Table of Contents
Contents
Preface
Abbreviations
Contributors
1: Molecular Biotechnology: From DNA Sequence to Therapeutic Protein
Introduction
Pharmaceutical Biotechnology, Why This Book, Why This Chapter?
Economics and Use
From an In Silico DNA Sequence to a Therapeutic Protein
■ Selection of a Therapeutic Protein
■ DNA Sequence
■ Selection of Expression Host
■ CopyDNA
Box 1.1 ■ The Central Dogma of Molecular Biology
■ Cloning PCR Products into an Expression Vector
Box 1.2. ■ Plasmids .
Box 1.3 ■ DNA Sequencing .
■ Transfection of Host Cells and Recombinant Protein Production
■ Cell Culture
■ Purification; Downstream Processing
Monoclonal Antibodies
Yields
Conclusion
Self-Assessment Questions
Recommended Reading and References
2: Biophysical and Biochemical Analysis of Recombinant Proteins
Introduction
Protein Structure
Primary Structure
Secondary Structure
α-Helix
β-Sheet
Loops and Turns
Tertiary Structure
Forces
Hydrophobic Interactions
Hydrogen Bonds
Electrostatic Interactions
Van der Waals Interactions
Hydration
Protein Folding
Techniques Specifically Suitable for Characterizing Protein Folding
Protein Stability
Analytical Techniques
Blotting Techniques
Transfer of Proteins
Detection Systems
Immunoassays
ELISA
Electrophoresis
Polyacrylamide Gel Electrophoresis
Isoelectric Focusing (IEF)
2-Dimensional Gel Electrophoresis
Detection of Proteins Within Polyacrylamide Gels
Capillary Electrophoresis
Chromatography
Size-Exclusion Chromatography
Reversed-Phase High-Performance Liquid Chromatography
Hydrophobic Interaction Chromatography
Ion-Exchange Chromatography
Other Chromatographic Techniques
Bioassays
Mass Spectrometry
Concluding Remarks
Self-Assessment Questions
Further Reading
3: Production and Purification of Recombinant Proteins
Introduction
Upstream Processing
■ Expression Systems
General Considerations
Transgenic Animals
Plants
■ Cultivation Systems
General
Single-Use Systems
Fermentation Protocols
■ Cultivation Medium
Downstream Processing
■ Introduction
■ Filtration/Centrifugation
Filtration
Centrifugation
■ Precipitation
■ Chromatography
Introduction
Chromatographic Stationary Phases
Adsorption Chromatography
Ion-Exchange Chromatography
(Immuno)Affinity Chromatography
Affinity Chromatography
Immunoaffinity Chromatography
Hydrophobic Interaction Chromatography
Gel-Permeation Chromatography
Expanded Beds
Contaminants
■ Viruses
■ Bacteria
■ Cellular DNA
■ Protein Contaminants and Product Variants
N- and C-Terminal Heterogeneity
Conformational Changes/Chemical Modifications
Glycosylation
Proteolytic Processing
Bacteria: Protein Inclusion Body Formation
Commercial-Scale Manufacturing and Innovation
Self-Assessment Questions
References
4: Formulation of Biotech Products, Including Biopharmaceutical Considerations
Introduction
Microbiological Considerations
Sterility
Viral Decontamination
Pyrogen Removal
Excipients Used in Parenteral Formulations of Biotech Products
Solubility Enhancers
Anti-adsorption and Anti-aggregation Agents
Buffer Components
Preservatives and Antioxidants
Osmotic Agents
Shelf Life of Protein-Based Pharmaceuticals
Freeze-Drying of Proteins
Freezing
Primary Drying
Secondary Drying
