Decoy Oligodeoxynucleotides to Treat Inflammatory Diseases

Markus Hecker, Swen Wagner, Stefan W. Henning and Andreas H. Wagner

7.1 Introduction 163

7.2 Decoy Oligonucleotide Synthesis 164

7.3 Decoy Oligonucleotide Administration 165

7.3.1 Delivery 165

7.3.2 Pharmacokinetics 166

7.3.3 Toxicology 168

7.4 Mechanism of Action 168

7.4.1 Target Identification 169

7.4.2 Target Specificity 170

7.4.3 Sequence Optimization for Cellular Uptake 172

7.4.4 Stability 174

7.5 Therapeutic Applications 174

7.5.1 Asthma 174

7.5.2 Atherosclerosis and Related Vascular Remodelling Processes 176

7.5.3 Inflammatory Skin Disease 178

7.5.4 Rheumatoid Arthritis 181

7.5.5 Acute and Chronic Transplant Rejection 182

7.5.6 Other 183

7.6 Perspective 184

7.6.1 Nucleic Acid Based Drugs in Comparison 184

7.6.2 Clinical Development 185 References 185

Chapter 8 AS1411: Development of an Anticancer Aptamer

Nigel Courtenay-Luck and Donald M. Miller

8.1 An Introduction to Aptamers 189

8.2 AS1411: An Anticancer Aptamer 190

8.2.1 Nucleolin: An Anticancer Target 191

8.2.2 Anticancer Mechanism of Action of AS1411 192

8.3 In vitro Inhibition of Growth by AS1411 193

8.4 In vivo Biodistribution of AS1411 193

8.5 In vivo Antitumour Activity of AS1411 194

8.6 Preclinical Toxicology of AS1411 196

8.7 Clinical Studies with AS1411 196

8.8 Future Development of AS1411 197 References 197

Chapter 9 Spiegelmer NOX-E36 for Renal Diseases

Dirk Eulberg, Werner Purschke, Hans-Joachim Anders, Norma Selve and Sven Klussmann

