Antisense Therapy: Technical Aspects and Commercial Opportunities

Published by: Business Insights

Published: Mar. 1, 2000 - 336 Pages

Table of Contents

1. Executive Summary
   
2. Chapter 1 Introduction to Antisense Therapeutics
   
   • Definitions
     
   • Historical evolution
     
   • Basics of antisense therapy
     
   • Gene regulation
     
   • Naturally occurring antisense RNA
     
   • Antisense approaches
     
   • Antisense RNA and DNA
     
   • Mechanism of antisense oligonucleotide inhibition
     
   • Antisense RNA vs. antisense oligonucleotides
     
   • Role of antisense in clinical medicine
     
   • Human diseases due to disturbances of mRNA
     
   • RNA mutations
     
   • Non-coding RNAs
     
   • RNA triple repeats
     
   • Nonsense-mediated mRNA decay
     
   • Potential clinical applications of antisense therapy
     
   • Advantages of antisense approach over conventional pharmacotherapy
     
   • Limitations of antisense therapy
     
   • Non-clinical applications of antisense technologies
     
   • The role of antisense technologies in the biopharmaceutical industry
     
   • Antisense versus traditional drug development
     
   • Role of antisense in the bioprocessing industry
     
3. Chapter 2 Chemistry and Pharmacology Of Antisense
   Oligonucleotides
   
   • Chemistry
     
   • Oligonucleotide structure
     
   • RNA structure
     
   • Synthesis, purification, and analysis of oligonucleotides
     
   • First generation oligonucleotides
     
   • Pharmacology
     
   • Pharmacokinetics
     
   • Entry and distribution of oligonucleotides into cells
     
   • Mechanisms of action of antisense drugs
     
   • Inhibition of mRNA translation
     
   • Activation of ribonucleases H (RNases H)
     
   • Proof of mechanism
     
   • Non-specific and non-antisense effects
     
   • Pharmacological basis of applications of antisense oligonucleotides
     
4. Chapter 3 Antisense Technologies
   
   • Introduction
     
   • Techniques of delivery of oligonucleotides to the body tissues
     
   • Routes of administration
     
   • Gastrointestinal tract-oral and rectal
     
   • Iontophoretic delivery into subcutaneous tumors
     
   • Local application
     
   • Pulmonary administration
     
   • Targeted delivery to the arteries
     
   • Pressure-mediated transfer to arterial wall
     
   • Microbubble contrast agent
     
   • Targeted delivery to brain cells
     
   • Delivery across the BBB
     
   • High flow microinfusion into the brain parenchyma
     
   • Intracerebroventricular administration using Alzet Osmotic Pumps
     
   • Intracellular guidance by special techniques
     
   • Biochemical microinjection
     
   • Receptor-mediated endocytosis
     
   • Liposomes-mediated oligonucleotide delivery
     
   • Polyethylenimine-mediated oligonucleotide delivery
     
   • Terplex-mediated oligonucleotide delivery
     
   • Use of histidylated oligolysines to facilitate cytosolic delivery of antisense
     
   • oligonucleotides
     
   • Biodegradable microparticles
     
   • Electroporation
     
   • Ex vivo approach
     
   • Delivery of oligonucleotides: summary
     
   • Antisense drug design
     
   • Selection of optimal oligonucleotide targets
     
   • Second generation oligonucleotides
     
   • Third generation oligonucleotides
     
   • Incorporation of 2'-O-(2-methoxy)ethyl chemistry
     
   • Cytosine analogues
     
   • Phenoxazine-modified oligonucleotides
     
   • Morpholino-type oligonucleotides
     
   • Peptide nucleic acid (PNA)
     
   • PNA structure
     
   • Biological activity of PNA
     
   • Systemic administration of peptide nucleic acids (PNAs)
     
   • PNAs versus oligonucleotides
     
   • PNA-DNA chimeras
     
   • Applications of PNA technology
     
   • Locked nucleic acid (LNA)
     
   • Structure
     
   • Biological activity
     
   • Applications
     
   • RNA Therapeutics
     
   • RNA as a drug target
     
   • Sense RNA versus plasmid DNA
     
   • Antisense RNA molecules
     
   • Chimeras in antisense therapy
     
   • Chimeric oligonucleotides
     
   • Chimeric 2-5A antisense molecules
     
   • RNA-DNA chimeras/chimeraplasty
     
   • Aptamers
     
   • Structure
     
   • RNA and DNA aptamers
     
   • Clinical applications
     
   • Assessment of antisense effects
     
   • The ideal antisense oligonucleotide
     
   • Development of cost-effective oligonucleotides
     
   • Antisense oligonucleotides for functional genomics and drug target validation
     
   • Antisense oligonucleotides in a high-throughput approach for target validation
     
   • Technical approach to RNA as drug target
     
   • PNA antisense for target validation
     
   • Antisense oligonucleotides and molecular diagnostics
     
   • Use of antisense approaches for diagnostics
     
   • Molecular diagnostic technologies for monitoring antisense oligonucleotide action
     