Other Approaches to Stabilize Proteins
Delivery of Proteins: Routes of Administration and Absorption Enhancement
The Parenteral Route of Administration
The Oral Route of Administration
Alternative Routes of Administration
Examples of Absorption-Enhancing Effects
Delivery of Proteins: Approaches for Rate-Controlled and Target Site-Specific Delivery by the Parenteral Route
Approaches for Rate-Controlled Delivery
Open-Loop Systems: Mechanical Pumps
Open-Loop Systems: Osmotically Driven Systems
Open-Loop Systems: Biodegradable Microspheres
Closed-Loop Systems: Biosensor-Pump Combinations
Protein Delivery by Self-Regulating Systems
Protein Delivery by Microencapsulated Secretory Cells
Site-Specific Delivery (Targeting) of Protein Drugs
Anatomical, Physiological, and Pathological Considerations Relevant for Protein Targeting
Soluble Carrier Systems for Targeted Delivery of Proteins
Monoclonal Antibodies (MAB) as Targeted Therapeutic Agents: Human and Humanized Antibodies (See Also with More Details: Chap. 7)
Bispecific Antibodies (See Also Chap. 7)
Immunoconjugates: Combinations Between an Antibody and an Active Compound
Potential Pitfalls in Tumor Targeting
Nanotechnology at Work: Nanoparticles for Targeted Delivery of Proteins
Perspectives for Targeted Protein Delivery
Self-Assessment Questions
References
5: Pharmacokinetics and Pharmacodynamics of Peptide and Protein Therapeutics
Introduction
Pharmacokinetics of Protein Therapeutics
■ Absorption of Protein Therapeutics
Enteral Administration
Parenteral Administration
■ Distribution of Protein Therapeutics
Distribution Mechanisms and Volumes
Protein Binding of Protein Therapeutics
Distribution via Receptor-Mediated Uptake
■ Elimination of Protein Therapeutics
Proteolysis
Gastrointestinal Protein Metabolism
Renal Protein Metabolism
Hepatic Protein Metabolism
Target-Mediated Protein Metabolism
Modulation of Protein Disposition by the FcRn Receptor
■ Immunogenicity and Protein Pharmacokinetics
■ Species Specificity and Allometric Scaling
■ Chemical Modifications for Optimizing the Pharmacokinetics of Protein Therapeutics
Pharmacodynamics of Protein Therapeutics
■ Direct Link PK/PD Models
■ Indirect Link PK/PD Models
■ Indirect Response PK/PD Models
■ Cell Life Span Models
■ Complex Response Models
Conclusion
Self-Assessment Questions
References
Further Reading
6: Immunogenicity of Therapeutic Proteins
Introduction
The New Paradigm
The Immunological Response
Factors Influencing Antibody Formation to Therapeutic Proteins
Structural Factors
Impurities
Formulation
Route of Administration
Dose
Patient Features
Assays for Antibodies
Issues Specifically Related to Monoclonal Antibodies
Clinical Effects of Induced Antibodies
Predicting and Reducing Immunogenicity
Reducing Immunogenicity
Conclusions
Self-Assessment Questions
References
Further Reading
7: Monoclonal Antibodies: From Structure to Therapeutic Application
Introduction
Antibody Structure and Classes
■ Murine, Chimeric, Humanized, and Fully Humanized MABs
■ Key Structural Components of MABs
■ Modifying Fc Structures
■ Antibody Derivatives (F(ab’)2, Fab, Antibody Drug Conjugates) and Fusion Proteins
How Do Antibodies Function as Therapeutics?
