Nonviral Vectors for Gene Therapy (eBook)

Front Cover 1
NONVIRAL VECTORS for GENE THERAPY 4
Contents 8
Foreword by Jean-Marie Lehn 22
Foreword by John Mendelsohn 24
Contributors 26
PART I: INTRODUCTION 30
Chapter 1. Introduction 32
I. Gene Therapy 33
II. Virus vs Nonvirus as a Vector 33
III. Characteristics of a Nonviral Vector 37
IV. Delivery Barriers That a Vector Must Overcome 40
V. Cytoplasmic Expression 44
VI. Hybrid Viral/Nonviral Vectors 45
VII. Conclusion 45
References 46
PART II: CATIONIC LIPOSOMES 52
Chapter 2. Progress in Gene Delivery Research and Development 54
I. Early in Vitro Transfection Studies 55
II. Molecular Biology and Biotechnology Applications 56
III. Application of Synthetic Vectors for Gene Therapy 57
IV. Developing More Efficient Synthetic Gene Delivery Systems 62
References 65
Chapter 3. Cationic Lipid-Mediated Gene Delivery to the Airways 68
I. Introduction 69
II. The Lung as a Target for Gene Transfection 69
III. Cystic Fibrosis 70
IV. Cationic Lipids for CF Gene Therapy 74
V. Efficiency of Cationic Lipids at Mediating Gene Transduction to the Lung 83
VI. Limitations of Present Cationic Lipid Formulations 84
VII. Clinical Studies 88
VIII. Summary 90
References 90
Chapter 4. Structure and Structure–Activity Relationships of Lipid-Based Gene Delivery Systems 98
I. Introduction and History 98
II. Structure–Activity Relationships 100
III. Conclusion and Future Prospects 115
References 116
Chapter 5. Self-Assembled Structures of Lipid/DNA Nonviral Gene Delivery Systems from Synchrotron X-Ray Diffraction 120
I. Introduction 121
II. Synchrotron X-Ray Diffraction Studies 126
III. Future Directions 142
Acknowledgments 143
References 143
Endnote 146
Chapter 6. Sites of Uptake and Expression of Cationic Liposome/DNA Complexes Injected Intravenously 148
I. Introduction 149
II. Methodology 150
III. Interactions of Liposomes and Liposome/DNA Complexes with Blood 151
IV. Liposome Uptake in the Vasculature 152
V. Liposome Uptake in Angiogenic Blood Vessels 156
VI. Tissue-Specific Expression of Reporter Genes 157
VII. Implications for the Use of Cationic Liposomes for DNA Delivery 160
Acknowledgments 163
References 163
PART III: OTHER VECTORS 166
Chapter 7. Nuclear Transport of Exogenous DNA 168
I. Introduction 169
II. The Nuclear Transport of Macromolecules 170
III. The Nuclear Transport of Exogenous DNA 171
IV. Attempts to Increase the Efficiency of Nuclear Uptake 177
V. Viral Strategies for DNA or RNA Nuclear Transport 182
VI. Conclusions and Future Prospects 192
References 192
Chapter 8. Particle-Mediated Gene Delivery: Applications to Canine and Other Larger Animal Systems 200
I. Introduction 200
II. Ex Vivo Gene Transfer into Canine Tumor Cell Explants and Derived Primary Cultures 202
III. Ex Vivo Gene Transfer to Normal Canines Using Established Melanoma Cell Lines 206
IV. Clinical Trial of ex Vivo Transfected Autologous Cancer Vaccines in Spontaneous Tumors in Canines 208
V. In Vivo Gene Transfer into Skin and Oral Mucosal Epithelial Cells in Normal Dogs 212
VI. Gene Gun Technology as a Delivery Mechanism DNA Vaccines 215
VII. Conclusions 217
References 217
Chapter 9. Polyethylenimines. A Family of Potent Polymers for Nucleic Acid Delivery 220
I. Introduction 221
II. Synthesis, Structure, and Topology of Polyethylenimines 222
III. DNA Condensation 224