   • Antisense gene therapy
     
   • Antisense RNA using vectors
     
   • Single strand (ss) DNA oligonucleotide mediated antisense
     
   • Insertion of a gene that will produce specific antisense nucleic acids in cells
     
   • Decoy oligodeoxynucleotides
     
   • Antisense technologies for basic research in neurobiology
     
   • Inhibition of neurotransmitters using antisense oligonucleotides
     
   • Antisense technology for study of immediate-early response genes in the CNS
     
   • Antisense transgenesis
     
   • Patenting of antisense technologies
     
   • Basics of antisense patenting
     
   • What is patentable in antisense technology?
     
   • Patenting strategies
     
   • Patenting activities and positions
     
5. Chapter 4 Clinical Applications Of Antisense Pharmaceuticals
   
   • Introduction
     
   • Inflammatory processes
     
   • Pathomechanism in relation to antisense oligonucleotide action
     
   • Intercellular adhesion molecule 1
     
   • Antisense phosphorothioate oligonucleotide to p65 subunit of NF-?B
     
   • Use of antisense oligonucleotides in inflammatory diseases
     
   • Crohn's disease
     
   • Asthma
     
   • Cancer
     
   • Antisense targets related to solid tumors
     
   • Use of antisense oligonucleotides for inhibiting oncogenes
     
   • Inhibition of tumor growth by targeting antisense oligonucleotide to cell signaling
     
   • Antisense oligonucleotides targeted to growth factors
     
   • Antisense oligonucleotides targeted to matrix metalloprotease
     
   • Inhibition of fusion genes by antisense oligonucleotides
     
   • Inhibition of lipoxygenase
     
   • Targeting DNA methyltransferase
     
   • Telomerase inhibitors
     
   • Induction of apoptosis
     
   • Radiosensitizing effect of antisense oligonucleotides
     
   • Combination of antisense and chemotherapy
     
   • Antisense oligonucleotides against multidrug resistance
     
   • Antisense targets related to type and location of malignancy
     
   • Antisense oligonucleotides for leukemia
     
   • Antisense oligonucleotides for lymphoma
     
   • Brain tumors
     
   • Antisense therapy of prostate cancer
     
   • Antisense therapy of non-small cell lung cancer
     
   • Antisense clinical trials for cancer
     
   • Future prospects of antisense oligonucleotides in cancer therapy
     
   • Antisense oligonucleotides for virus infections
     
   • Antisense oligonucleotides for HIV-1 infection
     
   • Antisense approach to hepatitis viruses
     
   • Hepatitis B virus (HBV)
     
   • Hepatitis C virus (HCV)
     
   • Hepatitis Delta virus (HDV)
     
   • Antisense approach to respiratory syncytial virus
     
   • Recently introduced/clinical trials of antisense oligonucleotides for viral infections
     
   • Fomivirsen for CMV retinitis
     
   • Antisense oligonucleotides for protozoal infections
     
   • Malaria
     
   • Leishmaniasis
     
   • Trypanosomiasis
     
   • Antisense oligonucleotides for cardiovascular diseases
     
   • Hypertension
     
   • Prevention of restenosis after angioplasty
     
   • Pathomechanism of restenosis after angioplasty
     
   • Antisense approaches for prevention of restenosis after angioplasty
     
   • Methods of delivery of antisense oligonucleotides to the site of restenosis
     
   • Prevention of atherosclerosis in vascular grafts
     
   • Prevention of arterial thrombus formation
     
   • Antisense oligonucleotides for neurological disorders
     
   • Neurodegenerative disorders
     
   • Cerebrovascular disease
     
   • Use of antisense approach in neurotransmitter regulation
     
   • Drug abuse
     
   • Neuropsychiatric disorders
     
   • Antisense approach to anxiety disorders
     
   • Antisense oligonucleotides in renal disease
     
   • Future prospects of antisense oligonucleotides
     
6. Chapter 5 Triple Helix Oligonucleotides
   
   • Molecular structure of triplex oligonucleotides
     
   • Mechanism of action
     
   • Cellular delivery
     
   • Triplex drug design
     
   • Potential clinical applications of triplex oligonucleotides
     
   • Viral infections
     
   • Cancer
     
   • Genetic diseases
     
   • Future prospects of triple helix compounds
     
7. Chapter 6 Ribozymes
   
   • Introduction
     
   • Molecular structure
     
   • RNase P
     
   • Hairpin ribozyme
     
   • Hammerhead ribozymes
     
   • Ribozyme motif in HDV
     
   • Deoxyribozymes (DNAzymes)
     
