Adenoviral Vectors for Gene Therapy

3rd Edition - April 9, 2025
Imprint: Academic Press
Editors: David T. Curiel, Alan L. Parker
Language: English
Hardback ISBN:
9 7 8 - 0 - 3 2 3 - 8 9 8 2 1 - 8
eBook ISBN:
9 7 8 - 0 - 3 2 3 - 9 5 8 1 4 - 1

Adenoviral Vectors for Gene Therapy, Third Edition, provides detailed, comprehensive coverage of gene delivery vehicles based on the adenovirus that is emerging as an important… Read more

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Adenoviral Vectors for Gene Therapy, Third Edition, provides detailed, comprehensive coverage of gene delivery vehicles based on the adenovirus that is emerging as an important tool in gene therapy. These exciting new therapeutic agents have great potential for the treatment of disease, as platforms for gene therapy and gene editing, as well as for oncology approaches, making them class leading agents in the gene-advanced therapies arena.

The fully updated and expanded third edition covers the basic biology of adenoviruses and highlights the potential use of adenoviral vectors for the treatment of disease, including their construction, propagation, and purification, cutting-edge vectorology, and the use of adenoviral vectors in preclinical animal models. The book also considers the regulatory issues surrounding human clinical gene therapy trials. New chapters include adenoviral vaccines for veterinary applications, adenoviruses for gene editing, nonhuman primate adenoviruses, COVID-19 vaccines, vaccine applications, and oncolytic adenoviruses for antitumor immunization. This broad scope of information provides a solid overview of the field, allowing the reader to gain a complete understanding of the development and use of adenoviral vectors.

