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Tables of Contents for Adenoviral Vectors for Gene Therapy
Adenovirus Structure
Phoebe L. Stewart
Structure of the Intact Virion
3
1
Structure of the Capsid Components
4
8
Hexon, Polypeptide II4
2
Penton Base, Polypeptide III6
2
Fiber, Polypeptide IV8
2
Polypeptide IIIa10
1
Polypeptide VI10
1
Polypeptide VIII11
1
Polypeptide IX11
1
References14
5
Biology of Adenovirus Cell Entry
Glen R. NemerowPathway of Adenovirus Cell Entry
19
2
Cell Receptors Involved in Attachment
21
3
CAR21
2
Other Adenovirus Receptors23
1
Adenovirus Internalization Receptors
24
5
Role of αv Integrins as Coreceptors24
2
Structural Features of Penton Base-αv Integrin Association26
1
Signaling Events Associated with Adenovirus Internalization26
3
Virus-Mediated Endosome Disruption and Uncoating
29
1
Role of Penton Base and αv Integrins29
1
Role of the Adenovirus Cysteine Protease30
1
Beyond the Endosome: Trafficking of Viral Capsids and Import of Viral DNA into the Nucleus
30
1
Intracytoplasmic Transport of Viral Capsids30
1
Docking at the Nuclear Pore and Translocation of Viral DNA31
1
References32
7
Adenovirus Replication
Jared D. Evans and
Patrick Hearing
Late Gene Expression and Virus Assembly
59
3
References64
7
Adenoviral Vector Construction I: Mammalian Systems
Philip Ng and
Frank L. Groham
Adenovirus Biology71
2
Adenovirus Vectors73
1
Early Methods of Constructing Recombinant Adenoviruses73
2
The Two-Plasmid Rescue System
75
10
Development of the Two-Plasmid Rescue System77
2
Refinements to the Two-Plasmid Rescue Method79
3
The Ad Genomic Plasmid82
1
The Shuttle Plasmid82
3
Protocols for the Two-Plasmid Rescue System
85
20
Preparation of Plasmid DNA85
3
Cell Culture88
1
Cotransfection89
4
Analysis of Recombinant Vectors and Preparation of Working Vector Stocks93
1
Titration of Adenovirus94
1
Preparation of High-Titer Viral Stocks (Crude Lysate)95
2
Purification of Adenovirus by CsCI Banding97
2
Characterization of Adenoviral Vector Preparations99
2
Alternative Procedures to Expedite Vector Production101
1
References101
4
Adenoviral Vector Construction II: Bacterial Systems
M. Lusky E. Degryse M. Mehtali and
C. Chartier
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
References123
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
Scope of the Chapter129
1
Adenoviruses130
1
Adenovirus Replication131
3
Cells Expressing E1 of Adenovirus
134
2
Transformation of Cells by E1 of Adenovirus134
1
El-Expressing Cell Lines for Adenoviral Vector Production135
1
PER.C6 Prevents RCA during Vector Production
136
5
RCA136
1
PER.C6: Absence of Sequence Overlap Eliminates RCA Generation137
2
Frequency of RCA Occurrence139
2
Production of Adenoviral Vectors
141
5
Vector Stability141
2
The Production Process143
2
Yields of Adenoviral Vectors145
1
Scale of Adenoviral Vector Production145
1
Safety Considerations of PER.C6
146
13
QC Testing of PER.C6 Cells for Use in the Manufacture of Biologicals and Vaccines146
4
Tumorigenicity150
6
Prion-Related Issues156
1
Genetic Characterization of PER.C6 Cells157
2
References160
7
Purification of Adenovirus
Paul Shabram Gary Vellekamp and
Carl Scandella
The Physical Characteristics of the Adenovirus Particle in Solution167
3
Features of the Milieu170
3
Summary of Characteristics173
1
Recovery and Purification of Adenoviral Particles
173
17
Harvest Methods173
2
Lysis Methods175
4
Clarification179
2
Purification181
8
Buffer Exchange189
1
Analytical Methods for Process Development and Process Tracking
190
6
Plaque-Forming Titer Assays190
1
Adenovirus 96-Well Titer Plate Assay191
3
Flow Cytometry194
1
Particle Concentration Determination by Ultraviolet Absorbance194
1
Analytical Reverse-Phase HPLC195
1
Analytical Anion-Exchange HPLC196
1
Formulation and Stability
196
4
References200
5
Targeted Adenoviral Vectors I: Transductional Targeting
Victor Krasnykh and
Joanne T. Douglas
The Pathway of Adenoviral Infection
206
1
Strategies and Considerations
207
2
Conjugate-Based Targeting
209
7
Bispecific Chemical Conjugates209
4
Bispecific Recombinant Fusion Proteins213
2
Bispecific Peptides215
1
Polymer-Mediated Coupling of Ligands to Ad Capsid Proteins215
1
Biotinylated Ad/Avidin Bridge/Biotinylated Ligand216
1
Ad-Targeting Strategies Involving Genetic Manipulations of the Fiber Protein217
14
Ad-Targeting Strategies Involving Genetic Manipulations of the Hexon and Penton Base Proteins231
1
Transductionally Targeted Ad Vectors for Clinical Gene Therapy Applications
232
3
References236
11
