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Tables of Contents for Adenoviral Vectors for Gene Therapy
Chapter/Section Title
Page #
Page Count
Contributors
xxiii
Preface
xxvii
Adenovirus Structure
Phoebe L. Stewart
Introduction
1
1
Molecular Composition
2
1
Structure of the Intact Virion
3
1
Structure of the Capsid Components
4
8
Hexon, Polypeptide II
4
2
Penton Base, Polypeptide III
6
2
Fiber, Polypeptide IV
8
2
Polypeptide IIIa
10
1
Polypeptide VI
10
1
Polypeptide VIII
11
1
Polypeptide IX
11
1
Core Structure
12
1
Adenovirus Protease
12
1
Summary
13
6
References
14
5
Biology of Adenovirus Cell Entry
Glen R. Nemerow
Pathway of Adenovirus Cell Entry
19
2
Cell Receptors Involved in Attachment
21
3
CAR
21
2
Other Adenovirus Receptors
23
1
Adenovirus Internalization Receptors
24
5
Role of αv Integrins as Coreceptors
24
2
Structural Features of Penton Base-αv Integrin Association
26
1
Signaling Events Associated with Adenovirus Internalization
26
3
Virus-Mediated Endosome Disruption and Uncoating
29
1
Role of Penton Base and αv Integrins
29
1
Role of the Adenovirus Cysteine Protease
30
1
Beyond the Endosome: Trafficking of Viral Capsids and Import of Viral DNA into the Nucleus
30
1
Intracytoplasmic Transport of Viral Capsids
30
1
Docking at the Nuclear Pore and Translocation of Viral DNA
31
1
Conclusions
31
8
References
32
7
Adenovirus Replication
Jared D. Evans and Patrick Hearing
Introduction
39
1
Classification
40
1
Genome Organization
40
2
Virus Infection
42
1
Early Gene Expression
42
1
Early Region 1A (E1A)
43
3
Early Region 1B (E1B)
46
1
Early Region 2 (E2)
47
2
Early Region 3 (E3)
49
3
Early Region 4 (E4)
52
3
Viral DNA Replication
55
4
VA RNA Genes
59
1
Late Gene Expression and Virus Assembly
59
3
Vector Design
62
1
Conclusion
63
8
References
64
7
Adenoviral Vector Construction I: Mammalian Systems
Philip Ng and Frank L. Groham
Introduction
71
4
Adenovirus Biology
71
2
Adenovirus Vectors
73
1
Early Methods of Constructing Recombinant Adenoviruses
73
2
The Two-Plasmid Rescue System
75
10
Development of the Two-Plasmid Rescue System
77
2
Refinements to the Two-Plasmid Rescue Method
79
3
The Ad Genomic Plasmid
82
1
The Shuttle Plasmid
82
3
Protocols for the Two-Plasmid Rescue System
85
20
Preparation of Plasmid DNA
85
3
Cell Culture
88
1
Cotransfection
89
4
Analysis of Recombinant Vectors and Preparation of Working Vector Stocks
93
1
Titration of Adenovirus
94
1
Preparation of High-Titer Viral Stocks (Crude Lysate)
95
2
Purification of Adenovirus by CsCI Banding
97
2
Characterization of Adenoviral Vector Preparations
99
2
Alternative Procedures to Expedite Vector Production
101
1
References
101
4
Adenoviral Vector Construction II: Bacterial Systems
M. Lusky E. Degryse M. Mehtali and C. Chartier
Introduction
105
1
Generation of Ad: Traditional Approaches
106
1
Generation of Ad: Bacterial Systems
107
1
Homologous Recombination in E. coli
108
1
Homologous Recombination with Linear Ad Vector Genome Plasmids
109
7
Homologous Recombination with Circular Ad Vector Genome Plasmids
116
2
Ad Vector Construction by Transposon-Mediated Recombination
118
1
Ad Vector Construction by in Vitro Ligation
119
2
Conclusion
121
8
References
123
6
