Analysis of the strengths and weaknesses of different approaches to RNAi delivery and selectivity - Future direction of RNAi research and the development of second generation siRNAs, miRNAs and multifunctional siRNAs Key Findings: - The two key challenges to RNAi-based therapies are ensuring efficient drug delivery and avoiding 'off-target' gene suppression. - RNAi-based screens have provided new opportunities for the discovery and validation of novel therapeutic targets and offer new hope for "smarter targets", ultimately having a significant effect on the drug development process and drug attrition rates. - Companies are already developing "second generation" gene silencing agents including: multifunctional siRNAs, hyperfunctional or superactive siRNAs, no-ribose siNAs and siRNAs conjugated with small molecule drugs, which may have critical advantages over their predecessors. About the author Dr CL Barton has over 10 years practical pharmaceutical research experience with a leading pharmaceutical company and Pan-European Pharmaceutical analyst with a European Bank. Dr CL Barton Ltd. aims to provide independent, tailor-made, pharmaceutical thematic research to investment houses. Where applicable the research reports combine independent scientific analysis with patients- and prescription-based models to forecast the potential sales growth of key developmental drugs and isolate the key drivers within the pharmaceutical sector. Contents: Chapter 1 Current RNA technologies Summary Introduction History of RNAi From DNA to RNA to proteins mRNA regulation Gene expression Antisense technology Oligonucleotides (OGNs) Peptide nuclei acids (PNAs) Locked nucleic acids (LNA) Triple helix DNA or triple helix-forming oligonucleotides (TFOs) Ribozymes DNAzymes Aptamers RNA interference siRNAs versus dsRNA siRNAs versus shRNA Conclusions Chapter 2 Design, production and delivery of RNAi Summary Introduction Cost-effective RNA design Cost-effective synthesis of siRNA Chemical synthesis Conclusions In vitro transcription DICER reaction Expression vectors DNA-directed RNAi (ddRNAi) Expressed interfering RNA (eiRNA) Conclusions Improvements in siRNA stability Chemical modifications Formulation modifications Small molecule conjugation Synthetic vector systems Conclusion RNAi delivery options Viral vectors Conclusions Chapter 3 The future of RNAi in research and drug discovery Summary Introduction Applications of RNAi in research Functional genomics Signaling pathways Applications of RNAi in drug discovery Gene expressions studies Target validation Toxicogenomics Applications of RNAi in drug development Transgenics The impact of RNAi in R&D Chapter 4 The future of RNAi drug therapies Summary Introduction Shift from antisense to RNAi 98 Ocular diseases Age-related Macular Degeneration (AMD) Key RNAi players Diabetic Retinopathy (DR) Key RNAi players Conclusions Infectious diseases Hepatitis C virus (HCV) Key RNAi players HIV CMV (cytomegalovirus) Key RNAi players Conclusions Respiratory Respiratory Syncytial Virus (RSV) Key RNAi players Asthma Key RNAi players Cystic fibrosis Key RNAi players Conclusions Neurological diseases Huntingdon's disease (HD) Key RNAi players Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's disease) Key RNAi players Spinal Cord Injury (SCI) Key RNAi players Parkinson's disease (PD) Alzheimer's disease (AD) Pain Conclusions Oncology Angiogenesis Key RNAi players Oncogenes Key RNAi players Drug resistance and enhancement Key RNAi players Conclusions on RNAi in oncology Cardiovascular diseases Key RNAi players Conclusions Metabolic disorders Diabetes Key RNAi players The future role of RNAi-based therapeutics Chapter 5 Emerging RNA technologies and future trends Summary Introduction Second generation siRNAs Multifunctional siRNAs Hyperfunctional or superactive siRNAs No-ribose small inhibitory nucleic acids (siNAs) siRNAs conjugated with small molecule drugs Alternative RNA based therapies: Micro RNAs (miRNAs) miRNA processing miRNA in embryonic development miRNA in neurological disorders miRNA in cancer Future direction of miRNA research Small nucleolar RNAs (snoRNAs) Aptamers Chapter 6 Patents and strategic alliances in RNAi technology Summary Introduction Patents for siRNA reagents Patents for siRNA therapeutics Alnylam Pharmaceuticals (Cambridge, MA, US) Patent position Strategic alliances, 2003-2005 Benitec Ltd (Queensland, Australia) Patent position Strategic alliances, 2003-2005 Sirna Therapeutics (formerly Ribozyme Pharmaceuticals) Patent position Strategic alliances, 2003-2005 Acuity Pharmaceuticals (Philadelphia, PA, US) Patent position Strategic alliances, 2003-2005 Atugen AG (Dresden, Germany) Patent position Strategic alliances, 2003-2005 CytRx Labs (Los Angeles, MA, USA) Patent position Strategic alliances, 2003-2005 Intradigm (Rockville, MD, USA) Nucleonics Inc. (Horsham, PA, USA) Future impact of IP on RNAi research Chapter 7 RNAi markets and trends Summary Introduction The RNAi market