Advanced Delivery and Therapeutic Applications of RNAi

 
 
Wiley (Verlag)
  • erschienen am 4. April 2013
  • |
  • 536 Seiten
 
E-Book | PDF mit Adobe-DRM | Systemvoraussetzungen
978-1-118-61075-6 (ISBN)
 
RNA interference (RNAi) is a process in living cells whereby small double stranded RNA interferes with the expression of specific genes with complementary nucleotide sequence. Like many nucleic acid-based therapies, RNAi has great potential in treating various life-threatening diseases. However, the poor stability and cellular uptake of RNAi molecules remain considerable barriers to their efficient delivery which is paramount to a successful therapy. This book provides a comprehensive introduction to RNAi delivery, then goes on to discuss different delivery strategies, and concludes with current applications in various diseases. It covers:
* Mechanisms, Barriers, and Analysis of RNAi Delivery
* Nonclinical Safety Assessments and Clinical Pharmacokinetics: A Regulatory Perspective
* Bioconjugation of siRNA for Site Specifi c Delivery
* Nanoscale Delivery Systems for RNAi
* Environmentally-Responsive Delivery Systems for RNAi
* Light-sensitive RNAi
* Viral-Mediated Delivery of shRNA and miRNA
* RNAi applications in Cancer Therapy, Liver Diseases, Hepatitis B, and Ocular Disease
* miRNA as therapeutic agents and targets
Advanced Delivery and Therapeutic Applications of RNAi combines the essential aspects of developing RNAi therapeutics from bench to clinic, and is invaluable for researchers working on RNAi, drug discovery and delivery, biomedical engineering, biomaterials, molecular biology, and biotechnology.
weitere Ausgaben werden ermittelt
  • Advanced Delivery and Therapeutic Applications of RNAi
  • Contents
  • Preface
  • Contributors
  • About the Editors
  • Part 1: Introduction and Basics of RNAi
  • 1 Mechanisms and Barriers to RNAi Delivery
  • 1.1 Introduction
  • 1.2 Barriers to Systemic RNAi Delivery
  • 1.3 Rational Design to Improve RNAi Efficacy
  • 1.4 Chemical Modifications to Enhance siRNA Stability and Reduce Immune Response
  • 1.5 Cellular Uptake and Intracellular Release of siRNA
  • 1.6 Combinatorial Targeting for Targeted RNAi Delivery
  • 1.7 Cell-Specific Aptamer-Functionalized Nanocarriers for RNAi Delivery
  • 1.8 The Clinical Development and Challenges of siRNAs Therapeutics
  • 1.9 Conclusion and Perspectives
  • References
  • 2 Analysis of siRNA Delivery Using Various Methodologies
  • 2.1 Introduction
  • 2.2 Checkpoints for Analyzing siRNA Delivery
  • 2.2.1 Circulation Checkpoint
  • 2.2.2 Organ or Tissue Checkpoint
  • 2.2.3 Cellular Checkpoint
  • 2.2.4 RISC Checkpoint
  • 2.2.5 Target mRNA Knockdown (Indirect Checkpoint)
  • 2.2.6 Protein and Outcome (Indirect Checkpoint)
  • 2.2.7 Safety (Indirect Checkpoint)
  • 2.3 Methods for Analysis of siRNA
  • 2.3.1 General Considerations
  • 2.3.2 Hybridization-Based (Non-Imaging) Methods
  • 2.3.3 Non-Hybridization-Based (Non-Imaging) Methods
  • 2.3.4 Imaging-Based (Non-Hybridization) Methods
  • 2.3.5 Imaging-Based (Hybridization) Methods
  • 2.4 Case Study for siRNA Delivery Analysis
  • References
  • 3 Challenges and Opportunities in Bringing RNAi Technologies from Bench to Bed
  • 3.1 Introduction
  • 3.2 RNAi Mediator (siRNA or shRNA)
  • 3.2.1 siRNA
  • 3.2.2 Vector-derived shRNA
  • 3.2.3 miRNAs
  • 3.3 Safety Issues of RNAi Mediators
  • 3.3.1 Immune Stimulation
  • 3.3.2 RNAi Overexpression
  • 3.4 Efficacy of RNAi Mediators
  • 3.4.1 Therapeutic Response
  • 3.5 RNAi Mediators in Clinical Trials
  • 3.6 Conclusion
  • References
  • 4 Nonclinical Safety Assessments and Clinical Pharmacokinetics for Oligonucleotide Therapeutics: A Regulatory Perspective
  • 4.1 Introduction
  • 4.2 Unique Properties of Oligonucleotide-based Therapeutics
