Advanced Delivery and Therapeutic Applications of RNAi

Professor Kun Cheng, Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, USAProfessor Cheng's research interests include the delivery and therapeutic applications of RNAi for breast cancer, prostate cancer, liver diseases, and type I diabetes. He has been working in the area of nucleic acids since 2002. He is co-editor of Advanced Drug Delivery with Dr. Ashim Mitra and Dr. Chi Lee (Wiley, 2012). He has also co-edited a themed issue entitled "siRNA Delivery" with Dr. Ram Mahato for the journal Molecular Pharmaceutics, and has developed and taught a graduate course entitled "Protein and Nucleic Acid Drug Delivery".Professor Ram I. Mahato, Department of Pharmaceutical Sciences, School of Pharmacy, University of Tennessee Health Science Center, USAProfessor Mahato is a full professor of Pharmaceutics and Drug/Gene Delivery at the University of Tennessee Health Science Center Memphis. He is the author or co-author of 85 peer reviewed articles and book chapters. He has also edited/written five books and six special journal issues. He is a Special Features Editor of Pharmaceutical Research and on the editorial board of several journals. His research interest includes delivery and targeting of small molecules, oligonucleotides, siRNA and genes.

• Preface xvii Contributors xixAbout the Editors xxiiiPart 1 Introduction and Basics of RNAi 11 Mechanisms and Barriers to RNAi Delivery 3Jiehua Zhou and John J. Rossi1.1 Introduction 31.2 Barriers to Systemic RNAi Delivery 51.3 Rational Design to Improve RNAi Efficacy 61.4 Chemical Modifications to Enhance siRNA Stability and Reduce Immune Response 71.5 Cellular Uptake and Intracellular Release of siRNA 71.6 Combinatorial Targeting for Targeted RNAi Delivery 81.7 Cell-Specific Aptamer-Functionalized Nanocarriers for RNAi Delivery 91.8 The Clinical Development and Challenges of siRNAs Therapeutics 101.9 Conclusion and Perspectives 12References 122 Analysis of siRNA Delivery Using Various Methodologies 19Yi Pei2.1 Introduction 192.2 Checkpoints for Analyzing siRNA Delivery 202.3 Methods for Analysis of siRNA 262.4 Case Study for siRNA Delivery Analysis 38References 393 Challenges and Opportunities in Bringing RNAi Technologies from Bench to Bed 45Sandesh Subramanya and Lance Ford3.1 Introduction 453.2 RNAi Mediator (siRNA or shRNA) 453.3 Safety Issues of RNAi Mediators 503.4 Efficacy of RNAi Mediators 523.5 RNAi Mediators in Clinical Trials 533.6 Conclusion 54References 55Nonclinical Safety Assessments and Clinical Pharmacokinetics for Oligonucleotide Therapeutics: A Regulatory Perspective 63Shwu-Luan Lee, Paul Brown, Jian Wang and Robert T. Dorsam4.1 Introduction 634.2 Unique Properties of Oligonucleotide-based Therapeutics 634.3 Regulation of Oligonucleotide-Based Therapeutics 654.4 Conclusion 79Disclaimer 79 Appendix 79 References 80Role of Promoters and MicroRNA Backbone for Efficient Gene Silencing 83Feng Li and Ram I. Mahato5.1 Introduction 835.2 Promoters for shRNA Expression 845.3 miRNA-based shRNAs 965.4 Concluding Remarks 100 References 101Part 2 RNAi Delivery Strategies 109 6 Bioconjugation of siRNA for Site-specific Delivery 111Bin Qin, Wei Jin and Kun Cheng6.1 Introduction 1116.2 Conjugation Strategy 1126.3 Bioconjugates for Site-specific Delivery 1206.4 Conclusion 129References 1297 Multifunctional RNAi Delivery Systems 137China Malakondaiah Kummitha, Anthony S. Malamas and Zheng-Rong Lu7.1 Introduction 137 7.1.1 Chapter Objectives 1397.2 Lipid-Based Delivery Systems 1397.3 Polymeric Multifunctional siRNA Delivery Systems 1507.4 Conclusion 157References 1578 Dendrimers in RNAi Delivery 163Jose Luis Jimenez Fuentes, Paula Ortega, Sara Ferrando-Martýnez, Rafael Gomez, Manuel Leal, Javier de la Mata and MaAngeles Munoz-Fernandez8.1 Introduction 1638.2 Challenges in RNAi Delivery 1648.3 Dendrimers as Non Viral Vectors 1669 Development of Pharmaceutically Adapted Mesoporous Silica Nanoparticles for siRNA Delivery 187Wilson X. Mai, Tian Xia and Huan Meng9.1 Introduction 1879.2 Mesoporous Silica Nanoparticles as Novel Inorganic Nanocarriers for siRNA Delivery 1889.3 Safety Assessment of Nanocarrier and Design of Safe MSNP Carrier 199References 1799.4 Summary References 20210 Environmentally-Responsive Nanogels for siRNA Delivery 207Atsushi Tamura and Yukio Nagasaki10.1 Introduction 20710.2 Reductive Environment-Responsive Disulfide Crosslinked Nanogels 20910.3 Temperature-Responsive Nanogels 21110.4 pH-Responsive Nanogels 21210.5 PEGylated and Partially Quaternized Polyamine Nanogels 21610.6 Conclusions 220References 22011 Viral-Mediated Delivery of shRNA and miRNA 225Fredric P. Manfredsson11.1 Introduction 22511.2 RNAi – A Brief Overview 22611.3 shRNA or miRNA? 