Advanced Delivery and Therapeutic Applications of RNAi

Professor Kun Cheng, Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, USA Professor 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, USA Professor 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 xix

About the Editors xxiii

Part 1 Introduction and Basics of RNAi 1

1 Mechanisms and Barriers to RNAi Delivery 3
Jiehua Zhou and John J. Rossi

1.1 Introduction 3

1.2 Barriers to Systemic RNAi Delivery 5

1.3 Rational Design to Improve RNAi Efficacy 6

1.4 Chemical Modifications to Enhance siRNA Stability and Reduce Immune Response 7

1.5 Cellular Uptake and Intracellular Release of siRNA 7

1.6 Combinatorial Targeting for Targeted RNAi Delivery 8

1.7 Cell-Specific Aptamer-Functionalized Nanocarriers for RNAi Delivery 9

1.8 The Clinical Development and Challenges of siRNAs Therapeutics 10

1.9 Conclusion and Perspectives 12

References 12

2 Analysis of siRNA Delivery Using Various Methodologies 19
Yi Pei

2.1 Introduction 19

2.2 Checkpoints for Analyzing siRNA Delivery 20

2.3 Methods for Analysis of siRNA 26

2.4 Case Study for siRNA Delivery Analysis 38

References 39

3 Challenges and Opportunities in Bringing RNAi Technologies from Bench to Bed 45
Sandesh Subramanya and Lance Ford

3.1 Introduction 45

3.2 RNAi Mediator (siRNA or shRNA) 45

3.3 Safety Issues of RNAi Mediators 50

3.4 Efficacy of RNAi Mediators 52

3.5 RNAi Mediators in Clinical Trials 53

3.6 Conclusion 54

References 55

Nonclinical Safety Assessments and Clinical Pharmacokinetics for Oligonucleotide Therapeutics: A Regulatory Perspective 63
Shwu-Luan Lee, Paul Brown, Jian Wang and Robert T. Dorsam

4.1 Introduction 63

4.2 Unique Properties of Oligonucleotide-based Therapeutics 63

4.3 Regulation of Oligonucleotide-Based Therapeutics 65

4.4 Conclusion 79

Disclaimer 79

Appendix 79

References 80

Role of Promoters and MicroRNA Backbone for Efficient Gene Silencing 83
Feng Li and Ram I. Mahato

5.1 Introduction 83

5.2 Promoters for shRNA Expression 84

5.3 miRNA-based shRNAs 96

5.4 Concluding Remarks 100 References 101

Part 2 RNAi Delivery Strategies 109

6 Bioconjugation of siRNA for Site-specific Delivery 111
Bin Qin, Wei Jin and Kun Cheng

6.1 Introduction 111

6.2 Conjugation Strategy 112

6.3 Bioconjugates for Site-specific Delivery 120

6.4 Conclusion 129

References 129

7 Multifunctional RNAi Delivery Systems 137
China Malakondaiah Kummitha, Anthony S. Malamas and Zheng-Rong Lu

7.1 Introduction 137 7.1.1 Chapter Objectives 139

7.2 Lipid-Based Delivery Systems 139

7.3 Polymeric Multifunctional siRNA Delivery Systems 150

7.4 Conclusion 157

References 157

8 Dendrimers in RNAi Delivery 163
Jose Luis Jimenez Fuentes, Paula Ortega, Sara Ferrando-Martýnez, Rafael Gomez, Manuel Leal, Javier de la Mata and MaAngeles Munoz-Fernandez

8.1 Introduction 163

8.2 Challenges in RNAi Delivery 164

8.3 Dendrimers as Non Viral Vectors 166

9 Development of Pharmaceutically Adapted Mesoporous Silica Nanoparticles for siRNA Delivery 187
Wilson X. Mai, Tian Xia and Huan Meng