Adenoviral Vectors for Gene Therapy
Cover image
Title page
Table of Contents
Copyright
Contributors
Chapter 1 Structural biology of adenovirus
Abstract
Acknowledgments
1 Introduction
2 General organization of the adenovirus virion
3 Structure of major capsomers
3.1 Hexon
3.2 Penton
4 Structure of minor capsid proteins
4.1 Protein IIIa
4.2 Protein VI
4.3 Protein VIII
4.4 Protein IX
5 Structure of core proteins
5.1 Protein VII
5.2 Protein V
5.3 Protein μ (X)
5.4 Protein IVa2
5.5 Protein L1-52/55 kDa
5.6 Terminal protein
5.7 DNA-binding protein
5.8 Adenovirus protease (AVP/adenain)
6 Nonstructural, host-interacting adenovirus proteins
6.1 Protein E1A
6.2 Protein E3-19K
6.3 Protein E4-ORF3
7 Conclusions
References
Chapter 2 Adenovirus cell entry
Abstract
Acknowledgments
1 Introduction
2 Fiber-host factor interactions
2.1 Fiber interactions with the coxsackie and adenovirus receptor (CAR)
2.2 Fiber-interactions with CD46 and desmoglein-2
2.3 Fiber interactions with heparan sulfate- and sialic acid-containing molecules
3 Hexon-host factor interactions
3.1 Hexon interactions with CD46
3.2 Hexon interactions with coagulation factors and complement
3.3 Hexon interactions with lactoferrin and lactoferricin
3.4 Hexon interactions with scavenger receptors
4 Penton base-host factor interactions
4.1 Penton base interactions with integrins
4.2 Penton base interactions with RGD-binding integrins
4.3 Penton base interactions with other integrins
4.4 Integrins as attachment factors
4.5 Role of integrins in endocytosis and endosomal escape
5 Additional host factors
6 Concluding remarks
References
Chapter 3 Adenovirus replication
Abstract
1 Introduction
2 HAdV genome organization
3 HAdV infection and innate cellular responses
4 Early gene expression
4.1 Early region 1A
4.2 Early region 1B
4.3 Early region 2
4.4 Early region 3
4.5 Early region 4
5 Viral DNA replication
6 Virus-associated RNAs
7 Late gene expression
8 Virus assembly and genome encapsidation
9 Conclusion
References
Chapter 4 Adenoviral vector construction I: Mammalian systems
Abstract
Acknowledgments
1 Introduction
1.1 Adenovirus biology
1.2 Adenovirus vectors
2 Cell lines for propagating adenovirus vectors
2.1 Propagation of adenovirus vectors encoding toxic transgenes
3 Construction of first-generation adenoviral vectors
3.1 Early methods
3.2 The two-plasmid rescue system
4 Steps involved in adenovirus vector rescue and propagation
4.1 Preparation of adenovirus genomic and shuttle plasmid DNA for co-transfection
4.2 Co-transfection of HEK293 cells with cosmid and AdApter plasmid
4.3 Plaque purification of adenoviral vectors
4.4 Analysis of the rescued recombinant adenovirus vectors
4.5 Preparation of high-titer virus stock (crude lysate)
4.6 Purification of high-titer adenovirus vector by CsCl gradient ultracentrifugation
4.7 Characterization of adenovirus vectors
5 Conclusion
References
Chapter 5 Adenoviral vector construction II: Bacterial systems
Abstract
1 Introduction
2 Construction of first-generation adenovirus vectors
2.1 Early methods for adenovirus vector construction
2.2 Homologous recombination method in Escherichia coli
2.3 Improved in vitro ligation method
2.4 Homologous recombination method in yeast
2.5 Transposon-mediated recombination method
2.6 DNA assembly method
2.7 Other methods
3 Conclusion
References
Chapter 6 Adenoviral vector packaging cell lines
Abstract
1 Introduction
2 The transforming potential of the adenoviral E1 genes
3 E1 trans-complementing cell lines
4 E2/E4 trans-complementing cell lines
5 Helper-dependent adenoviral vectors
6 Concluding remarks
References
Chapter 7 Purification of adenovirus
Abstract
1 Introduction
2 Adenovirus: Relevant characteristics for purification schemes
3 Adenovirus production
4 Purification of adenoviral vectors
5 Cell harvest and lysis
5.1 Chemical lysis with detergents
5.2 Lysis by freezing/thawing cycles
6 Clarification
6.1 DNA digestion, centrifugation
6.2 Filtration
6.3 Depth filtration
6.4 Tangential flow filtration
7 Purification by ultracentrifugation
8 Chromatography purification
8.1 Purification by ion-exchange chromatography
8.2 Polishing step by size-exclusion chromatography
8.3 Polishing step using Capto Core 700 multimodal resin
9 Membrane-based chromatography
10 Scale-up of chromatography steps
11 Sterile filtration and formulation
12 Challenges
13 Analytical methods for process characterization and quality control
13.1 Quantitation by high-performance liquid chromatography