Propagation of Adenoviral Vectors: Use of PER. C6 Cells
W. W. Nichols R. Lardenoije B. J. Ledwith K. Brouwer S. Manam R. Vogels D. Kaslow D. Zuidgeest A. J. Bett L. Chen M. van der Kaaden S. M. Galloway R. B. Hill S. V. Machotka C. A. Anderson J. Lewis D. Martinez J. Lebron C. Russo D. Valerio and A. Bout
Introduction
129
5
Scope of the Chapter
129
1
Adenoviruses
130
1
Adenovirus Replication
131
3
Cells Expressing E1 of Adenovirus
134
2
Transformation of Cells by E1 of Adenovirus
134
1
El-Expressing Cell Lines for Adenoviral Vector Production
135
1
PER.C6 Prevents RCA during Vector Production
136
5
RCA
136
1
PER.C6: Absence of Sequence Overlap Eliminates RCA Generation
137
2
Frequency of RCA Occurrence
139
2
Production of Adenoviral Vectors
141
5
Vector Stability
141
2
The Production Process
143
2
Yields of Adenoviral Vectors
145
1
Scale of Adenoviral Vector Production
145
1
Safety Considerations of PER.C6
146
13
QC Testing of PER.C6 Cells for Use in the Manufacture of Biologicals and Vaccines
146
4
Tumorigenicity
150
6
Prion-Related Issues
156
1
Genetic Characterization of PER.C6 Cells
157
2
Conclusions
159
8
References
160
7
Purification of Adenovirus
Paul Shabram Gary Vellekamp and Carl Scandella
Introduction
167
6
The Physical Characteristics of the Adenovirus Particle in Solution
167
3
Features of the Milieu
170
3
Summary of Characteristics
173
1
Recovery and Purification of Adenoviral Particles
173
17
Harvest Methods
173
2
Lysis Methods
175
4
Clarification
179
2
Purification
181
8
Buffer Exchange
189
1
Analytical Methods for Process Development and Process Tracking
190
6
Plaque-Forming Titer Assays
190
1
Adenovirus 96-Well Titer Plate Assay
191
3
Flow Cytometry
194
1
Particle Concentration Determination by Ultraviolet Absorbance
194
1
Analytical Reverse-Phase HPLC
195
1
Analytical Anion-Exchange HPLC
196
1
Formulation and Stability
196
4
Conclusions
200
5
References
200
5
Targeted Adenoviral Vectors I: Transductional Targeting
Victor Krasnykh and Joanne T. Douglas
Introduction
205
1
The Pathway of Adenoviral Infection
206
1
Strategies and Considerations
207
2
Conjugate-Based Targeting
209
7
Bispecific Chemical Conjugates
209
4
Bispecific Recombinant Fusion Proteins
213
2
Bispecific Peptides
215
1
Polymer-Mediated Coupling of Ligands to Ad Capsid Proteins
215
1
Biotinylated Ad/Avidin Bridge/Biotinylated Ligand
216
1
Genetic Targeting
216
16
Ad-Targeting Strategies Involving Genetic Manipulations of the Fiber Protein
217
14
Ad-Targeting Strategies Involving Genetic Manipulations of the Hexon and Penton Base Proteins
231
1
Transductionally Targeted Ad Vectors for Clinical Gene Therapy Applications
232
3
Conclusion
235
12
References
236
11
Targeted Adenoviral Vectors II: Transcriptional Targeting
Sudhanshu P. Raikwar Chinghai H. Kao and Thomas A. Gardner
Introduction: Rationale of Transcriptional Targeting
247
1
Regulation of Transcription in Eukaryotes
248
8
Molecular Organization of DNA
248
1
The Central Dogma
248
1
Transcription
249
2
Mechanism of Transcription
251
2
Structural Motifs
253
3
Regulation of Adenoviral DNA Transcription Process
256
1
Approaches of Transcriptional Regulation
256
15
Prior Rationale Universal Promoters
256
1
Current Rationale of Tissue-Specific Promoters