Targeted Adenoviral Vectors II: Transcriptional Targeting
Sudhanshu P. Raikwar Chinghai H. Kao and
Thomas A. GardnerIntroduction: Rationale of Transcriptional Targeting
247
1
Regulation of Transcription in Eukaryotes
248
8
Molecular Organization of DNA248
1
The Central Dogma248
1
Transcription249
2
Mechanism of Transcription251
2
Structural Motifs253
3
Regulation of Adenoviral DNA Transcription Process256
1
Approaches of Transcriptional Regulation
256
15
Prior Rationale Universal Promoters256
1
Current Rationale of Tissue-Specific Promoters257
11
MN/CA9 Promoter268
1
Inducible Transcription269
2
Enhanced Control of Transgene Expression
271
1
Safety Improvements271
1
Potency Concerns272
1
Enhancement of Weak But Specific Promoters272
2
Improving Specificity with Multiple Promoter Segments274
1
Tumor-Specific Oncolysis274
1
Combined Targeting Approaches274
1
References275
12
Development of Attenuated Replication Competent Adenoviruses (ARCAs) for the Treatment of Prostate Cancer
Daniel R. Henderson and
De-Chao Yu
ARCAs for Prostate Cancer: CV706 and CV787
290
8
Adenovirus: Gene Expression and Regulation290
1
Tissue Specificity of ARCA291
4
Antitumoral Efficacy of ARCA295
1
Mechanism for Cell-Killing of ARCA296
2
Synergy of ARCA and Conventional Therapy
298
7
Synergy of CV706 and Irradiation299
3
Synergy of CV787 and Chemotherapy302
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 Activity309
4
SIAPA: Screening and Immunoapheresis of Preexistent Antibody for Monitoring and Removing Preexistent Ad5 Antibodies from Blood313
1
Clinical Development of CV706 and CV787
314
4
CV706 Phase I/II Trial for Locally Recurrent Prostate Cancer314
3
Factors Impacting Clinical Efficacy and Safety317
1
References319
10
Replication-Selective Oncolytic Adenovirus E1-Region Mutants: Virotherapy for Cancer
David Kirn
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 Adenovirus337
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
Toxicity340
1
Viral Replication340
2
Immune Response342
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
References346
3
Innate Immune Responses to in Vivo Adenovirus Infection
Bruce C. Trapnell and
Thomas P. ShanleyOverview: Components of Innate Immunity
349
5
Distribution and Clearance of Adenovirus from the Respiratory Tract
354
5
Clinical Aspects of Natural Adenoviral Infection in Humans354
1
Distribution of Recombinant, Replication-Deficient Adenoviral Vectors355
1
Kinetics and Mechanisms of Clearance of Adenovirus356
3
Molecular Mediators of Inflammation
359
5
Clinical Adenovirus Infections in Humans360
1
Adenovirus Infections in Animal Models361
1
Acute Cytokine Responses362
1
Intermediate Cytokine Responses363
1
Late Cytokine Responses364
1
Inflammatory Cell Recruitment
364
3
Innate Immunity and Programming of Adaptive Responses
367
1
Innate Immunity and in Vivo Gene Therapy
368
1
References369
6
Humoral Immune Response
Catherine O'Riordan
Adenovirus Structure and Serotype
376
5
Classification of Adenoviruses376
1
Adenoviral Structural Proteins and Type-Specific Epitopes376
3
Chimeric Adenovirus Vectors379
1
Influence of Serotypic Variations on Adenoviral Cell Interactions380
1
Host Response to Gene Therapy Vectors
381
3
Innate Immune Response381
1
Adaptive Immune Response: B-T Cell Interactions382
2
Strategies to Overcome the Humoral Immune Response
384
6
General Immunosuppression384
2
Transient Selective Immunosuppression386
1
Oral Tolerance387
1
Serotype Switching388
1
Masking Neutralizing Epitopes389
1
Immunoapheresis390
1
Factors Modulating Host Responses to Gene Transfer Vectors
390
6
Viral Vector Backbone390
3
Species and Strain393
2
Route of Delivery395
1
Immune Response to Adenoviral-based Vectors in Humans
396
2
References399
10
Novel Methods to Eliminate the Immune Response to Adenovirus Gene Therapy
Hoang-Ge Zhang Hui-Chen Hsu and
John D. Mountz
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
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
References424
5
High-Capacity ``Gutless'' Adenoviral Vectors: Technical Aspects and Applications
Gudrun Schiedner Paula R. Clemens Christoph Volpers and
Stefan Kochanek
Vector Production430
2
Stuffer DNA432
2
Vector Capsid Modification434
1
Liver Gene Transfer435
4
Gene Transfer into Skeletal Muscle439
1
Gene Transfer into the Eye and into the CNS440
2
References442
5
Xenogenic Adenoviral Vectors
Gerald W. BothImpetus and Rationale
447
1
Classification of Adenoviruses
447
1
Factors Affecting Vector Design and Utility
448
12
Host Range and Pathogenicity448
2
Neutralization450
