Delivering RNAi-Based Therapeutics & Diagnostics

Challenges & Opportunities

Product Code PAV00010
Publication Date July 2009
Publisher PharmaVision
Product Type Report
Pages 225
ISBN Number not applicable
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Delivering RNAi-Based Therapeutics & Diagnostics

Challenges & Opportunities

This cutting edge & insightful report can be used to interpret & assess the potential of RNAi-based medicines. It provides opinions & market projections to:

  • Assess the commercial potential of RNAi-based therapies in all of the key therapeutic areas: cancer, CNS disorders, viral infectious diseases, ocular diseases, cardiovascular, metabolic and other conditions;
  • Identify key pharma & delivery specialists advancing RNAi-based therapeutics & diagnostics;
  • Gain an in-depth understanding of the technological & delivery issues which face companies developing RNAi-based therapies;
  • Evaluate the options available for chemically and structurally modifying RNAi silencing agents and delivering them to target tissues now & in the future;
  • Discover which companies are tackling efficacy and safety issues & are in a prime position to exploit new opportunities;
  • Analyze how the market will evolve over the next decade highlighting key trends, opportunities & challenges.

""Several novel RNAi-based therapeutics are expected to be launched in the next ten years as companies have made significant advances in identifying, characterising, designing and delivering gene silencing agents to a variety of target tissues. A plethora of RNAi start up companies have emerged during the last few years as the field hots up and large pharma such as Novartis, Merck, Pfizer and Roche begin to make strategic acquisitions and collaborations with market leaders. The results of a number of Phase 2 clinical trials may help to quell researchers' fears regarding the efficacy of RNAi-based therapeutics and drive investment for the future."" - Dr Cheryl Barton

Over the last decade, tremendous advances have been made in the field of RNAinterference (RNAi), a naturally occurring mechanism for gene regulation. Researchers have begun to unravel the underlying mechanisms of gene silencing and along the way a number of new gene silencing agents have been uncovered such as microRNAs.

Whilst RNAi has become a useful tool for understanding the function of specific genes and a means of identifying new targets for small molecule intervention, many scientists have harnessed its power to develop RNAi-based therapeutics, which can treat and in some cases prevent disease and have expanded the repertoire of targets previously deemed 'undruggable'.

The development of RNA-based therapeutics has faced many challenges, namely stability, efficacy, potency and delivery. Whilst many of these hurdles have been overcome, delivery has played a key role in tempering the speed at which RNAi therapeutics have progressed into the clinic. The first generation RNAi therapeutics to reach the clinic are chemically unmodified, naked short interfering RNA (siRNA) and although these have proved the concept that gene silencing has potential to regulate disease specific genes, the jury is still out regarding their therapeutic mechanism of action and long-term safety.

Meanwhile a plethora of delivery platforms have evolved to improve targeted delivery, duration of action, stability and to reduce the off-target effects of RNAi agents and this has also helped to expand their ease of administration from localized and topical formulations to systemic and more recently oral delivery.

In addition, a second generation of RNAi therapeutics, dicer substrate RNA (disRNA), have been discovered that act higher up the RNAi pathway than siRNAs and use endogenous enzymes to process them into siRNAs. Interestingly, this new class of RNA-based therapeutics appear to be more potent and have a longer duration of action than their siRNA counterparts.

However, this field is still in its infancy and the full potential of RNA-based therapeutics has yet to be realized. To date, no RNAi-based therapeutic has been approved, although several products are in clinical development.

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
    • 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
    • & Other 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 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 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
    • 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)