9.1 Introduction 187

9.2 Mesoporous Silica Nanoparticles as Novel Inorganic Nanocarriers for siRNA Delivery 188

9.3 Safety Assessment of Nanocarrier and Design of Safe MSNP Carrier 199

References 179

9.4 Summary References 202

10 Environmentally-Responsive Nanogels for siRNA Delivery 207
Atsushi Tamura and Yukio Nagasaki

10.1 Introduction 207

10.2 Reductive Environment-Responsive Disulfide Crosslinked Nanogels 209

10.3 Temperature-Responsive Nanogels 211

10.4 pH-Responsive Nanogels 212

10.5 PEGylated and Partially Quaternized Polyamine Nanogels 216

10.6 Conclusions 220

References 220

11 Viral-Mediated Delivery of shRNA and miRNA 225
Fredric P. Manfredsson

11.1 Introduction 225

11.2 RNAi – A Brief Overview 226

11.3 shRNA or miRNA? 226

11.4 Rational Design 227

11.5 Viral Vectors 227

11.6 Tissue-specific Transduction 233

11.7 Applications of Virally Expressed shRNAs 241

11.8 Viral Gene Therapy in the Clinic 241

11.9 Conclusion 242

References 242

12 The Control of RNA Interference with Light 255
Simon H. Friedman

12.1 Introduction 255 12.2 The Importance of Gene Expression 255

12.3 Light Control of Gene Expression 257

12.4 Why Use RNA Interference as a Basis for Light Control of Gene Expression? 258

12.5 Light Activated RNA Interference (LARI), the work of Friedman and Co-Workers 259

12.6 Work of McMaster and Co-Workers, 50 Antisense Phosphate Block 262

12.7 Work of Heckel and Co-Workers, Nucleobase Block 263

12.8 Use of 20 FsiRNA, work of Monroe and Co-Workers 264

12.9 Photochemical Internalization 265

12.10 Future Directions and Conclusions 266

Acknowledgments 267

References 267

Part 3 Applications of RNAi in Various Diseases 269

13 RNAi in Cancer Therapy 271
Cristian Rodriguez-Aguayo, Arturo Chavez-Reyes, Gabriel Lopez-Berestein and Anil K. Sood

13.1 Introduction 271

13.2 Therapeutic Opportunities for Noncoding RNAs 274

13.3 RNAs as Drugs 277

13.4 Overcoming Anatomical and Physiologic Barriers 278

13.5 Advanced Delivery 283

13.6 Clinical Experience 294

13.7 The Next Steps 298

Acknowledgments 298

References 298

14 Adenovirus-mediated siRNA Delivery to Cancer 309
Chae-Ok Yun

14.1 Introduction 309

14.2 shRNA-expressing Adenoviruses: Cancer Biological Studies and Therapeutic Implications 312

14.3 Exploiting Oncolytic Adenovirus for siRNA Expression 315

14.4 Current Limitations of Adenovirus-mediated siRNA Therapy and Future Directions: Smart Adenovirus Nanocomplexes Expressing siRNA for Systemic Administration 318

14.5 Conclusion 320

References 321

15 RNAi in Liver Diseases 327
Jiang Li, Jianqin Lu, Yifei Zhang, Mohammed Ghazwani, Peng Zhang, Xiang Gao and Song Li

15.1 Introduction 327

15.2 RNAi in Viral Hepatitis 327

15.3 RNAi in Hepatocellular Carcinoma 336

15.4 RNAi in Liver Fibrosis 340

15.5 Delivery Systems in RNAi 345

15.6 Conclusion 352

Acknowledgments 353

References 353

16 Approaches to Delivering RNAi Therapeutics that Target Hepatitis B Virus 367
Carol Crowther, Mohube Betty Mowa, Abdullah Ely and Patrick Arbuthnot

16.1 Introduction 367

16.2 Vectors Suitable for Hepatic Delivery of HBV Gene Silencers 369

16.3 Conclusions 381

Acknowledgments 382

References 382

17 RNAi in Respiratory Diseases 391
Ciara Kelly, Awadh B. Yadav, Paul J. McKiernan, Catherine M. Greene and Sally-Ann Cryan

17.1 Introduction 391

17.2 Respiratory Disease and RNA Interference 392

17.3 Delivery and Development of RNAi Therapies for Respiratory Disease 397

17.4 Conclusions 408

Acknowledgements 408 References 408

18 RNAi in Ocular Diseases 417
Andrey Turchinovich, Georg Zoidl and Rolf Dermietzel

18.1 Introduction 417

18.2 The Principle of RNAi 418

18.3 In vivo Delivery of siRNA 419

18.4 Delivery of siRNA into the Eye 420

18.5 Conclusions 431

Abbreviations 432

References 432

19 micro RNAs as Therapeutic Agents and Targets 439
D.S. Karolina and K. Jeyaseelan

19.1 Introduction 439

19.2 miRNA Therapeutics 440

19.3 MicroRNAs and Cancer 447

19.4 MicroRNAs in Stroke 450

19.5 MicroRNAs in Heart Diseases 452

19.6 MicroRNAs in Diabetes Mellitus 454

19.7 MicroRNAs in Liver Diseases 457

19.8 MicroRNAs and Ocular Diseases 461

19.9 MicroRNAs and Respiratory Diseases 462

19.10 MicroRNAs and Stem Cell Research 465

19.11 Conclusion 468

References 469

20 Delivery of Micro RNA Sponges for Interrogation of MicroRNA Function In Vitro and In Vivo 483
Jiakai Lin and Shu Wang

20.1 MicroRNA Loss-of-Function Studies 483

20.2 Considerations in MicroRNA Sponge Design 486

20.3 Advantages and Limitations of MicroRNA Sponge over Other MicroRNA Loss-of-Function Strategies 489

20.4 Interrogating MicroRNA Function via Transient MicroRNA Sponge Expression 493

20.5 Interrogating MicroRNA Function via Stable MicroRNA Sponge Expression 494

20.6 Utility of MicroRNA Sponge in Living Organisms 496

20.7 Future Perspectives 498

References 499

Index 505