■ Direct Modulation of Target Antigen
■ Complement-Dependent Cytotoxicity (CDC)
■ Antibody-Dependent Cellular Cytotoxicity (ADCC)
■ Apoptosis
Translational Medicine/Development Process
■ Preclinical Safety Assessment of MABs
■ Pharmacokinetics
Absorption
Distribution
Antibody Clearance
Therapeutic MAB–Drug Interactions
■ Prediction of Human PK/PD Based on Preclinical Information
■ PK/PD in Clinical Development of Antibody Therapeutics
Pre-phase I Studies
Identification of MOA and PD Biomarkers
Role of Surrogate Molecules
Pharmacokinetics of Efalizumab
Clinical Program of Efalizumab: PK/PD Studies, Assessment of Dose, Route, and Regimen
■ IV Administration of Efalizumab
■ Determination of SC Doses
■ SC Administration of Efalizumab
Mechanistic Modeling Approaches
Pharmacokinetic Analysis
Pharmacodynamic Analysis
Efficacy Analysis
Model Results
■ Population Pharmacokinetics of Monoclonal Antibodies
Future Perspective
Self-Assessment Questions
References
8: Genomics, Other “Omic” Technologies, Personalized Medicine, and Additional Biotechnology-Related Techniques
Introduction
An Introduction to “Omic” Technologies
■ Genomics
Structural Genomics and the Human Genome Project
Next-Generation Genome Sequencing (NGS) and the $1,000 Genome
Functional Genomics and Comparative Genomics
■ “Omic”-Enabling Technology: Bioinformatics
■ Transcriptomics
■ Proteomics, Structural Proteomics, and Functional Proteomics
■ “Omic”-Enabling Technology: Microarrays
■ “Omic”-Enabled Technology: Brief Introduction to Biomarkers
■ Metabonomics and Metabolomics
■ Pharmacogenetics and Pharmacogenomics
Single-Nucleotide Polymorphisms (SNPs)
Pharmacogenetics Versus Pharmacogenomics
Genome-Wide Association Studies (GWAS)
■ On the Path to Personalized Medicine: A Brief Introduction
Human Genomic Variation Affecting Drug Pharmacokinetics
Human Genomic Variation Affecting Drug Pharmacodynamics
Value of Personalized Medicine in Disease
Challenges in Personalized Medicine
Epigenetics and Epigenomics
■ Toxicogenomics
■ Glycomics and Glycobiology
Glycosylation and Medicine
■ Lipidomics
■ Nutrigenomics
■ Other “Omic” Technologies
■ “Omics” Integrating Technology: Systems Biology
Transgenic Animals and Plants in Drug Discovery, Development, and Production
■ Transgenic Animals
Production of Transgenic Animals by DNA Microinjection and Random Gene Addition
Production of Transgenic Animals by Retroviral Infection
Production of Transgenic Animals by Homologous Recombination in Embryonic Stem Cells Following Microinjection of DNA
■ Transgenic Plants
Biopharmaceutical Protein Production in Transgenic Animals and Plants: “Biopharming”
■ Xenotransplantation: Transplantable Transgenic Animal Organs
■ Knockout Mice
Site-Directed Mutagenesis
Synthetic Biology
Biotechnology and Drug Discovery
■ Screening and Synthesis
Advances in Screening: High-Throughput Screening (HTS)
High-Throughput Chemistry: Combinatorial Chemistry and Multiple Parallel Synthesis
■ Chemical Genomics
Conclusion
Self-Assessment Questions
References
9: Dispensing Biotechnology Products: Handling, Professional Education, and Product Information
Introduction
Pharmacist Readiness
■ Types of Information Needed by Pharmacists
■ Sources of Information for Pharmacists
■ The Pharmacist and Handling of Biotech Drugs
Storage
■ Temperature Requirements
■ Storage in Dosing and Administration Devices
■ Storage in IV Solutions
■ Light Protection
Handling
■ Mixing and Shaking
■ Travel Requirements
Preparation
Administration
■ Routes of Administration
■ Filtration
■ Flushing Solutions
■ Prophylaxis to Prevent Infusion Reactions
Biosimilars: Almost to Market
Outpatient/Home Care Issues
■ Patient Assessment and Education
■ Monitoring
Reimbursement
Educational Materials
■ Educational Materials for Health Professionals
■ Educational Materials for Patients
■ The Internet and Biotech Information
Concluding Remarks
Self-Assessment Questions
References
Further Reading
10: Economic Considerations in Medical Biotechnology
Introduction
The Value of a New Medical Technology
An Overview of Economic Analysis for New Technologies
Pharmacoeconomics
■ Importance of Pharmacoeconomics
■ Understanding Costs
Direct Costs
Indirect Costs
Intangible Costs
Opportunity Costs
Understanding Pharmacoeconomic Methods
■ Cost of Illness
■ Cost-Minimization Analysis
■ Cost-Benefit Analysis
■ Cost-Effectiveness Analysis (CEA)
■ Cost-Utility Analysis (CUA)
Conclusions
References
Further Reading
11: Regulatory Framework for Biosimilars
Introduction
Background
Regulatory Framework in the USA
Scale-Up and Postapproval Changes (SUPAC) Concept and Comparability
Box 11.1 ■ Key Points of the FDA Guidance on Comparability .