   • Mechanism of action of ribozymes
     
   • Methods of delivery/ ribozyme gene therapy
     
   • Potential clinical applications
     
   • Potential of ribozymes as antiviral agents
     
   • Ribozymes as anti-HIV therapy
     
   • Influenza A virus
     
   • Hepatitis viruses
     
   • Applications in cancer
     
   • Ribozyme approach for carcinoma of the bladder
     
   • Ribozymes for treatment of human pancreatic carcinoma
     
   • Ribozyme for lung cancer
     
   • Ribozyme for breast cancer
     
   • Ribozyme approach for malignant melanoma
     
   • Ribozyme approach for chronic myelogenous leukemia
     
   • Ribozymes and multidrug resistance
     
   • Concluding remarks on the application of ribozymes in cancer
     
   • Treatment of restenosis following angioplasty
     
   • Potential applications of ribozymes in genetic disorders
     
   • Miscellaneous applications of ribozymes
     
   • Ribozymes in clinical development
     
   • Current status and future of ribozymes
     
8. Chapter 7 Toxicity and Drug Safety Issues
   
   • Introduction
     
   • Pathways for antisense oligonucleotide toxicity
     
   • Sequence-dependent toxicity
     
   • Sequence-independent toxicity
     
   • Safety testing of antisense oligonucleotides
     
   • Adverse effects of antisense oligonucleotides
     
   • Adverse effects in animal experimental studies
     
   • Adverse effects in clinical trials in humans
     
   • Immunological adverse effects
     
   • Cardiac adverse effects
     
   • Hematological adverse effects
     
   • Genotoxicity of antisense oligonucleotides
     
   • Summary of toxicity and drug safety issues
     
9. Chapter 8 Regulatory Aspects Of Antisense Oligonucleotides
   
   • Introduction
     
   • Preclinical studies of antisense oligonucleotides
     
   • Regulatory issues concerning the chemistry of oligonucleotides
     
   • Structure
     
   • Purity
     
   • Stability
     
   • Regulatory issues concerning the pharmacology of oligonucleotides
     
   • Regulatory issues concerning toxicology studies of oligonucleotides
     
   • Intravenous administration of phosphorothioates
     
   • Special considerations for toxicology studies of oligonucleotides
     
   • Targets
     
   • Oligonucleotides acting at protein sites
     
   • Delivery
     
   • Special toxicity
     
   • Cellular toxicity
     
   • Pharmacokinetic studies
     
   • Ex vivo antisense therapy
     
   • General recommendations
     
   • Regulatory requirement for submission of an IND
     
   • General requirements
     
   • Special requirements for antisense oligonucleotides
     
   • Identity and characteristics
     
   • Reagents
     
   • Manufacturing process
     
   • Test methods
     
   • Stability
     
   • Clinical trials with antisense oligonucleotides
     
   • Introduction
     
   • Phase I
     
   • Phases II and III
     
   • NDA (New Drug Application)
     
   • Clinical trials according to indication
     
   • Special requirements for clinical trials in cancer
     
   • Special requirements for clinical trials in HIV-related diseases
     
   • Clinical trials of antisense approach to prevention of restenosis
     
10. Chapter 9 Commercial Aspects Of Antisense Therapy
    
    • Introduction
      
    • The cost of antisense drug development
      
    • Market value of antisense technology
      
    • An approach to the calculation of potential markets for antisense therapy
      
    • Calculation of markets according to type of antisense technology
      
    • Antisense oligonucleotides
      
    • Ribozymes
      
    • Locked nucleic acid (LNA)
      
    • Peptide nucleic acid (PNA)
      
    • Antisense diagnostics
      
    • Antisense drug discovery
      
    • Biopharmaceutical processing industry
      
    • Calculation of markets according to therapeutic areas
      
    • HIV-1/AIDS
      
    • Genital warts/human papilloma virus (HPV)
      
    • Cytomegalovirus (CMV)
      
