Abstract
RNAi Therapeutics:
Challenges in Drug Development and Delivery
Interfering RNA (RNAi) offers tremendous therapeutic promise to silence genes that give rise to bad, proteins and, therefore, disease. RNAi Therapeutics: Challenges in Drug Development and Delivery thoroughly evaluates the field of RNAi therapeutics, with particular attention to the prospects and challenges faced in RNAi delivery. This report is a comprehensive blueprint for moving RNAi from the bench to the bedside.
RNAi research is accelerating rapidly. Two clinical trials are in progress to determine RNAi's effectiveness for treating age-related macular degeneration, and many products have already reached the market to test the promise that RNAi holds. As RNAi technology progresses, many companies are now trying to increase their shares in the research market by shifting some of their resources to in vitro and in vivo work.
The real prize, however, is in therapeutics, and a few companies have been started solely with this objective. To establish priority, patents that stake claims in many possible (as well as speculative) applications of RNAi are not only being filed but disputed.
RNAi Therapeutics: Challenges in Drug Development and Delivery analyzes these and other important developments in this dynamic field. Key points include the following:
- Background is provided on various attempts to silence genes before the advent of RNAi, namely aptamers, antisense, and ribozyme. Lessons learned from the failures of antisense clinical trials are discussed.
- The promise of tackling diseases using RNAi is evaluated in detail. Examples are included that support this technology, from human cell cultures, to preclinical models, to the first batch of clinical trials using siRNA (small interfering RNA). Wide-ranging diseases?cancer, influenza, malaria, HIV, rotavirus, Huntington's disease, and Lou Gehrig's disease-are discussed.
- Advances in in vitro work with cultured cells are examined. Progress made in in vivo gene silencing is catalogued, including the latest results in detection of in vivo knockdown in whole mice.
- The problems of RNAi delivery and possible solutions to overcome them are presented from the point of view of leading scientists in academia and pharmaceutical companies.
- The therapeutic potential, specific applications, and advantages and challenges of RNAi are considered, in particular, the prospects of improving on existing treatment modalities for some cancers such as chronic myelogenous leukemia.
- The market potential of RNAi drugs is assessed.
- Leading scientists in academia and industry are interviewed.
- Twenty-three companies are profiled, 13 of which are primarily engaged in RNAi therapeutics-related work and 10 of which are suppliers and service providers.