  • 4.3 Regulation of Oligonucleotide-Based Therapeutics
  • 4.3.1 Submission to the FDA
  • 4.3.2 Review Process for Non-clinical Studies
  • 4.3.3 Regulatory Issues
  • 4.3.4 Clinical Pharmacokinetics
  • 4.4 Conclusion
  • Disclaimer
  • Appendix
  • References
  • 5 Role of Promoters and MicroRNA Backbone for Efficient Gene Silencing
  • 5.1 Introduction
  • 5.2 Promoters for shRNA Expression
  • 5.2.1 Constitutive Promoters
  • 5.2.2 Inducible Promoters
  • 5.2.3 Site Specific Promoters
  • 5.3 miRNA-based shRNAs
  • 5.3.1 miRNA-based shRNA Enhances Gene Silencing
  • 5.3.2 miRNA-based shRNA Reduces Toxicities
  • 5.3.3 Application of miRNA-based shRNA for Combination Gene Therapy
  • 5.4 Concluding Remarks
  • References
  • Part 2: RNAi Delivery Strategies
  • 6 Bioconjugation of siRNA for Site-specific Delivery
  • 6.1 Introduction
  • 6.2 Conjugation Strategy
  • 6.2.1 RNA Chemical Modification
  • 6.2.2 Site of Conjugation
  • 6.2.3 Conjugation Chemistry
  • 6.3 Bioconjugates for Site-specific Delivery
  • 6.3.1 Antibody-siRNA Bioconjugates
  • 6.3.2 Aptamer-siRNA Bioconjugates
  • 6.3.3 Peptide-siRNA Bioconjugates
  • 6.3.4 Lipid-siRNA Bioconjugates
  • 6.3.5 Others
  • 6.4 Conclusion
  • References
  • 7 Multifunctional RNAi Delivery Systems
  • 7.1 Introduction
  • 7.1.1 Chapter Objectives
  • 7.2 Lipid-Based Delivery Systems
  • 7.2.1 Cationic Lipids
  • 7.2.2 Ionizable Cationic Lipids
  • 7.2.3 Lipid-Like Materials
  • 7.2.4 pH-sensitive Surfactants as Multifunctional siRNA Carriers
  • 7.3 Polymeric Multifunctional siRNA Delivery Systems
  • 7.3.1 Polyethylenimine
  • 7.3.2 Chitosan
  • 7.3.3 Cyclodextrins
  • 7.3.4 Dendrimers
  • 7.3.5 Polyalkylacrylic Acid-based pH-sensitive Polymers
  • 7.3.6 Other pH-sensitive Polymers
  • 7.4 Conclusion
  • References
  • 8 Dendrimers in RNAi Delivery
  • 8.1 Introduction
  • 8.2 Challenges in RNAi Delivery
  • 8.3 Dendrimers as Non Viral Vectors
  • 8.3.1 Dendritic Architectures
  • 8.3.2 Synthesis of Dendrimers
  • 8.3.3 Types of Dendrimers in Drug Delivery
  • References
  • 9 Development of Pharmaceutically Adapted Mesoporous Silica Nanoparticles for siRNA Delivery
  • 9.1 Introduction
  • 9.2 Mesoporous Silica Nanoparticles as Novel Inorganic Nanocarriers for siRNA Delivery
  • 9.2.1 Discovery and Synthesis
  • 9.2.2 Surface Modification of MSNP for Nucleic Acid Delivery
  • 9.2.3 MSNP for Dual siRNA and Drug Delivery
  • 9.2.4 Improving in vivo Implementation of MSNP-Based Delivery Platform
  • 9.2.5 Design of Pharmaceutically Adapted MSNP via the Knowledge Generated by Discoveries at the Nano/Bio Interface
  • 9.3 Safety Assessment of Nanocarrier and Design of Safe MSNP Carrier
  • 9.3.1 Safety of Nanocarriers
  • 9.3.2 Safe Design of MSNP Carrier
  • 9.4 Summary
  • References
  • 10 Environmentally-Responsive Nanogels for siRNA Delivery
  • 10.1 Introduction
  • 10.1.1 siRNA Delivery System
  • 10.1.2 Crosslinked Nanogels for siRNA Delivery
  • 10.2 Reductive Environment-Responsive Disulfide Crosslinked Nanogels
  • 10.3 Temperature-Responsive Nanogels
  • 10.4 pH-Responsive Nanogels
  • 10.4.1 Acid-degradable Nanogels for Intracellular Release of siRNA
  • 10.4.2 Design of pH-Responsive PEGylated Nanogels with Endosomal Escape Ability
  • 10.4.3 Cytoplasmic Delivery of PEGylated Nanogel/siRNA Complexes
  • 10.5 PEGylated and Partially Quaternized Polyamine Nanogels
  • 10.5.1 Design of Quaternized Polyamine Nanogels
  • 10.5.2 Enhanced Cellular Uptake of siRNA by Quaternized Polyamine Nanogels
  • 10.5.3 Enhanced Gene-Silencing Activity of Quaternized Polyamine Nanogel/siRNA Complexes
  • 10.6 Conclusions
  • References
  • 11 Viral-Mediated Delivery of shRNA and miRNA
  • 11.1 Introduction
  • 11.2 RNAi - A Brief Overview
  • 11.3 shRNA or miRNA?