Biosimilars and Drug Product Approval
Box 11.2 ■ FDA Routes for Biosimilars .
Guidance Documents on Biosimilars
Scientific Considerations in Demonstrating Biosimilarity to a Reference Product
Characterization
Clinical Studies
EMA Regulatory Framework
Immunogenicity (Related to Overarching EMA Document)
Status of Biosimilars in the EU
The Challenge and the Future
Self-Assessment Questions
References
12: Insulin
Introduction
Chemical Description
Pharmacology and Formulations
■ Regular and Rapid-Acting Soluble Preparations
■ Ultrarapid Initiatives
■ Intermediate-Acting Insulin Preparations
■ Long-Acting Insulin Formulations
■ Concentrated Insulin Formulations
Pharmaceutical Concerns
■ Chemical Stability of Insulin Formulations
■ Physical Stability of Insulin formulations
Clinical and Practice Aspects
■ Vial Presentations
■ Injection Devices
■ Continuous Subcutaneous Insulin Infusion: External Pumps
■ Noninvasive Delivery
■ Storage
■ Usage
Resuspension
Dosing
Extemporaneous Mixing
Self-Assessment Questions
References
Recommended Reading
13: Follicle-Stimulating Hormone
Introduction
FSH Is a Glycoprotein Hormone
Production of Recombinant FSH
Description of Recombinant FSH
Structural Characteristics
Biological Properties of Recombinant FSH Isohormones
Pharmacokinetic Behavior of Recombinant FSH Isohormones
Pharmaceutical Formulations
Clinical Aspects
A Newly Developed FSH Analog
References
Further Reading
14: Human Growth Hormone
Introduction
hGH Structure and Isohormones
Pharmacology
■ Growth Hormone Secretion and Regulation
■ Growth Hormone Biologic Actions
■ hGH Receptor and Binding Proteins
■ Molecular Endocrinology and Signal Transduction
■ Dosing Schedules and Routes
■ Pharmacokinetics and Metabolism
Protein Manufacture, Formulation, and Stability
Clinical Usage
■ Growth Hormone Deficiency (GHD)
■ Idiopathic Short Stature (ISS)
■ Turner Syndrome (TS)
■ Prader-Willi Syndrome (PWS)
■ Small for Gestational Age (SGA)
■ Chronic Renal Insufficiency (CRI)/Chronic Kidney Disease (CKD)
■ Noonan Syndrome
■ Short Stature Homeobox-Containing Gene (SHOX)
■ Growth Hormone Deficient Adults
■ Clinical Malnutrition and Wasting Syndromes
■ Other Conditions Under Investigation
■ Safety Concerns
Concluding Remarks
Self-Assessment Questions
References
Further Reading
15: Recombinant Coagulation Factors and Thrombolytic Agents
Introduction
Factor VIII
Structure
Pharmacology
Recombinant Factor VIII
Pharmaceutical Considerations
Clinical Usage
Safety
Factor VIIa
Structure
Pharmacology
Recombinant Factor VIIa
Pharmacokinetics and Pharmacodynamics
Pharmaceutical Considerations
Clinical Usage
Safety
Recent Developments
Factor IX
Recombinant Coagulation Factor IX
Pharmacology
Pharmaceutical Considerations
Clinical Usage
Safety
Recent Developments
Factor XIII
Recombinant Coagulation Factor XIII
Clinical Usage
Recombinant Thrombolytic Agents
Tissue-Type Plasminogen Activator
Structure
First-Generation Recombinant Thrombolytic Agents: Recombinant t-PA (rt-PA)
Pharmacokinetics of rt-PA
Pharmaceutical Considerations