    • HBV
      
    • HCV
      
    • Influenza
      
    • Miscellaneous infections including protozoal infections
      
    • Cancer
      
    • Prevention of coronary restenosis after angioplasty
      
    • Rheumatoid arthritis
      
    • Crohn's disease
      
    • Calculation of markets according to geographical areas
      
    • Commercial opportunities in antisense technologies
      
    • Marketing strategies
      
    • View of the regulatory authorities
      
    • Development of competing technologies
      
    • Special requirements for manufacturing process of oligonucleotides
      
    • General strategies for marketing antisense drugs
      
    • Choosing of optimal indications
      
    • Partnership between antisense companies and large pharmaceutical companies
      
    • Reduction of manufacturing costs
      
    • Strategies according to the trends in healthcare in the 21st century
      
    • Physician education
      
    • Public education
      
    • Diseases
      
    • Drugs
      
    • Combination of diagnostics and therapeutics
      
    • Healthcare companies
      
    • Prevention
      
    • Unmet needs in antisense therapeutics
      
    • Summary of financial aspects of antisense therapy
      
11. Chapter 10 Companies Active In Development Of Antisense
    Products
    
    • Introduction
      
    • Pharmaceutical companies active in antisense therapy
      
    • Antisense company profiles
      
    • Aronex Pharmaceuticals Inc
      
    • Corporate overview
      
    • Products
      
    • Atlantic Pharmaceuticals Inc
      
    • Corporate overview
      
    • Antisense technology
      
    • Products/applications
      
    • Atugen Biotechnology AG
      
    • Corporate overview
      
    • Antisense technology
      
    • Services
      
    • Collaborations
      
    • AVI Biopharma Inc
      
    • Corporate overview
      
    • Antisense technology
      
    • Product pipeline
      
    • Research grants
      
    • Collaborations
      
    • Patents
      
    • Biognostik AG
      
    • Corporate overview
      
    • Products
      
    • BioSource International Inc
      
    • Corporate overview
      
    • Boron Biologicals Inc
      
    • Corporate overview
      
    • Antisense technology
      
    • Cryogenic Solutions
      
    • Corporate overview
      
    • Antisense technology/applications
      
    • Patents and intellectual property
      
    • Collaborations
      
    • Independent research studies
      
    • Enzo Therapeutic Inc
      
    • Corporate overview
      
    • Antisense technology/products
      
    • Patents
      
    • Epigenesis Pharmaceuticals
      
    • Corporate overview
      
    • Financials
      
    • Antisense technology
      
    • Products
      
    • Epoch Pharmaceuticals
      
    • Corporate overview
      
    • Financials
      
    • Antisense technology
      
    • Applications
      
    • Patents
      
    • Collaborations
      
    • Exiqon AG
      
    • Corporate overview
      
    • Collaborations
      
    • Antisense technology/products
      
    • Gene Tools LLC
      
    • Corporate overview
      
    • Products
      
    • Genta Inc
      
    • Corporate overview
      
    • Financials
      
    • Antisense technology
      
    • Products
      
    • Collaborations
      
    • Geron Inc
      
    • Corporate overview
      
    • Financials
      
    • Antisense technology
      
    • Gilead Sciences
      
    • Corporate overview
      
    • Financials
      
    • Product pipeline
      
    • Collaborations
      
    • Hybridon Inc
      
    • Corporate overview
      
    • Financials
      
    • Antisense technology
      
    • Patents/licensing/intellectual property 2
      
    • Product pipeline
      
    • Collaborations
      
    • Ibis Therapeutic
      
    • Corporate overview
      
    • Antisense technology
      
    • Product pipeline
      
    • Collaborations
      
    • Immusol Inc
      
    • Corporate overview
      
    • Antisense technology
      
    • Products
      
    • Collaborations
      
    • Patents
      
    • Integrated DNA Technologies (IDT)
      
