Adenoviral Vectors for Gene Therapy (eBook)

Front Cover 1
Adenoviral Vectors for Gene Therapy 4
Copyright Page 5
Contents 6
Contributors 24
Preface 28
Chapter 1. Adenovirus Structure 32
I. Introduction 32
II. Molecular Composition 33
III. Structure of the Intact Virion 34
IV. Structure of the Capsid Components 35
V. Core Structure 43
VI. Adenovirus Protease 43
VII. Summary 44
References 45
Chapter 2. Biology of Adenovirus Cell Entry 50
I. Pathway of Adenovirus Cell Entry 50
II. Cell Receptors Involved in Attachment 52
III. Adenovirus Internalization Receptors 55
IV. Virus-Mediated Endosome Disruption and Uncoating 60
V. Beyond the Endosome: Trafficking of Viral Capsids and Import of Viral DNA into the Nucleus 61
VI. Conclusions 62
References 63
Chapter 3. Adenovirus Replication 70
I. Introduction 70
II. Classification 71
III. Genome Organization 71
IV. Virus Infection 73
V. Early Gene Expression 73
VI. Early Region 1A (El A) 74
VII. Early Region 1B (E1B) 77
VIII. Early Region 2 (E2) 78
IX. Early Region 3 (E3) 80
X. Early Region 4 (E4) 83
XI. Viral DNA Replication 86
XII. VA RNA Genes 90
XIII. Late Gene Expression and Virus Assembly 90
XIV. Vector Design 93
XV. Conclusion 94
References 95
Chapter 4. Adenoviral Vector Construction I: Mammalian Systems 102
I. Introduction 102
II. The Two-Plosmid Rescue System 106
III. Protocols for the Two-Plasmid Rescue System 116
References 132
Chapter 5. Adenoviral Vector Construction II: Bacterial Systems 136
I. Introduction 136
II. Generation of Ad: Traditional Approaches 137
III. Generation of Ad: Bacterial Systems 138
IV. Homologous Recombination in E. coli 139
V. Homologous Recombination with Linear Ad Vector Genome Plasmids 140
VI. Homologous Recombination with Circular Ad Vector Genome Plasmids 147
VII. Ad Vector Construction by Transposon-Mediated Recombination 149
VIII. Ad Vector Construction by in Vitro Ligation 150
IX. Conclusion 152
References 154
Chapter 6. Propagation of Adenoviral Vectors: Use of PER.C6 Cells 160
I. Introduction 160
II. Cells Expressing E1 of Adenovirus 165
III. PER.C6 Prevents RCA during Vector Production 167
IV. Production of Adenoviral Vectors 172
V. Safety Considerations of PER.C6 177
VI. Conclusions 190
References 191
Chapter 7. Purification of Adenovirus 198
I. Introduction 198
II. Recovery and Purification of Adenoviral Particles 204
III. Analytical Methods for Process Development and Process Tracking 221
IV. Formulation and Stability 227
V. Conclusions 231
References 231
Chapter 8. Targeted Adenoviral Vectors I: Transductional Targeting 236
I. Introduction 236
II. The Pathway of Adenoviral Infection 237
III. Strategies and Considerations 238
IV. Conjugate-Based Targeting 240
V. Genetic Targeting 247
VI. Transductionally Targeted Ad Vectors for Clinical Gene Therapy Applications 263
VII. Conclusion 266
References 267
Chapter 9. Targeted Adenoviral Vectors II: Transcriptional Targeting 278
I. Introduction: Rationale of Transcriptional Targeting 278
II. Regulation of Transcription in Eukaryotes 279
III. Approaches of Transcriptional Regulation 287
IV. Enhanced Control of Transgene Expression 302
V. Future Directions 303
VI. Summary 305
References 306
Chapter 10. Development of Attenuated Replication Competent Adenoviruses (ARCAs) for the Treatment of Prostate Cancer 318
I. Introduction 318
II. ARCAs for Prostate Cancer: CV706 and CV787 321
III. Synergy of ARCA and Conventional Therapy 329
IV. Toxicity of Intravenously Administered ARCAs in the Absence or Presence of Docetaxel 336
V. Effects of Preexisting Adenovirus Antibody on Antitumor Activity and Immunoapheresis for Human Therapy 339
VI. Clinical Development of CV706 and CV787 345
VII. Summary 349
References 350
Chapter 11. Replication-Selective Oncolytic Adenovirus E1-Region Mutants: Virotherapy for Cancer 360
I. Introduction 360
II. Attributes of Replication-Selective Adenoviruses for Cancer Treatment 363
III. Biology of Human Adenovirus 363
IV. Mechanisms of Adenovirus-Mediated Cell Killing 364
V. Approaches to Optimizing Tumor-Selective Adenovirus Replication 364
VI. E1A–CR2 Region Deletion Mutants 365
VII. E1 B 55-kDa Gene Deletion Mutant: d/l 520 366
VIII. Clinical Trial Results with Replication-Competent Adenoviruses in Cancer Patients 368
IX. Results from Clinical Trials with d/1520 (Onyx-015 or CI-1042) 371
X. Clinical Trial Results with d/1520 (Onyx-015): Summary 374