Clinical Usage
Safety Concerns
Second-Generation Recombinant Thrombolytic Agents
Reteplase
Pharmacology
Pharmaceutical Considerations
Clinical Usage
Safety Concerns
Tenecteplase
Pharmacology
Pharmaceutical Considerations
Clinical Usage
Safety Concerns
Lanoteplase
Conclusions
Self-Assessment Questions
References
16: Recombinant Human Deoxyribonuclease I
Introduction
Historical Perspective and Rationale
Protein Chemistry, Enzymology, and Structure
Pharmacology
In Vitro Activity in CF Sputum
In Vivo Activity in CF Sputum
Pharmacokinetics and Metabolism
Protein Manufacturing and Formulation
Drug Delivery
Clinical Use
Indication and Clinical Dosage
Cystic Fibrosis
Non-cystic Fibrosis Respiratory Disease
Other Medical Conditions
Safety
Summary
Self-Assessment Questions
References
17: Monoclonal Antibodies in Cancer
Introduction
Classes of Monoclonal Antibodies: CD Antigens
■ Alemtuzumab
Pharmacology and Pharmacokinetics
Indications and Clinical Efficacy
Safety
■ Gemtuzumab
Pharmacology and Pharmacokinetics
Clinical Considerations
■ Rituximab, Yttrium-90 ( 90 Y) Ibritumomab Tiuxetan, Iodine-131 ( 131 I) Tositumomab
Pharmacology and Pharmacokinetics
Indications and Clinical Efficacy
Safety
Radioimmunotherapy
■ Brentuximab Vedotin
Pharmacology and Pharmacokinetics
Indications and Clinical Efficacy
Safety
Classes of Monoclonal Antibodies: Vascular Endothelial Growth Factor (VEGF) Inhibitors
■ Bevacizumab
Pharmacology and Pharmacokinetics
Indications and Clinical Efficacy
Safety
Classes of Monoclonal Antibodies: Endothelial Growth Factor Receptor (EGFR) Inhibitors
■ Trastuzumab
Pharmacology and Pharmacokinetics
Indications and Clinical Efficacy
Safety
■ Pertuzumab
Pharmacology and Pharmacokinetics
Indications and Clinical Efficacy
Safety
■ Cetuximab
Pharmacology and Pharmacokinetics
Indications and Clinical Efficacy
Safety
■ Panitumumab
Pharmacology and Pharmacokinetics
Indications and Clinical Efficacy
Safety
Classes of Monoclonal Antibodies: Antihuman Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4)
■ Ipilimumab
Pharmacology and Pharmacokinetics
Indications and Clinical Efficacy
Safety
Classes of Monoclonal Antibodies: Receptor Activator of Nuclear Factor Kappa Beta Ligand Inhibitor
■ Denosumab
Pharmacology and Pharmacokinetics
Indications and Clinical Efficacy
Safety
Conclusion
Self-Assessment Questions
References
18: Hematopoietic Growth Factors: Focus on Erythropoiesis-Stimulating Agents
Introduction
Erythropoiesis-Stimulating Agents
■ Regulation of Erythropoietin
■ Pharmacokinetics
Absorption
Bioavailability
Distribution
Elimination
■ Pharmacodynamics
■ Indications for Cancer Patients and Potential Adverse Events
Myeloid Hematopoietic Growth Factors
■ Granulocyte Colony-Stimulating Factor (G-CSF)
■ Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) and Stem Cell Factor (SCF)
■ Megakaryocyte Hematopoietic Growth Factors
Self-Assessment Questions
References
19: Monoclonal Antibodies in Solid Organ Transplantation
Introduction
Immunologic Targets: Rational Development/Use of Monoclonal Antibodies in Organ Transplant
