Outlook For Rnai, 2007: Sirna And Mirna In Biology, Diagnostics And Therapeutics

Published by: Business Insights

Published: Jun. 1, 2007 - 244 Pages

Table of Contents

Outlook for RNAi

Executive Summary

Introduction

Design and Production of RNAi effectors

RNAi Research and Applications

Delivering RNAi therapeutics

RNAi Therapeutics: Progress and the Future

miRNA: diagnostics and therapeutics

Regulatory issues and patents

RNAi markets and trends

Chapter 1 Introduction

Summary

Introduction

DNA to RNA to protein - a primer

Antisense technologies

RNA interference

Overview and significance

RNAi’s mechanism

Post-transcriptional gene silencing (PGTS) by siRNA

miRNA pathways

Transcriptional gene silencing (TGS) by siRNA

Other non-coding RNAs

Advantages and disadvantages of RNAi

Report Outline

Chapter 2 Design and Production of RNAi

effectors

Summary

Introduction

Design of RNAi effectors

siRNA design algorithms

Building silencing efficiency

Avoiding off-target effects

Chemical modification

Avoiding immunostimulation

Finding the right target sites

miRNA mimics

Production of RNAi effectors

Chemical Synthesis

siRNA pools

Dicer-substrate siRNAs (DsiRNAs)

Expression vectors

Plasmid expression vectors

Expression from a PCR product

Viral expression vectors

Conclusions

Chapter 3 RNAi Research and Applications

Summary

Introduction

Elucidating gene function

High throughput loss-of-function screening with RNAi

Choice of species and cell-line

RNAi reagents

Delivery method

Screening paradigm and format

Read-out methods

Building pathways

Investigating gene function in vivo

Applications of RNAi in drug discovery and development

Target discovery and validation

Optimization of drug therapy and development of personalized

medicine

miRNA Research

miRNA Databases and Algorithms

Identifying miRNAs, their targets and function

Isolation and enrichment of miRNA

Detection and quantification of miRNA

Functional analysis

Conclusions

Chapter 4 Delivering RNAi therapeutics

Summary

Introduction

Direct organ delivery

Stabilization of siRNAs

Non-viral delivery methods

Cholesterol and peptide conjugation

Liposomal delivery

Conjugation with cell penetrating peptides

Atelocollagen

Targeted polymeric delivery

Aptamer-siRNA complexes

FAb-siRNA complexes

MAb-siRNA complexes

Targeted nanoparticle delivery methods

Targeting with transferrin

Targeting with apatmers

Targeting with RGD peptide

Delivering RNAi via Plasmid DNA

Virosomes

Viral delivery methods

Conclusions

Chapter 5 RNAi Therapeutics: Progress and

the Future

Summary

Introduction

siRNA Therapeutics: Analysis by Therapeutic Area

Ocular Diseases

Age-related Macular Degeneration (AMD)

Key RNAi players

Diabetic Retinopathy

Viral diseases

Respiratory Syncytial Virus (RSV)

Key RNAi Players

HIV

Key RNAi players

Hepatitis C Virus (HCV)

Key RNAi players

Hepatitis B Virus (HBV)

Key RNAi players

Pandemic Flu

Key RNAi players

SARS

Key RNAi players

Herpes Simplex Virus (HSV)

Other viral diseases

Respiratory diseases

Asthma and Chronic Obstructive Pulmonary Disease (COPD)

Key RNAi Players

Cystic fibrosis (CF)

Key RNAi players

Neurological diseases

Oncology

Angiogenesis

Key RNAi players

Oncogenes

Key RNAi players

Cardiovascular disease

Key RNAi players

Metabolic disorders

Diabetes and Obesity

Key RNAi players

Dermatology

Hair Removal

Key RNAi players

Pachyonychia congenita and related disorders

Key RNAi Players

Acute renal failure

Key RNAi players

Acute hearing loss/ pressure sores ototoxicity

Key RNAi players

Inflammatory Diseases

Key RNAi players

Conclusions

Chapter 6 miRNA: diagnostics and

therapeutics

Summary

Introduction

miRNA as a diagnostic tool

Companies developing miRNA-based diagnostics

Rosetta Genomics

Cepheid

Stratagene

miRNA-based therapeutics

Companies developing miRNA-based therapeutics

Alnylam Pharmaceuticals

Asuragen Inc

Santaris

Sirna

Conclusions

Chapter 7 Regulatory issues and patents

Summary

Introduction

Patents in RNAi

Seminal patents in RNAi

Alnylam

Sirna

Chemical modifications

DNA directed RNAi

Patents for specific RNAi targets

The future - more patent litigation?

