Delivering RNAi-based Therapeutics & Diagnostics: Challenges & Opportunities

Table of Contents

Chapter 1 RNA Interference & Delivery

• Key Findings
• Introduction
• RNAi a Natural Phenomenon
  • Antisense technologies
  • RNAi silencing agents
  • RNA silencing pathways
  • microRNAs and antagomirs
  • miRNA gene silencing
• Pros & Cons of RNAi Silencing Agents
• RNAi R&D
  • High throughput in vitro screening
  • RNAi in vivo screening
  • RNAi diagnostic makers
• RNAi Therapeutics
• RNAi Diagnostics
• RNAi Therapy - A Discovery Timeline
• Major Scientific Challenges for the Development of RNAi-Based Diagnostics Therapies
• Report Structure

Chapter 2 RNAi-Based Therapeutics: Pipeline Analysis

• Key Points
• Key Therapy Areas Covered by RNAi-Based Therapies
  • Product pipelines
• RNAi for Diagnostics
• RNAi Companies Analyzed in This Report

Chapter 3 RNAi-Based Therapies for Cancer

• Key Findings
• Introduction
  • RNAi delivery in cancer
• RNAi-Based Therapies -siRNA
  • Case study: ALN-VSP (Alnylam Pharmaceuticals)
  • Case study: CALAA-01 (Calando Pharmaceuticals)
  • Case study: Dicer substrate RNA (Dicerna Pharmaceuticals)
  • Case study: Intratumoral siRNA (Genesis Research & Development Corporation)
  • Case study: NPX delivery technology (Intradigm Corporation)
  • Case study: SNS-01 (Senesco Technologies)
  • Case study: Atu027 (Silence Therapeutics)
  • Case study: STP702 (Sirnaomics)
  • Case study: PLK SNALP (Tekmira Pharmaceutical Corporation)
• RNAi-Based Therapies -shRNA
  • Case study: CEQ501 (Cequent Pharmaceuticals)
• Alternative RNA Approaches to Develop Cancer Therapies
• miRNA in Cancer
  • Case study: miRNAs (Mirna Therapeutics)
  • Case study: miRNAs (Regulus Therapeutics)
  • Case study: SPC2996 & EZN3042 (Santaris Pharma A/S/Enzon Pharmaceuticals)
• MiRNA-Based Diagnostics
• mRNA Antagonists
  • Case study: LOR-2040 (Lorus Therapeutics)
• Antisense
  • Case study: OGX-011 (Isis Pharmaceuticals/OncoGenex) & LY2181308 (Isis Pharmaceuticals/Eli Lilly)
  • Case study: TF siRNA (siRNAsense A/S/Polyplus Transfection)
• Conclusions
• Our Opinion on RNAi-Based Therapies & Diagnostics for Cancer
  • Where the technology is now, its evolution, achievements and pitfalls
  • Competition
  • Potential future applications
  • Activity in the market, major players and winners

Chapter 4 RNAi-Based Therapies for CNS Disorders

• Key Findings
• Introduction
• Neurodegenerative Diseases
  • Amyotrophic lateral sclerosis
  • Case study: SOD1 siRNA (RXi Therapeutics)
  • Case study: SOD1 shRNA (Oxford BioMedica)
  • Huntington' s Disease
  • Case study: ALN-HTT (Alnylam Pharmaceuticals/Medtronic)
  • Case study: AVV-HTT (Targeted Genetics Corporation)
  • Parkinson' s Disease
  • Case study: SNCA-siRNA (Alnylam Pharmaceuticals)
  • Case study: biotinylated siRNA (ArmaGen Technologies)
  • Other CNS conditions
• Conclusions
• Our Opinion on RNAi-Based Therapies for CNS disorders
  • Where the technology is now, its evolution, achievements and pitfalls
  • Competition
  • Potential future applications
  • Activity in the market, major players and winners