■ Monoclonal Antibodies Administered Pre-transplant
■ Monoclonal Antibodies Administered at the Time of Transplant
■ Monoclonal Antibodies Administered Following Transplant
Specific Agents Used in Solid Organ Transplant
■ Muromonab
■ Interleukin-2 Receptor Antagonists
Daclizumab
Basiliximab
■ Alemtuzumab
■ Rituximab
■ Eculizumab
■ Belatacept
Conclusion
Self-Assessment Questions
References
20: Monoclonal Antibodies and Antibody-Based Biotherapeutics in Inflammatory Diseases
Introduction
Arthritides
■ Abatacept
■ Adalimumab
■ Certolizumab Pegol
■ Etanercept
■ Golimumab
■ Infliximab
■ Rituximab
■ Tocilizumab
Systemic Lupus Erythematosus
■ Belimumab
Psoriasis
■ Alefacept
■ Anti-TNFα Antagonists (Adalimumab, Etanercept, Infliximab)
■ Ustekinumab
Inflammatory Bowel Disease
■ Adalimumab
■ Certolizumab Pegol
■ Infliximab
■ Natalizumab
Allergic Asthma
■ Omalizumab
Multiple Sclerosis
■ Natalizumab
Cryopyrin-Associated Periodic Syndromes
■ Canakinumab
■ Rilonacept
Conclusion
Self-Assessment Questions
References
21: Interferons and Interleukins
Introduction
Interferons: Nomenclature and Functions
Interleukins: Nomenclature and Functions
Interleukin-1 Family
Interleukin-1
Interleukin-1Ra
Interleukin-18
Interleukin-33
Interleukin-36A, B, and G
Interleukin-36RN
Interleukin-37
Interleukin-38
Interleukin-2 Family
Interleukin-2
Interleukin-4
Interleukin-7
Interleukin-9
Interleukin-15
Interleukin-21
Interleukin-10 Family
Interleukin-10
Interleukin-19
Interleukin-20
Interleukin-22
Interleukin-24
Interleukin-26
Interleukin-28A and B and Interleukin-29
Interleukin-12 Family
Interleukin-12
Interleukin-23
Interleukin-27
Interleukin-35
Interleukin-17 Family
Interleukin-25
Hematopoietin Family
Interleukin-3
Interleukin-5
Interleukin-6
Interleukin-11
Interleukin-13
Others Not (Yet) Assigned to a Family
Interleukin-8
Interleukin-16
Interleukin-31
Interleukin-32
Interleukin-34
Therapeutic Use of Recombinant Interferons
IFN-α Therapeutics
IFN-β Therapeutics
IFN-γ Therapeutics
Therapeutic Use of Recombinant Interleukins
Aldesleukin
Oprelvekin
Anakinra
PEGylated Interferons and Interleukins: The Next Generation
Outlook and Conclusions
Self-Assessment Questions
References
Further Reading
Interferons
Interleukins
PEGylation
22: Vaccines
Introduction
Immunological Principles
■ Introduction
■ Active Immunization: Generation of an Immune Response
■ Innate Response
■ Activation and Migration
■ Antigen Presentation and Lymphocyte Activation
■ The Adaptive Immune System
■ Vaccine Design in Relation with the Immune Response
■ Route of Administration
Classical Vaccines
■ Classification
■ Live Attenuated Vaccines
■ Nonliving Vaccines: Whole Organisms
■ Nonliving Vaccines: Subunit Vaccines
Diphtheria and Tetanus Toxoids
Acellular Pertussis Vaccines
Polysaccharide Vaccines
Modern Vaccine Technologies
■ Modern Live Vaccines
Genetically Attenuated Microorganisms
Live Vectored Vaccines
■ Modern Subunit Vaccines
Recombinant Protein Vaccines
Recombinant Peptide Vaccines
Synthetic Peptide-Based Vaccines