9.1 Spiegelmers: Functional Mirror-Image Oligonucleotides 200 9.1.1 Identification of Spiegelmer Products 201

9.2 MCP-1 and Inflammatory Kidney Diseases 201

9.2.1.1 Species Homology 205

9.2.1.2 Pathophysiology of MCP-1 206

9.2.2 Inflammatory Kidney Diseases 207

9.2.2.1 Expression of MCP-1 in Inflamed Kidneys 208

9.2.2.2 Role of MCP-1 in Inflammatory

Renal Diseases 208

9.2.2.3 Main Indication: Lupus Nephritis 208

9.3 Identification and Characterization of NOX-E36 209

9.3.1 Path of Selection for NOX-E36 209

9.3.1.1 Biophysical Properties of NOX-E36 210

9.3.1.2 Biophysical Properties of NOX-E36-5'-Polyethyleneglycol (PEG) 210

9.3.2 In vitro Profiling of NOX-E36 211

9.3.2.1 Calcium-Release Assay 212

9.3.2.2 Chemotaxis Assay 213

9.3.2.3 In vitro Activity of NOX-E36-5'-PEG 213

9.3.2.4 Specificity of NOX-E36 213

9.3.2.5 Selectivity of NOX-E36 214

9.3.3 In vivo Efficacy of an Anti-MCP-1 Spiegelmer 215

9.3.3.1 Murine-Specific Spiegelmer: mNOX-E36 216

9.3.3.2 Functional in vitro Profile of Murine-Specific mNOX-E36 216

9.3.3.3 MRLlpr/lpr Mouse ('Lupus Mouse') -Chronic Progressive Renal Inflammation 217

9.3.3.4 mNOX-E36-3'-PEG Improves

Kidney Disease of MRLlpr/lpr Mice 218

9.3.3.5 mNOX-E36 Treatment Improves Condition of Skin and Eyes 219

9.3.3.6 mNOX-E36-3'-PEG Improves

Survival of MRLlpr/lpr Mice 220

9.4 Summary and Outlook 221

Acknowledgements 221

References 221

Chapter 10 Strategies for the Delivery of Oligonucleotides in vivo

Christian Reinsch, Evgenios Siepi, Andreas Dieckmann and Steffen Panzner

10.1 Introduction 226

10.2 Degradation and Excretion: Progress with Chemically Modified Oligonucleotides 227

10.2.1 Antisense Oligonucleotides 227

10.2.2 Small Interfering RNAs (siRNAs) 228

10.3 Unassisted Cellular Uptake of Oligonucleotides 228

10.4 Carriers for Oligonucleotide Delivery 230

10.4.1 Cationic Carriers 230

10.4.1.1 CLP-2-Based Liposomes 230

10.4.1.2 Atuplex Technology 230

10.4.1.3 Stable Antisense-Lipid Particles and Stable Nucleic Acid-Lipid Particles 232

10.4.1.4 Cyclodextrin Nanoparticles 233

10.4.1.5 Polyethylenimine-Based Delivery System 233

10.4.1.6 Dendrimer-Based Delivery System 234

10.4.2 Anionic and Neutral Carriers 234

10.4.2.1 Dioleoyl Phosphatidylcholine Liposomes 234

10.4.2.2 Egg-PC-Cholesterol Liposomes 235

10.4.3 Summary of Common Building Principles for Oligonucleotide Carriers 235

10.5 Summary 236 Acknowledgement 237 References 237

Chapter 11 Lipid-Mediated in vivo Delivery of Small Interfering RNAs

Ian MacLachlan

11.1 Lipid-Mediated Drug Delivery 241

11.2 Liposome Constituents 243

11.2.1 Cationic Lipids 244

11.2.2 Neutral Helper Lipids 245

11.2.3 PEG-Lipids 245

11.3 Methods of Encapsulating Nucleic Acids 246

11.3.1 Passive Encapsulation 247

11.3.2 The Ethanol Drop Method of Encapsulation 247

11.3.3 Encapsulation in Ethanol-Destabilized Liposomes 249

11.3.4 The Spontaneous Vesicle Formation by Ethanol Dilution Method of Encapsulation 250

11.4 Pharmacology of Liposomal Nucleic Acids 251

11.4.1 Pharmacokinetics and Biodistribution of Liposomal siRNAs Following

Systemic Administration 251

11.4.2 Toxicity of Liposomal Nucleic Acid Formulations 255

11.4.3 Immune Stimulation 255

11.4.4 Immunogenicity 257

11.4.5 Efficacy of Liposomally Formulated

Nucleic Acid Drugs 258

References 262

Chapter 12 Vector-Mediated and Viral Delivery of Short Hairpin RNAs

Henry Fechner and Jens Kurreck

12.1 Introduction 267

12.2 Plasmid-derived Short Hairpin RNAs 268

12.3 Generation of Transgenic Animals for Knockdown Studies 271

12.4 MicroRNA-type shRNAs 272

12.5 Inducible RNAi Systems 274

12.6 Viral Vectors for Delivery of shRNAs 282

12.6.1 Retrovirus Vectors 282

12.6.2 Adenovirus Vectors 285

12.6.3 Vectors Based on Adeno-associated Viruses 287

12.7 Summary 288 Acknowledgement 289 References 289

Chapter 13 Development of an RNAi-Based Gene Therapy against HIV-1

Olivier ter Brake and Ben Berkhout

13.1 Introduction 296

13.2 The HIV-1 Life Cycle 297

13.3 RNA Interference as an Antiviral Strategy 299 13.3.1 Combinatorial RNAi Approach 1: Highly

Conserved Targets 300

13.3.2 Combinatorial RNAi Approach 2: Second-Generation shRNAs 303

13.3.3 Combinatorial Approach 3:

Include Cellular Factors as RNAi Targets 304

13.4 Gene Therapy for HIV-1 Infection 306

13.4.1 Lentiviral Vector Development 308

13.4.2 Preclinical Evaluation: Safety and Efficacy 309 Acknowledgements 311 References 311

Chapter 14 RNA Based Therapies for Treatment of HIV Infection

Lisa Scherer, Marc S. Weinberg and John J. Rossi

14.1 Introduction: Challenges to Conventional Therapies 316

14.2 Potential HIV Targets for RNA-based Therapeutics 317

14.2.1 Ribozymes, External Guide Sequences and Aptamers as Therapeutics 318

14.2.2 RNAi Approaches to Inhibit

HIV Replication 319

14.3 RNAi-induced Transcriptional Gene Silencing 323

14.4 Delivery of Anti-HIV RNAs to Hematopoietic Cells 324

14.5 Future Prospects 324 References 325

Subject Index 329

CHAPTER 1

Arthritis Joint Pain

Arthritis Joint Pain

Arthritis is a general term which is commonly associated with a number of painful conditions affecting the joints and bones. The term arthritis literally translates to joint inflammation.

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