257
11
MN/CA9 Promoter
268
1
Inducible Transcription
269
2
Enhanced Control of Transgene Expression
271
1
Safety Improvements
271
1
Potency Concerns
272
1
Future Directions
272
2
Enhancement of Weak But Specific Promoters
272
2
Improving Specificity with Multiple Promoter Segments
274
1
Tumor-Specific Oncolysis
274
1
Combined Targeting Approaches
274
1
Summary
274
13
References
275
12
Development of Attenuated Replication Competent Adenoviruses (ARCAs) for the Treatment of Prostate Cancer
Daniel R. Henderson and De-Chao Yu
Introduction
287
3
ARCAs for Prostate Cancer: CV706 and CV787
290
8
Adenovirus: Gene Expression and Regulation
290
1
Tissue Specificity of ARCA
291
4
Antitumoral Efficacy of ARCA
295
1
Mechanism for Cell-Killing of ARCA
296
2
Synergy of ARCA and Conventional Therapy
298
7
Synergy of CV706 and Irradiation
299
3
Synergy of CV787 and Chemotherapy
302
3
Toxicity of Intravenously Administered ARCAs in the Absence or Presence of Docetaxel
305
3
Effects of Preexisting Adenovirus Antibody on Antitumor Activity and Immunoapheresis for Human Therapy
308
6
Preexisting Adenovirus Antibodies Inhibit Systemic Toxicity and Antitumor Activity
309
4
SIAPA: Screening and Immunoapheresis of Preexistent Antibody for Monitoring and Removing Preexistent Ad5 Antibodies from Blood
313
1
Clinical Development of CV706 and CV787
314
4
CV706 Phase I/II Trial for Locally Recurrent Prostate Cancer
314
3
Factors Impacting Clinical Efficacy and Safety
317
1
Summary
318
11
References
319
10
Replication-Selective Oncolytic Adenovirus E1-Region Mutants: Virotherapy for Cancer
David Kirn
Introduction
329
3
Attributes of Replication-Selective Adenoviruses for Cancer Treatment
332
1
Biology of Human Adenovirus
332
1
Mechanisms of Adenovirus-Mediated Cell Killing
333
1
Approaches to Optimizing Tumor-Selective Adenovirus Replication
333
1
E1A-CR2 Region Deletion Mutants
334
1
E1B 55-kDa Gene Deletion Mutant: d/1520
335
2
Clinical Trial Results with Replication-Competent Adenoviruses in Cancer Patients
337
3
Clinical Trial Results with Wild-Type Adenovirus
337
1
A Novel Staged Approach to Clinical Research with Replication-Selective Viruses: The Example of d/1520 (Onyx-015)
338
2
Results from Clinical Trials with d/1520 (Onyx-015 or Cl-1042)
340
3
Toxicity
340
1
Viral Replication
340
2
Immune Response
342
1
Clinical Trial Results with d/1520 (Onyx-015): Summary
343
1
Future Directions: Why Has d/1520 (Onyx-015) Failed to Date as a Single Agent?
344
1
Improving the Efficacy of Replication-Selective Oncolytic Adenoviral Agents
345
1
Summary
345
4
References
346
3
Innate Immune Responses to in Vivo Adenovirus Infection
Bruce C. Trapnell and Thomas P. Shanley
Overview: Components of Innate Immunity
349
5
Distribution and Clearance of Adenovirus from the Respiratory Tract
354
5
Clinical Aspects of Natural Adenoviral Infection in Humans
354
1
Distribution of Recombinant, Replication-Deficient Adenoviral Vectors
355
1
Kinetics and Mechanisms of Clearance of Adenovirus
356
3
Molecular Mediators of Inflammation
359
5
Clinical Adenovirus Infections in Humans
360
1
Adenovirus Infections in Animal Models
361
1
Acute Cytokine Responses
362
1
Intermediate Cytokine Responses
363
1
Late Cytokine Responses