IV. In Vitro DNA Delivery 225
V. Receptor-Mediated Gene Delivery 225
VI. Endosomal Release of PEI/DNA Complexes 228
VII. Nuclear Transport of the DNA (Complexes) 230
VIII. In Vivo Gene Delivery 231
IX. PEI. An Efficient Carrier for Oligonucleotide Delivery 232
X. Conclusions and Prospects 232
Acknowledgments 233
References 233
Chapter 10. Ligand–Polycation Conjugates for Receptor-Targeted Gene Transfer 236
I. Introduction 237
II. Targeting Ligands 238
III. Ligand–Polycation Conjugates and DNA Complexes 239
IV. Cellular Barriers and in Vitro Applications 244
V. Extracellular Hurdles and in Vivo Applications 249
VI. Conclusions 251
Acknowledgments 251
References 251
Chapter 11. The Perplexing Delivery Mechanism of Lipoplexes 258
I. Introduction 259
II. Pathway for Interaction with Cells in Culture 265
III. In Vivo Transfection 271
Acknowledgments 289
References 289
Chapter 12. Biopolymer–DNA Nanospheres 296
I. Introduction 297
II. Properties of Carriers 298
III. Synthesis 300
IV. Ligand Conjugation 302
V. Physico-chemical Properties 303
VI. In Vitro Transfection 306
VII. In Vivo Transfection 309
VIII. Conclusions and Summary 312
Acknowledgments 314
References 314
Chapter 13. Novel Lipidic Vectors for Gene Transfer 318
I. Introduction 319
II. Cellular and Molecular Barriers for Cationic Lipid-Mediated Gene Transfer 319
III. Structures of Cationic Lipid/DNA Complexes and the Role of Polycations in DNA Condensation 323
IV. Cationic Liposome-Entrapped, Polycation-Condensed DNA (LPD-I) 324
V. Anionic Liposome-Entrapped, Polycation-Condensed DNA (LPD-II) 331
VI. Reconstituted Chylomicron Remnants for in Vivo Gene Delivery 333
VII. Conclusions 335
Acknowledgments 335
References 335
PART IV: ANIMAL MODELS AND CLINICAL TRIALS 340
Chapter 14. Mechanisms of Cationic Liposome-Mediated Transfection of the Lung Endothelium 342
I. Introduction 343
II. Anatomic and Physiological Characteristics of the Lung 344
III. Physicochemical Factors Affecting the Systemic Transfection Efficiency of DNA/Liposome Complexes 346
IV. Mechanisms of Cationic Liposome-Mediated Gene Transfer into the Lung Endothelium 352
V. Conclusions 362
Acknowledgments 363
References 363
Chapter 15. Cystic Fibrosis Gene Therapy 366
I. Introduction 367
II. Research Leading to Preclinical Studies for CF Gene Therapy 369
III. Preclinical Studies for CF Gene Therapy 370
IV. Considerations Proceeding Phase I Clinical Trials 372
V. Clinical Trials 373
VI. Considerations before Proceeding into Phase II and III Clinical Trials 377
VII. Summary and Outlook 379
References 379
Chapter 16. Targeting HER-2/neu-Overexpressing Cancer Cells with Transcriptional Repressor Genes Delivered by Cationic Liposome 386
I. Introduction 387
II. Preclinical Study Using DC-Chol Liposome Complexing with the E1A, SV40 Large T, or PEA3 Gene 390
III. A Phase I Clinical Trial Using the E1A–Liposome 399
IV. Conclusions 400
Acknowledgments 401
References 401
Chapter 17. Immune Pathways Used in Nucleic Acid Vaccination 408
I. Introduction 408
II. Generation of Immunity 411
III. Immune Mechanisms 420
IV. Modulation of Immunity 427
V. Summary 428
Acknowledgments 429
References 429
Chapter 18. A Novel Gene Regulatory System 438
I. Inducible Systems 439
II. A Novel Inducible System 441
III. Conclusions 451
Acknowledgments 452
References 452
Index 456