    • Corporate overview
      
    • Antisense technology/services
      
    • Collaborations
      
    • Patents
      
    • Inex Pharmaceuticals Corporation
      
    • Corporate overview
      
    • Financials
      
    • Antisense technology
      
    • Products
      
    • Patents
      
    • Collaborations
      
    • Isis Pharmaceuticals
      
    • Corporate overview
      
    • Financials
      
    • Antisense technology
      
    • Product pipeline
      
    • Collaborations
      
    • Patents
      
    • Kimeragen Inc
      
    • Corporate overview
      
    • Financials
      
    • Antisense technology
      
    • Collaborations
      
    • Potential applications
      
    • Lorus Therapeutics
      
    • Corporate overview
      
    • Financials
      
    • Antisense technology
      
    • Product pipeline
      
    • MethylGene Inc
      
    • Corporate overview
      
    • Financials
      
    • Antisense technology
      
    • Product pipeline
      
    • Collaborations
      
    • NeoPharm Inc
      
    • Corporate overview
      
    • Products
      
    • Collaborations
      
    • Patents
      
    • Oligo Therapeutics Inc
      
    • Corporate overview
      
    • Antisense technology
      
    • Patents
      
    • OriGenix Technologies
      
    • Corporate overview
      
    • Financials
      
    • Antisense technology/product pipeline
      
    • Pantheco AG
      
    • Corporate overview
      
    • Financials
      
    • Antisense technology/applications
      
    • Ribotargets Ltd
      
    • Corporate overview
      
    • Financials
      
    • Antisense technology
      
    • Product pipeline
      
    • Ribozyme Pharmaceuticals
      
    • Corporate overview
      
    • Financials
      
    • Antisense technology
      
    • Patents/licenses
      
    • Product pipeline
      
    • Collaborations
      
    • Salus Therapeutics Inc
      
    • Corporate overview
      
    • Antisense technology
      
    • Applications
      
    • Research grants
      
    • Sequitur Inc
      
    • Corporate overview
      
    • Antisense technology
      
    • Services
      
    • Collaborations
      
    • Patents
      
    • Trilink Biotechnologies Inc
      
    • Corporate overview
      
12. Chapter 11 Appendix
    
    • Abbreviations
      
    • Glossary
      
13. References
    
14. List of Figures
    
    • Figure 1.1: Regulatory processes in the normal cell
      
    • Figure 1.2: Antisense strategies
      
    • Figure 1.3: Potential clinical applications of antisense therapy
      
    • Figure 1.4: Relation of antisense technologies to other segments of
      
    • biopharmaceutical industry
      
    • Figure 2.5: Structural formulae of oligonucleotide analogues
      
    • Figure 3.6: Mechanism of action of peptide nucleic acid (PNA)
      
    • Figure 5.7: The triple helix forming oligonucleotide (shown in bold) binds to the
      
    • double helix of the DNA target
      
    • Figure 5.8: Proposed mechanism of action of triplex-forming oligonucleotides
      
    • Figure 6.9: Mechanism of control of viral replication by ribozymes
      
    • Figure 9.10: Forecast total value of the global antisense market, 2000-2010
      
    • Figure 9.11: Unfulfilled potential in antisense therapeutics
      
15. List of Tables
    
    • Table 1.1: Historical landmarks in the development of antisense therapeutics
      
    • Table 1.2: Molecular basis of antisense therapeutics
      
    • Table 2.3: Molecular mechanisms of action of antisense drugs
      
    • Table 3.4: Methods of administration of oligonucleotides
      
    • Table 3.5: Antisense technologies as gene therapy approaches
      
    • Table 3.6: Potential applications of vectors expressing antisense RNA
      
    • Table 4.7: Mechanisms of anti-cancer effect of antisense oligonucleotides
      
    • Table 4.8: Antisense oligonucleotides targeted to oncogenes in solid tumors
      
    • Table 4.9: Antisense therapies in development for glioblastoma multiforme
      
    • Table 4.10: Antisense oligonucleotides in clinical trials for cancer
      
    • Table 4.11: Viruses amenable to antisense therapy in vitro
      
    • Table 4.12: Antisense oligonucleotides for viral infections: clinical
      trials/approved
      
    • Table 6.13: Ribozymes in clinical development
      
    • Table 9.14: Current market value of selected therapeutic areas relevant to
      antisense therapy
      
    • Table 9.15: Market size according to type of antisense technologies and their
      applications
      
    • Table 9.16: Markets for antisense therapy for selected indications, 2000-2010
      
    • Table 9.17: Market size according to type of antisense technologies and their
      applications
      
    • Table 10.18: Classification of antisense companies
      
    • Table 10.19: Pharmaceutical companies active in the antisense therapy sector
      
    • Table 10.20: Isis' product pipeline, 1999
      
    • Table 10.21: MethylGene's R&D pipeline, 1999
      
    • Table 10.22: NeoPharm antineoplastic products in development
      
      

      Abstract

      A vast range of human diseases is amenable to antisense therapy with initial emphasis on cancer, viral diseases, inflammatory disorders and restenosis following angioplasty. To position antisense in a competitive context, this report analyses the commercial premise of each of the antisense technologies and forecasts future market shares. The report also investigates the challenges of drug delivery with antisense oligonucleotides and the role of gene therapy.
      
      Get Full Details About This Report >>

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