XI. Future Directions: Why Has d/1520 (Onyx-015) Failed to Date as a Single Agent? 375
XII. Improving the Efficacy of Replication-Selective Oncolytic Adenoviral Agents 376
XIII. Summary 376
References 377
Chapter 12. Innate Immune Responses to in Vivo Adenovirus Infection 380
I. Overview: Components of Innate Immunity 380
II. Distribution and Clearance of Adenovirus from the Respiratory Tract 385
III. Molecular Mediators of Inflammation 390
IV. Inflammatory Cell Recruitment 395
V. Innate Immunity and Programming of Adaptive Responses 398
VI. Innate Immunity and in Vivo Gene Therapy 399
VII. Future Directions 400
References 400
Chapter 13. Humoral Immune Response 406
I. Introduction 406
II. Adenovirus Structure and Serotype 407
III. Host Response to Gene Therapy Vectors 412
IV. Strategies to Overcome the Humoral Immune Response 415
V. Factors Modulating Host Responses to Gene Transfer Vectors 421
VI. Immune Response to Adenoviral–based Vectors in Humans 427
VII. Conclusion 429
References 430
Chapter 14. Novel Methods to Eliminate the Immune Response to Adenovirus Gene Therapy 440
I. Introduction 440
II. Immune Suppression 441
III. Immune Modulation 442
IV. Treatment with Soluble TNFRl to Eliminate Ad Inflammation in Lung and Liver 445
V. Inhibition of Cell Cytolysis Which Combines Treatment with Soluble DR5, Soluble Fas, and Soluble TNFRl 446
VI. Immune Privilege 448
VII. APC-AdFasL Prolongs Transgene Expression and Specifically Minimizes T-Cell Response 450
VIII. Production of AdsTACI Prolongs Gene Expression and Minimizes B-Cell Response 452
IX. Summary 454
References 455
Chapter 15. High-Capacity ''Gutless'' Adenoviral Vectors: Technical Aspects and Applications 460
I. Introduction 460
II. Technical Aspects 461
III. Applications 466
IV. Conclusion 473
References 473
Chapter 16. Xenogenic Adenoviral Vectors 478
I. Impetus and Rationale 478
II. Classification of Adenoviruses 478
III. Factors Affecting Vector Design and Utility 479
IV. Utility of Xenogenic Vectors 491
V. Biosafety 497
VI. Vector Production and Purification 500
References 501
Chapter 17. Hybrid Adenoviral Vectors 512
I. Introduction 512
II. Hybrid Viral Vectors 523
III. Hybrid Adenoviral Vector Systems 525
IV. Conclusion 549
References 555
Chapter 18. Utility of Adenoviral Vectors in Animal Models of Human Disease I: Cancer 564
I. Introduction 564
II. Animal Models of Lung Cancer 566
III. Animal Models of Human Prostate Cancer 578
IV. Summary and Discussion 582
References 584
Chapter 19. Utility of Adenoviral Vectors in Animal Models of Human Disease II: Genetic Disease 596
I. Introduction 596
II. Pathophysiology of Cystic Fibrosis (CF) Lung Disease 597
III. Trials and Tribulations with Adenoviral Vectors for CF Lung Disease 598
IV. The Airway Epithelium: Cellular Targets for CF Gene Therapy 599
V. Adenoviral Vectors as Gene Transfer Vectors in the Lung 601
VI. Other Vectors 616
VII. Conclusion 617
References 617
Chapter 20. Utility of Adenoviral Vectors in Animal Models of Human Disease III: Acquired Diseases 626
I. Adenoviral Vectors for Infectious Disease 626
II. Chronic Inflammatory Diseases 634
III. Conclusions 639
References 639
Chapter 21. Testing of Adenoviral Vector Gene Transfer Products: FDA Expectations 646
I. Introduction 646
II. Manufacturing Control and Product Characterization 647
III. Developnnent of Recommendations for the Manufacture and Characterization of Adenoviral Vectors 649
IV. Considerations in Manufacturing Adenoviral Vectors 651
V. Process Controls 652
VI. Characterization of Adenoviral Vector Production Intermediates 654
VII. Characterization of Adenoviral Vector Final Products 659
VIII. Preclinical Testing of Adenoviral Vectors 661
IX. Toxicology Testing 663
X. Biodistribution 667
XI. Introduction to Clinical Testing 668
XII. Good Clinical Practices 670
XIII. Clinical Safety of Adenoviral Vector Products 673
XIV. Bioactivity of Adenoviral Vector Products 674
XV. Clinical Efficacy of Adenoviral Vector Products 675
XVI. How the Role of FDA Regulators Has Changed Since September 1999 677
XVI. Summary 682
References 683
Chapter 22. Imaging Adenovirus-Mediated Gene Transfer 686
I. Introduction 686
II. What Information Is Provided by Imaging? 687
III. Scientific Basis for Imaging 688
IV. Imaging and Gene-Therapy Vectors 694
V. Gene-Therapy Vectors May Advance Molecular Imaging 700
VI. Conclusion 702
References 702
Color Plate Section 710