13.2 Genome quantitation by PCR
13.3 Ultraviolet absorbance
13.4 Titration of infectious particles
13.5 Determination of host cell protein, total proteins, and total DNA
13.6 Benzonase and polysorbate 20 quantitation
13.7 Other techniques
14 Concluding remarks
References
Chapter 8 Innate immune response to adenovirus vectors following intravascular administration
Abstract
1 Introduction
2 Adenovirus interactions with blood cells and components of the plasma
2.1 Coagulation factors
2.2 Antibodies and complement
2.3 Defensins
2.4 Blood cells
3 Adenovirus interactions within liver tissue
3.1 Adenovirus interactions with Kupffer cells
3.2 Adenovirus interactions with hepatocytes
3.3 Adenovirus interactions with liver sinusoidal endothelial cells
4 Adenovirus interactions within spleen
5 Adenovirus interactions within lungs
6 Comparison of host responses to different adenoviruses after their intravascular administration
6.1 Comparison of safety of different adenovirus vectors reported in clinical trials
6.2 Comparison of safety of different adenovirus vectors in nonhuman primate models
6.3 Potential pathophysiological mechanisms of severe adverse responses observed after intravenous infusion of adenovirus vectors at high doses
6.4 Comparison of safety profiles of different adenoviruses and adenoviral vectors in mouse models
7 Conclusion and a new era for therapeutic applications of adenovirus vectors
References
Chapter 9 Antibodies against adenoviruses
Abstract
1 Antibodies against adenoviruses
1.1 Introduction
2 Antibodies against adenoviruses and mechanism of action
2.1 Neutralization by inhibiting attachment to host cells or intracellular routing
2.2 The role of complement, coagulation blood factors, and antibodies in innate responses to AdV
3 Approaches to avoid Abs binding to AdV
4 Clinical evaluation of modified and alternative adenoviral vectors
4.1 Influence of (neutralizing) Abs on vaccine approaches after intramuscular administration
4.2 Enhancing the effectivity of oncolytic vectors in clinical trials
4.3 Alternative/rare serotypes in antitumor AdVs
4.4 Capsid chimeras in antitumor AdV vectors
5 Considerations on applications for AdVs in therapy regarding Abs and immune induction
References
Chapter 10 Methods to mitigate immune response
Abstract
Acknowledgments
1 Introduction
2 Immune responses after adenovirus infection
2.1 Innate immunity
2.2 Adaptive immunity
3 Methods to mitigate immune responses
3.1 The use of pharmacological agents
3.2 Vector encapsulation with chemicals
3.3 Utilization of other adenoviruses
3.4 Pseudotyping
3.5 Route of administration
4 Other immune mitigation strategies
4.1 Sheathing with extracellular vesicles
5 Conclusions
References
Chapter 11 Xenogenic adenoviral vectors as vaccines
Abstract
1 Introduction
1.1 General characteristics of adenoviruses
2 Genome organization of adenoviruses
2.1 Early gene products
2.2 Late gene products
2.3 Engineering and production of vectors based on adenoviruses
3 Structure of adenoviruses
4 Viral entry
4.1 CAR-dependent entry
4.2 CAR-independent entry
4.3 Bridging interactions
4.4 Advantages of adenoviral vectors
4.5 Preexisting immunity to Ads in humans
5 Use of nonhuman Ads as vectors
5.1 Avian Ad vectors as vaccines
5.2 Bovine Ad vectors as vaccines
5.3 Canine Ad vectors
5.4 Ovine Ad vectors as vaccines
5.5 Porcine Ad vectors as vaccines
5.6 Simian Ad vectors as vaccines
5.7 Preclinical studies
5.8 Species B Ads
5.9 Species C Ads
5.10 Species E Ads
5.11 Species F and species G Ads
5.12 Advances in the clinical evaluation of nonhuman Ad vectors
6 Future directions
References
Chapter 12 Adenoviral vector targeting
Abstract
1 Introduction
2 General principles in adenoviral vector targeting
2.1 Virus entry must be detargeted from native receptor usage in addition to being guided toward novel targets of interest
2.2 The receptor toward which virus entry is directed must be readily available on the cell surface and expressed in a restricted manner
2.3 Retargeting modifications must be compatible with the intracellular adenoviral infection cycle
3 Chemical modification strategies
3.1 Cationic polymers
3.2 Polyethylene glycol
3.3 Poly(N-(2-hydroxypropyl)methacrylamide)
3.4 Bioresponsive polymers
4 Adaptor-based retargeting methods
4.1 Adaptors utilizing capsid binding domains capitalizing upon native interactions
4.2 Adaptors with synthetically engineered capsid-binding domains
4.3 Secretion of adaptors from infected cells