  • 11.4 Rational Design
  • 11.5 Viral Vectors
  • 11.5.1 Recombinant Adeno-associated Virus (rAAV)
  • 11.5.2 Retrovirus (RV)
  • 11.5.3 Lentivirus (LV)
  • 11.5.4 Adenovirus (AD)
  • 11.5.5 Herpes Simplex Virus (HSV)
  • 11.5.6 Baculovirus (BV)
  • 11.5.7 Poxvirus
  • 11.6 Tissue-specific Transduction
  • 11.6.1 CNS
  • 11.6.2 Ocular
  • 11.6.3 Respiratory System
  • 11.6.4 Liver
  • 11.6.5 Skeletal Muscle
  • 11.6.6 Heart
  • 11.6.7 Systemic
  • 11.6.8 Ex Vivo
  • 11.6.9 Cell Culture
  • 11.6.10 Transcription Cassettes
  • 11.7 Applications of Virally Expressed shRNAs
  • 11.7.1 Virally Mediated "Knockouts"
  • 11.7.2 Concomitant Expression of Therapeutic Genes
  • 11.8 Viral Gene Therapy in the Clinic
  • 11.9 Conclusion
  • References
  • 12 The Control of RNA Interference with Light
  • 12.1 Introduction
  • 12.2 The Importance of Gene Expression
  • 12.3 Light Control of Gene Expression
  • 12.4 Why Use RNA Interference as a Basis for Light Control of Gene Expression?
  • 12.5 Light Activated RNA Interference (LARI), the work of Friedman and Co-Workers
  • 12.6 Work of McMaster and Co-Workers, 50 Antisense Phosphate Block
  • 12.7 Work of Heckel and Co-Workers, Nucleobase Block
  • 12.8 Use of 20 FsiRNA, work of Monroe and Co-Workers
  • 12.9 Photochemical Internalization
  • 12.10 Future Directions and Conclusions
  • Acknowledgments
  • References
  • Part 3 Applications of RNAi in Various Diseases
  • 13 RNAi in Cancer Therapy
  • 13.1 Introduction
  • 13.2 Therapeutic Opportunities for Noncoding RNAs
  • 13.3 RNAs as Drugs
  • 13.4 Overcoming Anatomical and Physiologic Barriers
  • 13.4.1 Intravascular Degradation
  • 13.4.2 Tissue and Intracellular Delivery
  • 13.4.3 Immune-mediated Toxic Effects
  • 13.4.4 Nanocarrier-mediated Toxic Effects
  • 13.5 Advanced Delivery
  • 13.5.1 Localized siRNA Delivery
  • 13.5.2 Systemic siRNA Delivery
  • 13.5.3 Targeted siRNA Delivery
  • 13.5.4 Monitoring Delivery and Therapeutic Response
  • 13.6 Clinical Experience
  • 13.7 The Next Steps
  • Acknowledgments
  • References
  • 14 Adenovirus-mediated siRNA Delivery to Cancer
  • 14.1 Introduction
  • 14.1.1 shRNA-expressing Vectors
  • 14.1.2 Adenovirus Vectors
  • 14.2 shRNA-expressing Adenoviruses: Cancer Biological Studies and Therapeutic Implications
  • 14.2.1 Oncogene-targeted shRNA-expressing Ads
  • 14.2.2 shRNA-expressing Adenoviruses that Target Anti-apoptotic Genes
  • 14.3 Exploiting Oncolytic Adenovirus for siRNA Expression
  • 14.4 Current Limitations of Adenovirus-mediated siRNATherapy and Future Directions: Smart Adenovirus Nanocomplexes Expressing siRNA for Systemic Administration
  • 14.5 Conclusion
  • References
  • 15 RNAi in Liver Diseases
  • 15.1 Introduction
  • 15.2 RNAi in Viral Hepatitis
  • 15.2.1 Hepatitis B
  • 15.2.2 RNAi of HBV Infection via siRNA/shRNA
  • 15.2.3 RNAi of HBV Infection via miRNAs
  • 15.2.4 Hepatitis C
  • 15.2.5 RNAi of HCV Infection via siRNA/shRNA
  • 15.2.6 RNAi of HCV Infection via miRNAs
  • 15.3 RNAi in Hepatocellular Carcinoma
  • 15.3.1 RNAi of HCC via siRNA/shRNA
  • 15.3.2 RNAi of HCC via miRNAs
  • 15.4 RNAi in Liver Fibrosis
  • 15.4.1 RNAi of Liver Fibrosis via siRNA/shRNA
  • 15.4.2 RNAi of Liver Fibrosis via miRNAs