MicroRNA

Tuschl III patents

Zamore and other patents

Regulatory considerations for RNAi therapies

Conclusions

Chapter 8 RNAi markets and trends

Summary

Introduction

The RNAi market

Market size and future trends

RNAi suppliers: synthesis and reagents

Alliances with big pharma for RNAi in R&D

Delivery of RNAi therapeutics

RNAi-based therapeutics

Big pharma alliances for RNAi-based therapeutics

miRNA-based diagnostics

Conclusion

List of Figures

Figure 1.1: Summary of antisense technologies other than RNAi

Figure 1.2: Timeline of RNAi discoveries

Figure 1.3: Significance of RNAi

Figure 1.4: Mechanism of post-transcriptional gene silencing by siRNA

Figure 1.5: Mechanism of miRNA mediated translational repression

Figure 2.1: Types of RNAi effector

Figure 2.2: Points of the RNAi pathway involved in determining silencing efficiency

Figure 2.3: Influence of guide RNA structure on siRNA efficiency

Figure 2.4: siRNA design that avoids off-target effects

Figure 2.5: Mechansims of immunostimulation with siRNA

Figure 2.6: Advantages and disadvantages of siRNA synthesis methods

Figure 2.7: Mechanism of ddRNAi compared to RNAi triggered by an siRNA

Figure 2.8: Nucleonics multi-targeting Anti-HBV drug

Figure 3.1: Considerations for a HT RNAi screen

Figure 3.2: Structures of silencing reagents for RNAi screening

Figure 3.3: Read-out methods for high throughput screens

Figure 3.4: Method of ArteMiceTM RNAi development

Figure 3.5: Peer reviewed miRNA publications (2001-2006)

Figure 3.6: Comparison of Mirus’ LabelIT and enzymatically labelled samples

Figure 3.7: Inser Comparison of effectiveness of different knockdown methods t figuretitlehere, with date where appropriate

Figure 4.1: Chemical modifications of siRNAs increase stability and PK

Figure 4.2: Ribo-T siRNAs from Nastech Pharmaceuticals

Figure 4.3: Structure of a SNALP

Figure 4.4: Mirus Bio’s Dynamic PolyConjugates??delivery system for siRNA

Figure 4.5: Aptamer complexes for cell-type specific delivery of siRNAs

Figure 4.6: Heavy-chain antibody fragment for delivery of siRNAs to cell surface receptors

Figure 4.7: Targeted nanoparticles delivering siRNA

Figure 4.8: Aptamer directed nanoparticle formulation of docetaxel

Figure 4.9: Preparation of virosomes encapsulating siRNA

Figure 4.10: Viral delivery of shRNA

Figure 5.1: Development of AMD

Figure 5.2: siRNA targeting VEGF reduces blood vessel growth in the cornea

Figure 5.3: Visual Acuity data from Phase 1 studies of Sirna-027

Figure 5.4: Possible targets for suppressing HIV replication

Figure 5.5: siRNA mediated knockdown in Sirna’s primate model of HCV chimeric infection

Figure 5.6: Inhibition of three regions of the HCV genome by TT-033 for more than 2 months after a single administration to mice

Figure 5.7: Down regulation of Hepatitis B Surface Antigen after intravenous delivery of Nucleonic’s HBV candidate

Figure 6.1: Rosetta Genomics’ method for miRNA identification and validation

Figure 6.2: Illustration of Exiqon’s miRNA diagnostics

Figure 6.3: Structure of an antagomir

Figure 6.4: Asuragen’s development of miRNA-based therapeutics

Figure 6.5: let-7: tumor suppressor and future therapeutic

Figure 8.1: RNAi market sectors

Figure 8.2: Growth in the RNAi market 2006-2015

List of Tables

Table 1.1: Failures of antisense drugs

Table 1.2: Highly generalized comparison of siRNAs and miRNAs

Table 1.3: Advantages of RNAi

Table 1.4: Disadvantages of RNAi

Table 2.1: Selection of publicly available siRNA design tools

Table 2.2: Commercial siRNA design services

Table 2.3: Suppliers of custom and predesigned siRNAs

Table 2.4: Suppliers of siRNA pools and kits to create them

Table 2.5: Comparison of plasmid-based vectors and synthetic siRNA for research purposes