Market size and future trends siRNA synthesis and delivery RNAi reagents RNAi in drug discovery and target validation RNAi therapeutics Chapter 8 Appendix Acknowledgements Index Bibliography Glossary References List of Figures Figure 1.1: History of RNAi Figure 1.2: Schematic of DNA, genes and proteins Figure 1.3: Schematic of gene splicing Figure 1.4: Major mechanisms for antisense OGN action Figure 1.5: Mechanism of preventing translation using OGN technology Figure 1.6: Chemical structure of PNA versus DNA Figure 1.7: Chemical structure of LNA versus RNA Figure 1.8: Mechanism of preventing translation using triple helix DNA technology Figure 1.9: Mechanism of preventing translation using ribozymes Figure 1.10: Schematic of the mechanism of gene silencing by RNAi Figure 1.11: Schematic of the mechanism of shRNAs Figure 2.12: Advantages and disadvantages of siRNA synthesis methods Figure 2.13: In vitro transcription of siRNAs Figure 2.14: DICER digestion of dsRNAs Figure 2.15: psiRNA plasmid vector system Figure 2.16: Mechanism of ddRNAi Figure 2.17: Chemical modifications of siRNAs increase stability and PK Figure 2.18: Chol- siRNAs improve tissue uptake and PK Figure 2.19: Intradigm's nano-delivery technology TargeTran Figure 2.20: Summary of viral vector advantages and disadvantages Figure 3.21: The application of TCA in gene expression Figure 3.22: Optimization of lead compounds with siRNAs Figure 3.23: Comparison of gene expression profiles to optimize lead compounds Figure 3.24: Investigation of the intracellular mechanism of Endothelin A receptor Figure 3.25: Schematic of knock-out and knock-down transgenics Figure 3.26: Heritable suppression of Neil-1 in mouse model Figure 3.27: ArteMiceTM RNAi in vivo in 4 months Figure 3.28: Artemis Pharmaceutical timelines for transgenic animals Figure 3.29: Status leptinR knockdown using shRNAs Figure 3.30: Impact of RNAi in R&D Figure 4.31: Antisense drugs currently in clinical development Figure 4.32: RNAi drugs currently in clinical development Figure 4.33: Development of AMD Figure 4.34: siRNA targeting VEGF reduces blood vessel growth in the cornea Figure 4.35: Lead siRNA candidates block HCV replication Figure 4.36: HCV target destruction in mouse liver Figure 4.37: Efficacy of HIV drug in vitro Figure 4.38: In vivo efficacy of direct RNAi for RSV Figure 4.39: Systemic siRNA leads to significant reduction in apolipoproteins Figure 5.40: Conventional RISC silencing pathways and RISC pathway using "On-Target" siRNA reagents Figure 5.41: siRNA RISC process using "On-Target plus" siRNA Reagents Figure 5.42: Schematic representation of aptazyme development Figure 6.43: Key RNA-based companies targeting RNAi reagents Figure 6.44: Key RNA-based companies targeting therapeutic agents Figure 6.45: Sirna Therapeutics' IP portfolio and therapeutic areas Figure 7.46: RNAi market segments, 2004 Figure 7.47: Growth in the RNAi market 2004-2010 Figure 7.48: Alliances in RNAi R&D Figure 7.49: Potential value of therapy areas targeted by RNAi therapeutics, 2004 & 2010 List of Tables Table 1.1: Advantages and disadvantages of OGN technology Table 1.2: Advantages and disadvantages of modified OGNs Table 1.3: Advantages and disadvantages of TFOs Table 1.4: Advantages and disadvantages of ribozymes Table 1.5: Advantages and disadvantages of DNAzymes Table 1.6: Advantages and disadvantages of aptamers Table 1.7: Genes crucial for RNAi in model organisms Table 1.8: Advantages of RNAi Table 1.9: Disadvantages of RNAi Table 2.10: Algorithms available for designing siRNAs Table 2.11: Class of functional RNA molecule Table 2.12: Companies offering siRNA synthesis Table 2.13: Advantages of ddRNAi versus siRNA Table 2.14: Advantages of eiRNA versus siRNAs Table 3.15: Commercial siRNA libraries Table 4.16: Antiviral siRNA targets Table 4.17: RNAi-based targeted therapies Table 4.18: Examples of RNAi targets for neuronal pain Table 4.19: Chemotherapeutic siRNA targets Table 5.20: Animal miRNA genes with genetically assigned functions Table 6.21: RNA patents registered worldwide up to March 2005 Table 7.22: Companies involved in RNAi technologies, A-M Table 7.23: Companies involved in RNAi technologies, N-Z Table 7.24: Sales forecasts for total RNAi market, 2004-2015 Table 7.25: Sales forecasts for siRNA synthesis and delivery, 2004-2015 Table 7.26: Sales forecasts for RNAi reagents, 2004-2015 Table 7.27: Sales forecasts for RNAi in drug discovery & target validation, 2004-2015 Table 7.28: Sales forecasts for RNAi therapeutics, 2004-2015 Table 7.29: Sales forecasts for RNAi therapeutic drugs launched 2010-2015 Companies Mentioned - Alnylam Pharmaceuticals (Cambridge, MA, US) - Benitec Ltd (Queensland, Australia) - Sirna Therapeutics (formerly Ribozyme Pharmaceuticals) - Acuity Pharmaceuticals (Philadelphia, PA, US) - Atugen AG (Dresden, Germany) - CytRx Labs (Los Angeles, MA, USA) - Intradigm (Rockville, MD, USA) - Nucleonics Inc. 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