  • 15.5 Delivery Systems in RNAi
  • 15.5.1 Liver Anatomy
  • 15.5.2 Viral Delivery Systems
  • 15.5.3 Non-Viral Delivery Systems
  • 15.5.4 Cell-specific Targeting Strategies
  • 15.5.5 Cellular Events after the Uptake of Nucleic Acid-Carrier Complexes
  • 15.5.6 Lipid-based Delivery Systems
  • 15.5.7 Polymer-Based Systems
  • 15.5.8 Calcium Phosphate-Lipid Hybrid System
  • 15.5.9 Hydrophobitized Nucleic Acid Derivatives
  • 15.5.10 Targeted Delivery to Tumor Blood Vessels
  • 15.6 Conclusion
  • Acknowledgments
  • References
  • 16 Approaches to Delivering RNAi Therapeutics that Target Hepatitis B Virus
  • 16.1 Introduction
  • 16.1.1 RNAi Therapeutics
  • 16.1.2 Hepatitis B Virus as a Target for RNAi-based Gene Silencing
  • 16.2 Vectors Suitable for Hepatic Delivery of HBV Gene Silencers
  • 16.2.1 Viral Vectors
  • 16.2.2 Nonviral Vectors
  • 16.3 Conclusions
  • Acknowledgments
  • References
  • 17 RNAi in Respiratory Diseases
  • 17.1 Introduction
  • 17.2 Respiratory Disease and RNA Interference
  • 17.2.1 RNAi in Lung Cancer
  • 17.2.2 RNAi to Treat Respiratory Infections
  • 17.2.3 RNAi in Inflammatory Lung Disease
  • 17.3 Delivery and Development of RNAi Therapies for Respiratory Disease
  • 17.3.1 Inhalation of RNA-medicines
  • 17.3.2 Chemical Modifications of siRNA
  • 17.3.3 RNAi Vectors
  • 17.3.4 RNAi Therapy In Vivo
  • 17.4 Conclusions
  • Acknowledgements
  • References
  • 18 RNAi in Ocular Diseases
  • 18.1 Introduction
  • 18.2 The Principle of RNAi
  • 18.3 In vivo Delivery of siRNA
  • 18.4 Delivery of siRNA into the Eye
  • 18.4.1 Routes for Ocular Delivery of siRNA
  • 18.4.2 Delivery of Naked siRNA
  • 18.4.3 Delivery of siRNA Using Carriers
  • 18.4.4 Viral Delivery of shRNA
  • 18.5 Conclusions
  • Abbreviations
  • References
  • 19 microRNAs as Therapeutic Agents and Targets
  • 19.1 Introduction
  • 19.2 miRNATherapeutics
  • 19.2.1 Therapeutic miRNA Inhibition
  • 19.2.2 Therapeutic miRNA Mimicry
  • 19.3 MicroRNAs and Cancer
  • 19.4 MicroRNAs in Stroke
  • 19.5 MicroRNAs in Heart Diseases
  • 19.6 MicroRNAs in Diabetes Mellitus
  • 19.7 MicroRNAs in Liver Diseases
  • 19.8 MicroRNAs and Ocular Diseases
  • 19.9 MicroRNAs and Respiratory Diseases
  • 19.10 MicroRNAs and Stem Cell Research
  • 19.11 Conclusion
  • References
  • 20 Delivery of MicroRNA Sponges for Interrogation of MicroRNA Function In Vitro and In Vivo
  • 20.1 MicroRNA Loss-of-Function Studies
  • 20.2 Considerations in MicroRNA Sponge Design
  • 20.2.1 Vector
  • 20.2.2 Promoter
  • 20.2.3 Reporter Gene
  • 20.2.4 MicroRNA Binding Sites
  • 20.3 Advantages and Limitations of MicroRNA Sponge over Other MicroRNA Loss-of-Function Strategies
  • 20.4 Interrogating MicroRNA Function via Transient MicroRNA Sponge Expression
  • 20.5 Interrogating MicroRNA Function via Stable MicroRNA Sponge Expression
  • 20.5.1 MicroRNA and Cell Differentiation
  • 20.5.2 MicroRNAs in Disease Development
  • 20.6 Utility of MicroRNA Sponge in Living Organisms
  • 20.6.1 MicroRNA Knockdown in Plants
  • 20.6.2 MicroRNA Knockdown in Mouse
  • 20.6.3 MicroRNA Knockdown in Drosophila Melanogaster
  • 20.7 Future Perspectives
  • References
  • Index
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