Chapter 5 RNAi-Based Therapies for Viral Infectious Diseases 104

• Key Findings
• Introduction
  • Respiratory Syncytial Virus
  • Case study: ALN-RSV01 (Alnylam Pharmaceuticals)
  • Hepatitis C
  • Case study:TT-033 (Oncolys BioPharma/Pfizer/Tacere Therapeutics)
  • Case study: miR-122 (Regulus Therapeutics)
  • Case study: SPC3649 (Santaris Pharma A/S)
  • Human Immunodeficiency Virus
  • Case study: rHIV7-shl-TAR-CCR5RZ (Benitec Ltd/City of Hope)
  • Pandemic Influenza
  • Bioterrorism
  • Other Infectious Diseases
• Conclusions
• Our Opinion on RNAi-Based Therapies for Viral Infectious Diseases
  • Where the technology is now, its evolution, achievements and pitfalls
  • Competition
  • Potential future applications
  • Activity in the market

Chapter 6 RNAi-Based Therapies for Ocular Diseases

• Key Findings
• Introduction
  • Age-Related Macular Degeneration
  • Case study: AGN-745 (Allergan/Sirna Therapeutics)
  • Case study: VEGF-A165b sparing siRNA & Bevasiranib (Opko Health)
  • Case study: PF-4523655 (Quark Pharmaceuticals/Pfizer)
  • Diabetic Retinopathy & Diabetic Macular Edema
  • Glaucoma
• Conclusions
• Our Opinion on RNAi-Based Therapies for Ocular Diseases
  • Where the technology is now, its evolution, achievements and pitfalls
  • Competition
  • Potential future applications
  • Activity in the market

Chapter 7 RNAi-Based Therapies for Cardiovascular, Metabolic & Other Conditions

• Key Points
• Introduction
• RNAi-Based Therapeutics for Cardiovascular Diseases
  • Case study: miR-21 (Regulus Therapeutics)
  • Case Study: MHC miRNA inhibitors (MiRagen Therapeutics Inc)
• RNAi-Based Therapeutics for Metabolic Disorders
  • Case Study: ApoB SNALP (Tekmira Pharmaceutical Corporation)
  • Case study: MDR-04227 (MDRNA)
  • Case Study: PCSK9 siRNA (Alnylam Pharmaceuticals)
  • Case study: ApoB rxRNA and GeRP delivery (RXi Therapeutics)
• RNAi-Based Therapeutics in Other Therapeutic Areas
  • Case study: ALN-TTR siRNA (Alnylam Pharmaceuticals)
  • Case study: HSP47 siRNA (Nitto Denko Technical Corporation)
  • Case study: QPI-1002 (Silence Therapeutics/Quark Pharmaceuticals)
• Conclusion
• Our Opinion on RNAi-Based Therapies for Cardiovascular, Metabolic & Diseases
  • Where the technology is now, its evolution, achievements and pitfalls
  • Competition
  • Potential future applications
  • Activity in the market, major players and winners

Chapter 8 Challenges & Opportunities for RNAi-Based Therapeutics & Diagnostics

• Key Points
• Introduction
• Stability & Efficacy Issues for RNAi Research
  • Stability
  • Efficacy
• Safety Issues for RNAi Research
• Intellectual Property
• Delivering RNAi-Based Therapies
  • Challenges
  • Opportunities

Chapter 9 The Future of RNAi-Based Therapeutics & Diagnostics: Market Trends

• Key Points
• Key RNAi Companies
• Leading RNAi-Based Therapeutic Companies
• Leading miRNA-Based Therapeutic Companies
• Leading RNAi-Based Diagnostic Companies
• Recent Deals & Alliances
• The Global RNAi-Based Therapy Market 2008-2014
  • Analysis parameters
  • Market forecast 2008-2014
• Global RNAi-Based Therapy Market in 2020
  • Drivers and market trends
• Summary & Conclusions
• Acknowledgements
• Bibliography & Endnotes