22611.4 Rational Design 22711.5 Viral Vectors 22711.6 Tissue-specific Transduction 23311.7 Applications of Virally Expressed shRNAs 24111.8 Viral Gene Therapy in the Clinic 24111.9 Conclusion 242References 24212 The Control of RNA Interference with Light 255Simon H. Friedman12.1 Introduction 255 12.2 The Importance of Gene Expression 25512.3 Light Control of Gene Expression 25712.4 Why Use RNA Interference as a Basis for Light Control of Gene Expression? 25812.5 Light Activated RNA Interference (LARI), the work of Friedman and Co-Workers 25912.6 Work of McMaster and Co-Workers, 50 Antisense Phosphate Block 26212.7 Work of Heckel and Co-Workers, Nucleobase Block 26312.8 Use of 20 FsiRNA, work of Monroe and Co-Workers 26412.9 Photochemical Internalization 26512.10 Future Directions and Conclusions 266Acknowledgments 267References 267Part 3 Applications of RNAi in Various Diseases 26913 RNAi in Cancer Therapy 271Cristian Rodriguez-Aguayo, Arturo Chavez-Reyes, Gabriel Lopez-Berestein and Anil K. Sood13.1 Introduction 27113.2 Therapeutic Opportunities for Noncoding RNAs 27413.3 RNAs as Drugs 27713.4 Overcoming Anatomical and Physiologic Barriers 27813.5 Advanced Delivery 28313.6 Clinical Experience 29413.7 The Next Steps 298Acknowledgments 298References 29814 Adenovirus-mediated siRNA Delivery to Cancer 309Chae-Ok Yun14.1 Introduction 30914.2 shRNA-expressing Adenoviruses: Cancer Biological Studies and Therapeutic Implications 31214.3 Exploiting Oncolytic Adenovirus for siRNA Expression 31514.4 Current Limitations of Adenovirus-mediated siRNA Therapy and Future Directions: Smart Adenovirus Nanocomplexes Expressing siRNA for Systemic Administration 31814.5 Conclusion 320References 32115 RNAi in Liver Diseases 327Jiang Li, Jianqin Lu, Yifei Zhang, Mohammed Ghazwani, Peng Zhang, Xiang Gao and Song Li15.1 Introduction 32715.2 RNAi in Viral Hepatitis 32715.3 RNAi in Hepatocellular Carcinoma 33615.4 RNAi in Liver Fibrosis 34015.5 Delivery Systems in RNAi 34515.6 Conclusion 352Acknowledgments 353References 35316 Approaches to Delivering RNAi Therapeutics that Target Hepatitis B Virus 367Carol Crowther, Mohube Betty Mowa, Abdullah Ely and Patrick Arbuthnot16.1 Introduction 36716.2 Vectors Suitable for Hepatic Delivery of HBV Gene Silencers 36916.3 Conclusions 381Acknowledgments 382References 38217 RNAi in Respiratory Diseases 391Ciara Kelly, Awadh B. Yadav, Paul J. McKiernan, Catherine M. Greene and Sally-Ann Cryan17.1 Introduction 39117.2 Respiratory Disease and RNA Interference 39217.3 Delivery and Development of RNAi Therapies for Respiratory Disease 39717.4 Conclusions 408Acknowledgements 408 References 40818 RNAi in Ocular Diseases 417Andrey Turchinovich, Georg Zoidl and Rolf Dermietzel18.1 Introduction 41718.2 The Principle of RNAi 41818.3 In vivo Delivery of siRNA 41918.4 Delivery of siRNA into the Eye 42018.5 Conclusions 431Abbreviations 432 References 43219 micro RNAs as Therapeutic Agents and Targets 439D.S. Karolina and K. Jeyaseelan19.1 Introduction 43919.2 miRNA Therapeutics 44019.3 MicroRNAs and Cancer 44719.4 MicroRNAs in Stroke 45019.5 MicroRNAs in Heart Diseases 45219.6 MicroRNAs in Diabetes Mellitus 45419.7 MicroRNAs in Liver Diseases 45719.8 MicroRNAs and Ocular Diseases 46119.9 MicroRNAs and Respiratory Diseases 46219.10 MicroRNAs and Stem Cell Research 46519.11 Conclusion 468References 46920 Delivery of Micro RNA Sponges for Interrogation of MicroRNA Function In Vitro and In Vivo 483Jiakai Lin and Shu Wang20.1 MicroRNA Loss-of-Function Studies 48320.2 Considerations in MicroRNA Sponge Design 48620.3 Advantages and Limitations of MicroRNA Sponge over Other MicroRNA Loss-of-Function Strategies 48920.4 Interrogating MicroRNA Function via Transient MicroRNA Sponge Expression 49320.5 Interrogating MicroRNA Function via Stable MicroRNA Sponge Expression 49420.6 Utility of MicroRNA Sponge in Living Organisms 49620.7 Future Perspectives 498References 499Index 505