5 Genetic modification of adenoviral capsid proteins
5.1 Pseudotyping and xenotyping
5.2 Peptide-based adenoviral targeting
5.3 Genetic incorporation of complex targeting motifs
6 Combinatorial approaches
6.1 Biotinylated adenoviral vectors
6.2 Introduction of novel amino acid residues for the site-specific coupling of retargeting molecules
6.3 Genetic modifications can provide novel engagement points for binding molecules whose solubility and stability properties make them poor choices for direct capsid incorporation
7 Targeted liposomes, magnetic nanoparticles, and cell-based carriers for selective adenoviral delivery
8 Conclusion
References
Chapter 13 Systems of adenoviral gene transfer vectors moving into their fourth generation
Abstract
Conflict of interest
1 Adenoviruses
2 Vector production cells
3 Adenoviral vectors
4 First generation Ad vectors
5 Second generation Ad vectors
6 Third generation Ad vectors
7 The GreGT plug-and-play platform of fully deleted helper virus independent adenoviral vectors
8 Fully deleted vector genomes
9 Circular packaging expression plasmids
10 Engineering of host cells
11 Encapsidation of fully deleted GreGT vector genomes
12 The flexibility and versatility of the GreGT platform
13 Applications of FD adenoviral vectors
14 Vaccines
15 Gene therapy
16 Summary
References
Chapter 14 Hybrid adenoviral vectors
Abstract
1 Introduction
2 Hybrids of adenovirus with piggyBac transposon
3 Foamy virus adenovirus hybrids
4 Murine leukemia virus adenovirus hybrids
5 Ad/AAV hybrid vectors
6 Conclusion
References
Chapter 15 Canine adenovirus
Abstract
1 Introduction
2 Understanding canine adenoviral vectors
3 Applications in canine gene therapy
4 Engineering canine adenoviral vectors
5 Challenges and future directions
6 Conclusion
References
Chapter 16 Oncolytic adenovirus: Challenges and advancements of clinical translation
Abstract
Declaration of AI and AI-assisted technologies in the writing process
1 Introduction
2 Development and limitations of the first generation of oncolytic adenoviruses
3 Strategies to improve the therapeutic efficacy of oncolytic adenovirus-based therapy
3.1 Strategies for improving selectivity of oncolytic adenoviruses
3.2 Strategies for improving poor replication of oncolytic adenoviruses
3.3 Challenges associated with preexisting immunity: Balancing antiviral immune responses while preserving anticancer immune responses
4 Preclinical models to study the safety and efficacy of oncolytic adenoviruses
4.1 Murine models
4.2 Cotton rats and Syrian hamsters
4.3 Nonhuman primates
4.4 Swine models
4.5 Relevance of preclinical animal models to human clinical trials
5 Conclusion
References
Chapter 17 Imaging analysis of adenovirus particles during the cell entry and intracellular trafficking
Abstract
1 Introduction
2 General overview of major methods used for adenovirus imaging
3 Adenovirus labeling
4 Visualization of adenovirus cell binding and entry
5 Tracking adenovirus intracellular trafficking pathways
6 Adenovirus-cell interactions and modifications revealed by imaging
7 Temporal and spatial dynamics of adenovirus cell entry and intracellular trafficking
8 Insights and implications
9 Challenges and future perspectives
10 Conclusion
References
Chapter 18 Adenovirus-based strategies for cancer vaccines
Abstract
1 Introduction
1.1 Adenoviral vaccines
1.2 Cancer vaccines
1.3 Adenoviral cancer vaccines
2 Adenoviral vaccines targeting tumor-associated antigens
2.1 Introduction to tumor-associated antigens
2.2 Adenoviral vaccine strategies targeting TAAs
3 Adenoviral vaccines targeting cancer neoantigens
3.1 Introduction to cancer neoantigens
3.2 Experience to date with adenoviral vaccines targeting cancer neoantigens
4 Future directions
References
Chapter 19 Adenoviral vaccines—Infectious disease
Abstract
1 Introduction
2 Clinical evaluation of adenoviral vectored vaccines
2.1 Viral pathogens
2.2 Parasitic pathogens
2.3 Bacterial pathogens
3 Future of adenoviral vectored vaccines for infectious disease
References
Chapter 20 Adenoviral vaccines: COVID-19
Abstract
Acknowledgments
1 Introduction
2 Adenovirus-based SARS-CoV-2 vaccines
3 Effect of preexisting antibodies on immune responses elicited after adenovirus vector vaccination
4 Conclusions and perspectives
References
Chapter 21 Adenovirus vectored veterinary vaccines
Abstract
1 Introduction
2 Adenovirus
3 Virion structure
4 Animal adenovirus
5 Adenoviral vectors as vaccine delivery tool