Table 2.6: Selection of plasmid vector products for siRNA generation

Table 2.7: Suppliers of kits for generating siRNA expression cassettes by PCR

Table 2.8: Advantages and disadvantages of different viral and non-viral expression vectors

Table 2.9: Selection of suppliers of viral vectors for gene silencing

Table 3.1: Suppliers of siRNA libraries for HT screening (3.1)

Table 3.2: Commercial availability and coverage of shRNA libraries

Table 3.3: Summary of the pros and cons of the different silencing reagents for RNAi screening

Table 3.4: Advantages and disadvantages of RNAi knock-down in vivo

Table 3.5: Key databases and algorithms for miRNA target prediction

Table 3.6: Suppliers of miRNA mimics and inhibitors

Table 4.1: Non-viral methods for siRNA delivery

Table 5.1: RNAi therapeutics in, or close to, clinical development

Table 5.2: RNAi therapeutic targets in neurological disease

Table 5.3: Atugen’s pipeline of anticancer therapeutics

Table 6.1: miRNA expression profiling in human cancers

Table 7.1: Seminal patents in RNAi

Table 7.2: Issues in Tuschl I vs Tuschl II

Table 7.3: Licensees of Alnylam’s RNAi patents

Table 7.4: Chemical modifications - Sirna’s patent portfolio

Table 7.5: Therapeutic targets for RNAi - Sirna’s patent portfolio

Table 8.1: Companies involved in RNAi technologies, A-B

Table 8.2: Companies involved in RNAi technologies, C-G

Table 8.3: Companies involved in RNAi technologies, I-O

Table 8.4: Companies involved in RNAi technologies, P-Z

Table 8.5: Sales forecasts for total RNAi market, 2006-2015

Table 8.6: Sales forecasts for RNAi suppliers: synthesis and reagents, 2006 - 2015

Table 8.7: Pharma’s alliances for RNAi in R&D

Table 8.8: Sales forecasts for delivery of RNAi therapeutics, 2006-2015

Table 8.9: Costs associated with RNAi therapeutic development

Table 8.10: Potential value of therapy areas targeted by RNAi therapeutics, 2005 & 2010

Table 8.11: Sales forecasts for RNAi therapeutic drugs launched 2010-2015

Table 8.12: Pharma’s alliances for RNAi in R&D

Abstract

• The RNAi market is a relatively immature with global sales of approximately $447 million in 2006. It is projected to reach $0.9 billion by 2010, a compound annual growth rate (CAGR) of 19% between 2006-2010.
• One of the main reasons for RNAi’s popularity stems from its utility as a molecular biology tool enabling the in vivo functional analysis of thousands of genes. Recent advances in the field include the design of new libraries of RNAi effectors, delivery systems and read-out methods.
• In 2005, delivering RNAi triggers was the biggest obstacle in creating effective RNAi-based therapies. Subsequently, research into new and effective delivery methods has taken place at a frantic pace, although there are still major issues to be addressed. The first human trials of a systemic RNAi-based therapeutic were initiated in 2007 by Quark Biotech.
• In the last two years, a more thorough understanding of the mechanism of action and intracellular pathways of miRNA has developed. miRNA is now an alternative gene knock-down technology that is being applied in research and for therapeutic and diagnostic applications.

• What will the growth of the RNAi market be over the next 5 years?
• Who are the leading players in the RNAi market?
• How are big pharma companies capitalizing on this technology through strategic alliances with specialized players?
• Which areas of therapeutic interest are being explored with RNAi-based agents?
• What are the Intellectual Property implications of RNAi research?
• What challenges must be overcome for RNAi technology to yield commercially viable therapeutics and make a substantial improvement to drug-attrition rates?

• The value and breakdown of sub-sector performances of the RNAi market between 2006-2015.
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• The therapy areas, progress of clinical research, potential drug sales and patent position of companies at the forefront of RNAi-based therapeutics.
• The relative strengths and weaknesses of different approaches to RNAi delivery and selectivity.
• The key trends that are currently affecting the RNAi market such as the development of new reagents, availability of custom synthesized siRNA, development of RNA microarrays and their impact on the R&D process
• The development of miRNA for diagnostic and therapeutic purposes.

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