1
Genome Structure and Function450
4
Transforming Ability454
2
Cell Lines456
2
Strategies for Vector Construction and Rescue458
2
Utility of Xenogenic Vectors
460
6
Veterinary Studies460
2
Vector Biology462
4
Gene Therapy Studies466
1
Complementation and Recombination466
2
Oncogenes in Viral and Cellular DNA468
1
Virus/Cell Interactions468
1
Replication Competent Viruses469
1
Vector Production and Purification
469
12
References470
11
Hybrid Adenoviral Vectors
Stephen J. Murphy and
Richard G. Vile
Retroviral Vectors483
4
Adenoviral Vectors487
1
Adeno-associated Viruses487
1
Herpes Simplex Viruses488
1
Lentiviral Vectors488
1
The Choice of Gene Therapy Vector489
2
How to Maintain Stable Transgene Expression491
1
Are Hybrid Vectors Truly New Technology?493
1
Hybrid Adenoviral Vector Systems
494
24
Pseudotyping and Retargeting Adenoviral Vectors494
2
Adenoviral/Retroviral Hybrid Vector Technologies496
12
Adenoviral/Epstein-Barr Virus Hybrid Vectors508
3
Hybrid Retroviruses Trafficking to the Nucleus511
1
Hybrid Adenoviral/Adeno-Associated Virus Vectors512
6
References524
9
Utility of Adenoviral Vectors in Animal Models of Human Disease I: Cancer
Raj K. Batra Sherven Sharma and
Lily Wu
Animal Models of Lung Cancer
535
12
Human Lung Cancer535
2
Animal Models of Human Lung Cancer537
6
Gene Therapy of Lung Cancer Using Adenoviral Vectors543
4
Animal Models of Human Prostate Cancer
547
4
Human Prostate Cancer547
1
Spontaneous and Transgenic Models of Human Prostate Cancer547
1
Xenograft Models of Human Prostate Cancer548
2
Gene Therapy Approaches with Adenovectors in Prostate Cancer550
1
Summary and Discussion
551
14
References553
12
Utility of Adenoviral Vectors in Animal Models of Human Disease II: Genetic Disease
Raymond John Pickles
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 Studies570
1
Success and Limitations of Ad571
6
Overcoming the Limitations of Ad577
8
References586
9
Utility of Adenoviral Vectors in Animal Models of Human Disease III: Acquired Diseases
Erik Lubberts and
Jay K. KollsAdenoviral Vectors for Infectious Disease
595
8
Tuberculosis596
2
Pneumonia598
3
Opportunistic Infections601
2
Viral Hepatitis603
1
Chronic Inflammatory Diseases
603
5
Inflammatory Bowel Disease603
1
Arthritis604
3
Fibrotic Lung Disease607
1
References608
7
Testing of Adenoviral Vector Gene Transfer Products: FDA Expectations
Steven R. Bauer Anne M. Pilaro and
Karen D. Weiss
Manufacturing Control and Product Characterization
616
2
Purity, Safety, and Potency616
1
Regulation of Process as Well as Product617
1
Current Good Manufacturing Practices617
1
Development of Recommendations for the Manufacture and Characterization of Adenoviral Vectors
618
2
Considerations in Manufacturing Adenoviral Vectors
620
1
Components and Characterization620
1
Protocols621
1
Standard Operating Procedures621
1
Quality Assurance and Quality Control Programs622
1
Characterization of Adenoviral Vector Production Intermediates
623
5
Master Cell Bank623
3
Working Cell Bank626
1
Master Virus Bank626
2
Characterization of Adenoviral Vector Final Products
628
2
Preclinical Testing of Adenoviral Vectors
630
2
Pharmacologic Activity631
1
Scope of Toxicity Testing632
1
Species Selection633
1
Route of Administration634
1
Selection of Dose634
2
Good Laboratory Practices637
1
Introduction to Clinical Testing
637
2
Phases of Clinical Development638
1
Good Clinical Practices
639
3
Responsibilities of a Sponsor and Investigators639
1
Adverse Event Reporting639
1
Consent and Vulnerable Populations640
1
Monitoring and Auditing641
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 Control645
1
Endpoint Selection645
1
How the Role of FDA Regulators Has Changed Since September 1999
646
5
Safety Symposia in Conjunction with OBA647
1
Results of FDA's Directed Inspections648
1
Description of the March 6, 2000, Letter and Summary of Responses649
1
Results of Additional Inspections650
1
Sponsor Outreach and Education651
1
References652
3
Imaging Adenovirus-Mediated Gene Transfer
Kurt R. Zinn and
Tandra R. Chaudhuri
What Information Is Provided by Imaging?
656
1
Scientific Basis for Imaging
657
6
Electromagnetic Energy657
1
Contrast657
1
Gamma Rays and Detection657
4
Light-Based Imaging and Detection661
1
Magnetic Resonance Imaging and Spectroscopy662
1
Imaging and Gene-Therapy Vectors
663
6
Gamma-Ray Imaging663
3
Light-Based Imaging666
2
Magnetic Resonance Technologies668
1
Gene-Therapy Vectors May Advance Molecular Imaging
669
2
References671
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