Nucleic Acid Vaccines
■ Reverse Vaccinology
■ Therapeutic Vaccines
Cancer Vaccines
Vaccines Against Drug Abuse
■ Systems Biology and Vaccines
Pharmaceutical Aspects
■ Production
■ Formulation
Adjuvants, Immune Potentiators, and Delivery Systems
Combination Vaccines
■ Characterization
■ Storage
Concluding Remarks
Self-Assessment Questions
References
Further Reading
23: Oligonucleotides
Introduction
Direct Binding to Non-Nucleic Acids
■ Aptamers/Riboswitches
■ Stimulating Immune Responses
Gene Repair and Chromosomal Change
■ Triplex Helix-Forming Oligonucleotides
■ Antisense-Induced Exon Skipping
■ Antisense-Induced Ribonucleoprotein Inhibition
Interfering with Gene Expression
■ Triple Helix-Forming Oligonucleotides
■ Transcription Factor Decoys
■ Antisense/Ribozymes/External Guide Sequences
■ siRNA/miRNA
Pharmacokinetics of Oligonucleotide-Based Therapeutics
Improving Oligonucleotide Stability
Improving Cellular Uptake
Diagnostic Applications
Perspectives
Self-Assessment Questions
References
Further Reading
24: Gene Therapy
Introduction
Vectors for Gene Transfer
■ Basic Components of Plasmid (cf.Chap. 1)
Bacterial Elements
Transcription Regulatory Elements (TRE)
Multiple Cloning Site (MCS)
Untranslated Regions (UTR)
Introns
Polyadenylation (polyA) Sequence
Fusion Tag
Viral Vectors
■ Retrovirus
Biology
Suitability of Retroviruses as Vectors for Gene Transfer
Clinical Use of Retrovirus
■ Lentivirus
Biology
Suitability of Lentiviruses as Vectors for Gene Transfer
Clinical Use of Lentiviral Vectors
■ Adenovirus
Biology
Suitability of Adenoviruses as Vectors for Gene Transfer
Clinical Use of Adenoviral Vectors
■ Adeno-Associated Virus (AAV)
Biology
Suitability of Adeno-Associated Viruses for Gene Transfer
Clinical Use of Adeno-Associated Virus Vectors
Nonviral Vectors
■ Delivery Methods for Nonviral Gene Transfer
Physical Methods for Gene Transfer
Cationic Lipids
Peptides
Polymers
■ Clinical Use of Nonviral Vectors
Stem-Cell-Based Gene Therapy
Stem Cell Therapy (cf. Chap. 25)
Stem Cells as Gene Delivery Vehicles
Stem Cells as Regenerative Medicine (cf. Chap. 25)
Disease Targets for Gene Therapy
Cancer Gene Therapy
■ Correction of Genetic Mutations
■ Immunotherapy
■ Tumors Sensitization
■ Gene-Directed Enzyme-Prodrug Therapy
■ Oncolytic Viruses (Virotherapy)
■ Nonviral Gene Therapy
Monogenetic Diseases
Cardiovascular Diseases
Infectious Diseases
Neurological Diseases
Regulatory Issues of Gene Therapy Products
Concluding Remarks
Self-Assessment Questions and Answers
References
Further Reading
25: Stem Cell Technology
Introduction
■ Significance of Stem Cell Technology
■ What Is a Stem Cell?
■ Adult Stem Cells
■ Embryonic Stem Cells
■ Maintenance and Differentiation of ES Cells in Culture
■ Cell Therapy: The Broader Context
Immunological Considerations in Cell Therapy
IPS Cell Technology
Direct Reprogramming
Use of Products Derived from Stem Cells in Cell Therapy
Disease Modeling and Drug Discovery
Cancer Stem Cells
Regulatory Issues
Concluding Remarks
Self-Assessment Questions
References
Index