List of Figures

• Figure 1: siRNA - RISC mediated gene silencing
• Figure 2: miRNA - RISC mediated gene silencing
• Figure 3: High throughput RNAi screening for functional genomics and target validation
• Figure 4: Rapid lead generation
• Figure 5: ArteMicec RNAi model
• Figure 6: RNAi therapeutics applications
• Figure 7: Stages of pharmaceutical development
• Figure 8: RNAi research: a timeline
• Figure 9: RNAi-based therapeutics: defining therapeutic areas
• Figure 10: Number of projects in the different stages of pharmaceutical development
• Figure 11: Number of projects in each therapeutic area
• Figure 12: Proportions of naked and targeted/vehicle assisted RNAi species
• Figure 13: Delivery routes for RNAi therapeutics
• Figure 14: Current approaches for cancer treatment
• Figure 15: Potential RNAi approaches for cancer treatment
• Figure 16: RONDEL delivery platform
• Figure 17: In vivo efficacy studies with CALAA-01
• Figure 18: Dicer substrate processing
• Figure 19: Intratumoral siRNA delivery mediated with A) liposome and B) nanoparticles
• Figure 20: RNAi NPX delivery platform
• Figure 21: SNS-01 in mouse lung model
• Figure 22: AtuPlex proprietary delivery system
• Figure 23: SNALP delivery technology
• Figure 24: Cequent' s tkRNAi delivery system
• Figure 25: LNA monomer structure
• Figure 26: Polyplus transfection In-vivo-jetPEI system - RNAi delivery to the lung
• Figure 27: Photochemical Internalization enhances siRNA' s gene silencing effect
• Figure 28: RNAi applications in CNS disorders
• Figure 29: Medtronic' s SynchroMed II implantable infusion pump
• Figure 30: Alzet osmotic pump for brain infusion
• Figure 31: Diffusion profile of pressure and diffusion delivery
• Figure 32: Molecular schematic of ArmaGen' s molecular Trojan horse
• Figure 33: RNAi viral infectious disease targets
• Figure 34: PARI Pharma' s eFlow nebuliser
• Figure 35: Tacere' s shRNA construct to target HCV
• Figure 36: Benitec' s RNAi approach to HIV
• Figure 37: Proof of concept Ebola siRNAs
• Figure 38: RNAi ocular disease targets
• Figure 39: RNAi applications in CV, metabolic & other disorders
• Figure 40: miR-21 mechanism of action in myocardial infarction
• Figure 41: ApoB SNALP preclinical data in mouse model
• Figure 42: ApoB nanotransporter in mouse model
• Figure 43: GeRP mechanism of delivery
• Figure 44: NDT' s siRNA delivery platform
• Figure 45: Mechanism of action of siRNA HSP47 in liver cirrhosis
• Figure 46: Challenges and opportunities for RNAi research
• Figure 47: Safety issues
• Figure 48: RNAi-based therapeutics: market drivers

List of Tables

• Table 1: Antisense drugs in clinical development
• Table 2: Pros and cons of RNAi silencing agents
• Table 3: Leading RNAi diagnostic companies
• Table 4: Novel non-coding RNA
• Table 5: Diseases targeted by RNAi-based therapeutics
• Table 6: RNAi and RNA therapeutic & diagnostic companies discussed in this report
• Table 7: Leading companies evaluating RNAi therapies for cancer
• Table 8: Academic institutions with an interest in RNAi based cancer research
• Table 9: Potentially pro-oncogenic and tumor suppressor miRNAs
• Table 10: Identification of key tumor suppressor miRNAs
• Table 11: Leading companies evaluating RNAi-based therapies for CNS disorders
• Table 12: Academic institutions with an interest in RNAi for the treatment CNS disorders
• Table 13: Leading companies evaluating RNAi-based therapies for viral infectious diseases
• Table 14: Academic institutions with an interest in RNAi for the treatment of viral infectious diseases
• Table 15: Leading companies evaluating RNAi-based therapies for ocular diseasess
• Table 16: Academic institutions with an interest in RNAi for the treatment of ocular diseases
• Table 17: Leading companies evaluating RNAi-based therapies for cardiovascular disease
• Table 18: Academic institutions with an interest in RNAi for the treatment of cardiovascular disease, metabolic & other conditions
• Table 19: Leading companies evaluating RNAi-based therapies for metabolic disorders
• Table 20: Academic institutions with an interest in RNAi for the treatment of metabolic disorders
• Table 21: Leading companies evaluating RNAi-based therapies for other conditions
• Table 22: A seminal RNAi patents
• Table 23: Summary of leading RNAi-based therapeutic companies
• Table 24: Recent RNAi acquisitions & licensing deals
• Table 25: Recent RNAi alliances
• Table 26: RNAi-based therapies included in the market forecast
• Table 27: Forecast of pipeline RNAi therapy products 2008-2014 (US$m)
• Table 28: Forecast of pipeline RNAi therapy products 2015-2020 (US$m)