RNA Technologies in Cardiovascular Medicine and Research (eBook)

Preface 5
Contents 9
Contributors 11
Part I MicroRNA 16
An Overview of MicroRNA 17
1 Introduction 18
2 miRNA Biogenesis 19
3 Biological Functions of miRNAs 19
4 miRNAs in Human Disease 22
5 Summary 25
References 26
MicroRNAs and Their Potential 31
1 The Importance of Being miRNA 32
2 Post-Transcriptional Regulatory Mechanisms During Cardiac Hypertrophy 32
3 Post-Transcriptional Regulation by miRNA 32
4 Transcriptional and Post-Transcriptional Regulation of miRNA 37
5 The Mechanism of miRNA-Target Recognition 38
6 miRNA in Development and Disease 39
7 The Diagnostic and Prognostic Potential of miRNA 43
8 miRNA as Therapeutic Targets 44
9 Concluding Remarks 44
References 45
miRNAs and Their Emerging Role in Cardiac Hypertrophy 49
1 Introduction 50
2 Biology of miRNAs 50
3 miRNAs in Cardiovascular Development 54
4 miRNAs in the Hypertrophic Growth Response 58
5 Conclusions and Future Directions 62
References 62
MicroRNAs and the Control of Heart Pathophysiology 67
1 miRNA: Biogenesis and Mechanisms of Action 67
2 miRNAs and Muscle Development 73
3 miRNAs and Heart Pathophysiology 75
4 Conclusion and Future Prospects 79
References 79
MicroRNA Systems Biology 83
1 Introduction 84
2 miRNA Regulation of Cellular Signaling Networks 85
3 miRNA Regulation of Gene Regulatory Networks 91
4 miRNA Regulation of Metabolic Networks 93
5 miRNA Regulation of Protein Interaction Networks 94
6 miRNA Regulatory Network Motifs 95
7 Summary 98
References 98
Part II RNA Interference 101
Targeting Viral Heart Disease by RNA Interference 103
1 Introduction 103
2 Preclinical Results of Therapeutic Antiviral RNA Interference: Focus on CVB3- Associated Disease 106
3 Factors That Limit Early Efficacy of Antiviral RNA Interference 111
4 Factors That Limit Subsequent Efficacy of Antiviral RNA Interference 113
5 Conclusions and Future Prospects 116
References 117
Design of siRNAs and shRNAs for RNA Interference: Possible Clinical Applications 123
1 Introduction 124
2 Adverse Effects of Long dsRNAs 126
3 siRNA Structure and Design 127
4 shRNAs 134
5 Clinical Application 139
6 Concluding Remark 141
References 142
RNA Interference and MicroRNA Modulation for the Treatment of Cardiac Disorders 145
1 Introduction to RNA-Based and Gene Therapeutic Strategies 146
2 Key Issues of Current Vector Technologies 147
3 RNA Interference Targeting Early Pathogenic Steps in Cardiomyopathies 151
4 RNA Interference to Improve Cardiac Function in Advanced Heart Failure 165
5 Clinical Perspectives and Unanswered Questions 173
References 175
Cardiac Delivery of Nucleic Acids by Transcriptional and Transductional Targeting of Adeno- Associated Viral Vectors 181
1 Introduction 181
2 Vector Systems for Cardiac Nucleic Acid Transfer 183
3 Transductional Targeting of AAV Vectors for Cardiac Nucleic Acid Transfer 185
4 Transcriptional Targeting of AAV Vectors for Cardiac Nucleic Acid Transfer 187
5 Application Systems for Cardiac Gene Transfer 188
6 Perspective 191
References 191
Part III Ribozymes 197
Characterization of Hammerhead Ribozymes Potentially Suitable for the Treatment of Hyper- Proliferative Vascular Diseases 199
1 Introduction 200
2 Hammerhead Ribozyme 200
3 Potential Use of HRzs as Therapeutics for Artery Restenosis 211
4 HRzs and Small Interfering RNAs in the Cardiovascular Field 216
5 Conclusion 218
References 218
Applications of Ribozymes and Pyrrole – Imidazole Polyamides for Cardiovascular and Renal Diseases 223
1 Introduction 224
2 Ribozymes 225
3 Pyrrole–Imidazole (PI) Polyamides 236
4 Conclusions 240
References 241
Part IV Noncoding, Aptamer and Antisense RNAs 247
Noncoding RNAs in Human Diseases 249
1 Noncoding RNAs 250
2 Functions of ncRNAs 251
3 NcRNAs in Human Diseases 257
4 Perspectives 262
References 263
Aptamers and siRNAs in Cardiovascular Disease 269
1 Introduction 270
2 Coagulation and Thrombosis 271
3 Aptamers as Anticoagulants 272
4 VWF Aptamers as Antiplatelet Agents 276
5 Aptamers and Intimal Hyperplasia 278
6 Potential Challenges Facing Aptamers in Cardiovascular Disease 278
7 siRNA Background 288
8 siRNA as Therapeutic Agents 289
9 Current Clinical Uses of siRNA 290
10 siRNA for the Treatment of Cardiovascular Disease 291
11 Potential Challenges Facing siRNA in Cardiovascular Disease 295
12 Conclusion 297
References 297
Nucleic Acid Aptamers for Cardiovascular Therapeutics 303
1 Nucleic Acid Aptamers 303
2 Therapeutic Potential of Aptamers 304
3 Anticoagulant and Antithrombotic Aptamers 305
4 Antiadhesion Aptamers 307
5 Antiangiogenic Aptamers and Potential for Treatment of Atherosclerosis 309
References 310
NFkB Decoy Oligodeoxynucleotide- Based Therapy in Cardiovascular Diseases 313
1 Introduction 314
2 Application of NF- 315
Decoy ODN for Cardiovascular 315
Diseases 315
3 Recent Progress in Modification of NF- 318
Decoy 318
References 320
Antisense Therapy for Restenosis Following Percutaneous Coronary Interventions 325
1 Introduction 326
2 Local Drug Delivery 329
3 Perflourocarbon Gas Microbubble Carriers (PGMC) for Site- Specific Drug Delivery 334
4 Clinical Studies with AVI-4126 335
5 Conclusions 336
References 337
Toxic RNA in Pathogenesis of Human Neuromuscular Disorders 339
1 Introduction 340
2 Properties of Transcripts Containing Microsatellite Repeats 341
3 Myotonic Dystrophy Type 1 and 2 (DM1 and DM2) 345
4 Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) 352
5 Other Disorders Associated with Toxic RNAs 354
6 Toxic RNAs as Therapeutic Targets 357
References 361
Index 369