Table of Contents
Chapter 1. Introduction
1.1. Promising Therapeutic Avenue
1.2. Discovery of RNAi
1.3. RNAi Mechanism
1.4. Gene-Silencing Technology
- Aptamers
- Ribozymes
- Antisense
- Difficulties Plaguing Antisense Clinical Trials
1.5. Gene Therapy
- Approaches to Gene Therapy
- Latest Advances in RNAi Applications to Gene Therapy
Chapter 2. RNAi in Discovery and Development
2.1. Criteria to be Satisfied before Moving into RNAi Clinical Trials
2.2. Targeting and Validation Using RNAi
2.3. RNAi in Clinical Trials for (Wet) Age-Related Macular Degeneration
- Acuity Pharmaceuticals
- Sirna Therapeutics
Chapter 3. Prospects for Curing Disease By RNAi Gene Silencing
3.1. RNAi in Viral and Infectious Disease States
- Human Papilloma Virus
- Human Immunodeficiency Virus Type I
- Rotavirus
- Malaria
- Influenza
3.2. RNAi and Diabetes
3.3. RNAi and Cancer
- Progress in In Vitro RNAi Work with Cultured Cells
- Progress in In Vivo Gene Silencing
3.4. Prospects of Improving Existing Treatment for Chronic Myelogenous Leukemia Patients by RNAi
3.5. RNAi as a New Kind of Gene Therapy: Therapeutic Potential and Specific Applications
- RNAi and Spinocerebellar Ataxia
- RNAi-Mediated Gene Therapy and Intracranial Tumor
- Transposon-Delivered RNAi and Huntington's Disease
- Advantages and Challenges of RNAi Therapy
Chapter 4. RNA Delivery
4.1. Challenges to Overcome in Delivering RNA
4.2. Standard Delivery Methods
- Electroporation
- Viral Delivery
- Lipid Delivery
- Systemic Delivery
4.3. Is Delivery of Stabilized RNAi Molecules Essential?
- Use of Plasmid Vectors
4.4. Detection/Proof of Knockdown Efficiency In Vivo
4.5. Specific Academic and Industry Concerns about RNAi Delivery
Chapter 5. Market and Market Potential
Chapter 6. Profiles of Companies with Primary Interest in RNAi Therapeutics
6.1. Background
6.2. Company Profiles
- Acuity Pharmaceuticals
- Activities
- History
- Research and Development/Products
- Business Strategy
- Challenges
- Alnylam Pharmaceuticals
- Activities
- History
- Research and Development/Products
- Business Strategy
- Challenges
- Atugen
- Activities
- History
- Research and Development/Products
- Business Strategy
- Challenges
- Benitec
- Activities
- History
- Research and Development/Products
- Business Strategy
- Challenges
- Calando Pharmaceuticals
- Activities
- History
- Research and Development/Products
- Business Strategy
- Challenges
- CytRx Corporation
- Activities
- History
- Research and Development/Products
- Business Strategy
- Challenges
- Devgen
- Activities
- History
- Research and Development/Products
- Business Strategy
- Challenges
- Galenea
- Activities
- History
- Research and Development/Products
- Business Strategy
- Challenges
- Intradigm Corporation
- Activities
- History
- Research and Development/Products
- Business Strategy
- Challenges
- Nastech Pharmaceutical Company
- Activities
- History
- Research and Development/Products
- Business Strategy
- Challenges
- Nucleonics Inc.
- Activities
- History
- Research and Development/Products
- Business Strategy
- Challenges
- Santaris Pharma
- Activities
- History
- Research and Development/Products
- Business Strategy
- Challenges
- Sirna Therapeutics
- Activities
- History
- Research and Development/Products
- Business Strategy
- Challenges
Chapter 7. Profiles of Companies in Discovery/Research/ Reagents/Services in the RNAi Market
7.1. Background
7.2. Company Profiles
- Ambion
- Activities
- History
- Research and Development/Products
- Business Strategy
- Cenix Bioscience
- Activities
- History
- Research and Development/Products
- Business Strategy
- Challenges
- CombiMatrix
- Activities
- History
- Research and Development/Products
- Business Strategy
- Challenges
- Dharmacon
- Activities
- History
- Research and Development/Products
- Business Strategy
- Imgenex Corporation
- Activities
- History
- Research and Development/Products
- Business Strategy
- Invitrogen
- Activities
- History
- Research and Development/Products
- Business Strategy
- Challenges
- InvivoGen
- Activities
- History
- Research and Development/Products
- Business Strategy
- Mirus Bio
- Activities
- History
- Research and Development/Products
- Business Strategy
- Qiagen
- Activities
- History
- Research and Development/Products
- Business Strategy
- Challenges
- SomaGenics
- Activities
- History
- Research and Development/Products
- Business Strategy
Chapter 8. Expert Interviews
8.1. Background
8.2. Interviews/Summaries
- Dr. Mick W. Graham, Principal Scientist, Benitec
- Dr. Brian Johnston, President and CEO, SomaGenics Inc., and Consulting Associate Professor of Pediatrics, Stanford University School of Medicine
- Dr. Sujay Singh, President and CEO, Imgenex Corporation
- John Rossi, City of Hope
- Dr. Barry Polisky, Senior Vice President of Research and CSO, Sirna Therapeutics
- Dr. Jean-Paul Reynes, Chief Scientist, siRNA Project, InvivoGen
- Dr. Henrik Orum, Vice President and CSO, Santaris Pharma
- Dr. Sam Reich, Vice President of Research and Development, Acuity Pharmaceuticals
Chapter 9. Concluding Remarks
Acknowledgments
References
Suggested Reading
Glossary
Index