364
1
Inflammatory Cell Recruitment
364
3
Innate Immunity and Programming of Adaptive Responses
367
1
Innate Immunity and in Vivo Gene Therapy
368
1
Future Directions
369
6
References
369
6
Humoral Immune Response
Catherine O'Riordan
Introduction
375
1
Adenovirus Structure and Serotype
376
5
Classification of Adenoviruses
376
1
Adenoviral Structural Proteins and Type-Specific Epitopes
376
3
Chimeric Adenovirus Vectors
379
1
Influence of Serotypic Variations on Adenoviral Cell Interactions
380
1
Host Response to Gene Therapy Vectors
381
3
Innate Immune Response
381
1
Adaptive Immune Response: B-T Cell Interactions
382
2
Strategies to Overcome the Humoral Immune Response
384
6
General Immunosuppression
384
2
Transient Selective Immunosuppression
386
1
Oral Tolerance
387
1
Serotype Switching
388
1
Masking Neutralizing Epitopes
389
1
Immunoapheresis
390
1
Factors Modulating Host Responses to Gene Transfer Vectors
390
6
Viral Vector Backbone
390
3
Species and Strain
393
2
Route of Delivery
395
1
Immune Response to Adenoviral-based Vectors in Humans
396
2
Conclusion
398
11
References
399
10
Novel Methods to Eliminate the Immune Response to Adenovirus Gene Therapy
Hoang-Ge Zhang Hui-Chen Hsu and John D. Mountz
Introduction
409
1
Immune Suppression
410
1
Immune Modulation
411
3
Treatment with Soluble TNFR1 to Eliminate Ad Inflammation in Lung and Liver
414
1
Inhibition of Cell Cytolysis Which Combines Treatment with Soluble DR5, Soluble Fas, and Soluble TNFR1
415
2
Immune Privilege
417
2
APC-AdFasL Prolongs Transgene Expression and Specifically Minimizes T-Cell Response
419
2
Production of AdsTACl Prolongs Gene Expression and Minimizes B-Cell Response
421
2
Summary
423
6
References
424
5
High-Capacity ``Gutless'' Adenoviral Vectors: Technical Aspects and Applications
Gudrun Schiedner Paula R. Clemens Christoph Volpers and Stefan Kochanek
Introduction
429
1
Technical Aspects
430
5
Vector Production
430
2
Stuffer DNA
432
2
Vector Capsid Modification
434
1
Applications
435
7
Liver Gene Transfer
435
4
Gene Transfer into Skeletal Muscle
439
1
Gene Transfer into the Eye and into the CNS
440
2
Conclusion
442
5
References
442
5
Xenogenic Adenoviral Vectors
Gerald W. Both
Impetus and Rationale
447
1
Classification of Adenoviruses
447
1
Factors Affecting Vector Design and Utility
448
12
Host Range and Pathogenicity
448
2
Neutralization
450
1
Genome Structure and Function
450
4
Transforming Ability
454
2
Cell Lines
456
2
Strategies for Vector Construction and Rescue
458
2
Utility of Xenogenic Vectors
460
6
Veterinary Studies
460
2
Vector Biology
462
4
Gene Therapy Studies
466
1
Biosafety
466
3
Complementation and Recombination
466
2
Oncogenes in Viral and Cellular DNA
468
1
Virus/Cell Interactions
468
1
Replication Competent Viruses
469
1
Vector Production and Purification
469
12
References
470
11
Hybrid Adenoviral Vectors
Stephen J. Murphy and Richard G. Vile
Introduction
481
11
Retroviral Vectors
483
4
Adenoviral Vectors
487
1
Adeno-associated Viruses
487
1
Herpes Simplex Viruses
488
1
Lentiviral Vectors
488
1
The Choice of Gene Therapy Vector
489
2
How to Maintain Stable Transgene Expression
491
1
Hybrid Viral Vectors
492
2
Are Hybrid Vectors Truly New Technology?