6 Adenoviruses as vectors for veterinary vaccines
7 Animal adenoviruses as veterinary vaccine vector
7.1 Bovine adenovirus-3
7.2 Porcine adenovirus-3
7.3 Canine adenovirus
7.4 Fowl adenovirus-1/4/8/9/10
7.5 Ovine adenovirus
7.6 Chimpanzee/Simian adenoviral vectors
8 Human adenovirus as veterinary vaccine vector
8.1 Prime-boost
9 Animal adenovirus with the potential to be developed as a vaccine vector
9.1 Fish adenovirus
9.2 Bat adenovirus
9.3 Equine adenoviruses
9.4 Cervine adenovirus
9.5 Mouse adenovirus
10 Licensed adenovirus-vectored veterinary vaccines
10.1 ONRAB
10.2 AdtA24
11 Summary
References
Chapter 22 Utility of adenoviral vectors in animal models—CV disease
Abstract
Acknowledgments
1 Introduction
2 Adenoviral vectors for cardiovascular gene therapy
2.1 Barriers to vascular gene transfer
2.2 Adenovirus vectors and other virus vectors in vascular gene transfer
2.3 Adenovirus vectors and vascular targeting strategies
3 Animal models for cardiovascular gene transfer
3.1 Mouse models
3.2 Rat models
3.3 Rabbit models
3.4 Dog models
3.5 Pig models
4 Conclusions
References
Chapter 23 Utility of adenoviral vectors in animal models of human disease III: acquired diseases
Abstract
1 Adenoviral vectors for infectious disease
1.1 Tuberculosis
1.2 Pneumonia
1.3 Opportunistic infections
1.4 Viral hepatitis
2 Chronic inflammatory diseases
2.1 Inflammatory bowel disease
2.2 Arthritis
2.3 Fibrotic lung disease
3 Conclusions
References
Chapter 24 Utility of adenoviral vectors in animal models of human disease: Genetic diseases
Abstract
1 Introduction
2 AdV vectors as research tools in genetic diseases
3 Gene supplementation of therapeutic genes in animal models of monogenetic diseases
3.1 Liver-directed gene transfer
3.2 Cardiovascular diseases
3.3 Neurological diseases
3.4 Muscular dystrophies
4 Strategies to ensure long-term effects of adenoviral vectors
4.1 Integration of expression cassettes in the host genome
4.2 Site-specific genome modification
5 Ex vivo gene therapy
6 Conclusion
References
Chapter 25 Adenoviral vectors for gene editing
Abstract
1 Introduction
2 Fundamental CRISPR/Cas mechanisms
3 Novel CRISPR systems
4 Adenoviral vectors in gene editing
4.1 Ads for gene knock-out/inactivation/activation
4.2 Ads for HR-mediated gene knock-in
4.3 Ads and novel gene editors
5 Future outlooks
References
Chapter 26 Manufacturing and upscaling
Abstract
1 Introduction
2 Research grade production
2.1 Small scale production
2.2 General considerations for scale-up and process development
3 Large scale and clinical grade manufacturing
3.1 General considerations and critical starting materials
3.2 Upstream manufacturing—Production options
3.3 Upstream manufacturing overview and factors impacting productivity
3.4 Downstream manufacturing—Production options and factors affecting yield
3.5 Manufacturing of oncolytic, capsid-engineered, and non-Ad5 vectors
3.6 Challenges during manufacturing
3.7 Platform manufacturing processes
4 Product testing
4.1 In-process testing to monitor manufacturing performance
4.2 Product release testing
5 Future challenges
6 Summary
References
Chapter 27 Regulation of adenoviral vector-based therapies: A CBER/OTP perspective
Abstract
Acknowledgments
1 Introduction
2 Regulatory considerations in the design of adenoviral vector-based therapies
3 Chemistry, manufacturing, and control requirements
3.1 Establishing a cell bank
3.2 Establishing a virus bank
3.3 Production and purification strategies
3.4 Qualification of raw materials and reagents used in production
4 Manufacturing control
4.1 Product testing
4.2 Quality and current good manufacturing practices
5 Nonclinical evaluation of adenoviral vector-based therapies
5.1 Proof-of-concept studies
5.2 Safety testing
5.3 Biodistribution (BD) assessment
5.4 Good laboratory practice
5.5 Nonclinical considerations for late-phase clinical trials
6 Introduction to clinical investigations
6.1 Phases of clinical development
6.2 Good clinical practices
6.3 Clinical safety of adenoviral vector-based products
6.4 Bioactivity of adenoviral vector products
6.5 Clinical efficacy of adenoviral vector products
7 Sponsor outreach and education
References
Index

Life Sciences

Physical Sciences & Engineering

Social Sciences & Humanities

Health

Adenoviral Vectors for Gene Therapy

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David T. Curiel

Alan L. Parker

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