493
1
Hybrid Adenoviral Vector Systems
494
24
Pseudotyping and Retargeting Adenoviral Vectors
494
2
Adenoviral/Retroviral Hybrid Vector Technologies
496
12
Adenoviral/Epstein-Barr Virus Hybrid Vectors
508
3
Hybrid Retroviruses Trafficking to the Nucleus
511
1
Hybrid Adenoviral/Adeno-Associated Virus Vectors
512
6
Conclusion
518
15
References
524
9
Utility of Adenoviral Vectors in Animal Models of Human Disease I: Cancer
Raj K. Batra Sherven Sharma and Lily Wu
Introduction
533
2
Animal Models of Lung Cancer
535
12
Human Lung Cancer
535
2
Animal Models of Human Lung Cancer
537
6
Gene Therapy of Lung Cancer Using Adenoviral Vectors
543
4
Animal Models of Human Prostate Cancer
547
4
Human Prostate Cancer
547
1
Spontaneous and Transgenic Models of Human Prostate Cancer
547
1
Xenograft Models of Human Prostate Cancer
548
2
Gene Therapy Approaches with Adenovectors in Prostate Cancer
550
1
Summary and Discussion
551
14
References
553
12
Utility of Adenoviral Vectors in Animal Models of Human Disease II: Genetic Disease
Raymond John Pickles
Introduction
565
1
Pathophysiology of Cystic Fibrosis (CF) Lung Disease
566
1
Trials and Tribulations with Adenoviral Vectors for CF Lung Disease
567
1
The Airway Epithelium: Cellular Targets for CF Gene Therapy
568
2
Adenoviral Vectors as Gene Transfer Vectors in the Lung
570
15
Animal Models for CF Airway Gene Transfer Studies
570
1
Success and Limitations of Ad
571
6
Overcoming the Limitations of Ad
577
8
Other Vectors
585
1
Conclusion
586
9
References
586
9
Utility of Adenoviral Vectors in Animal Models of Human Disease III: Acquired Diseases
Erik Lubberts and Jay K. Kolls
Adenoviral Vectors for Infectious Disease
595
8
Tuberculosis
596
2
Pneumonia
598
3
Opportunistic Infections
601
2
Viral Hepatitis
603
1
Chronic Inflammatory Diseases
603
5
Inflammatory Bowel Disease
603
1
Arthritis
604
3
Fibrotic Lung Disease
607
1
Conclusions
608
7
References
608
7
Testing of Adenoviral Vector Gene Transfer Products: FDA Expectations
Steven R. Bauer Anne M. Pilaro and Karen D. Weiss
Introduction
615
1
Manufacturing Control and Product Characterization
616
2
Purity, Safety, and Potency
616
1
Regulation of Process as Well as Product
617
1
Current Good Manufacturing Practices
617
1
Development of Recommendations for the Manufacture and Characterization of Adenoviral Vectors
618
2
Considerations in Manufacturing Adenoviral Vectors
620
1
Components and Characterization
620
1
Protocols
621
1
Process Controls
621
2
Standard Operating Procedures
621
1
Quality Assurance and Quality Control Programs
622
1
Characterization of Adenoviral Vector Production Intermediates
623
5
Master Cell Bank
623
3
Working Cell Bank
626
1
Master Virus Bank
626
2
Characterization of Adenoviral Vector Final Products
628
2
Preclinical Testing of Adenoviral Vectors
630
2
Pharmacologic Activity
631
1
Toxicology Testing
632
4
Scope of Toxicity Testing
632
1
Species Selection
633
1
Route of Administration
634
1
Selection of Dose
634
2
Biodistribution
636
1
Good Laboratory Practices
637
1
Introduction to Clinical Testing
637
2
Phases of Clinical Development
638
1
Good Clinical Practices
639
3
Responsibilities of a Sponsor and Investigators
639
1
Adverse Event Reporting
639
1
Consent and Vulnerable Populations
640
1
Monitoring and Auditing
641
1
Clinical Safety of Adenoviral Vector Products
642
1
Bioactivity of Adenoviral Vector Products
643
1
Clinical Efficacy of Adenoviral Vector Products
644
2
Choice of Control
645
1
Endpoint Selection
645
1
How the Role of FDA Regulators Has Changed Since September 1999
646
5
Safety Symposia in Conjunction with OBA
647
1
Results of FDA's Directed Inspections
648
1
Description of the March 6, 2000, Letter and Summary of Responses
649
1
Results of Additional Inspections
650
1
Sponsor Outreach and Education
651
1
Summary
651
4
References
652
3
Imaging Adenovirus-Mediated Gene Transfer
Kurt R. Zinn and Tandra R. Chaudhuri
Introduction
655
1
What Information Is Provided by Imaging?
656
1
Scientific Basis for Imaging
657
6
Electromagnetic Energy
657
1
Contrast
657
1
Gamma Rays and Detection
657
4
Light-Based Imaging and Detection
661
1
Magnetic Resonance Imaging and Spectroscopy
662
1
Imaging and Gene-Therapy Vectors
663
6
Gamma-Ray Imaging
663
3
Light-Based Imaging
666
2
Magnetic Resonance Technologies
668
1
Gene-Therapy Vectors May Advance Molecular Imaging
669
2
Conclusion
671
1
References
671
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