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TitlePharmaceutical Biotechnology: Fundamentals and Applications
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Table of Contents
1: Molecular Biotechnology: From DNA Sequence to Therapeutic Protein
	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
	Self-Assessment Questions
	Recommended Reading and References
2: Biophysical and Biochemical Analysis of Recombinant Proteins
	Protein Structure
		„ Primary Structure
		„ Secondary Structure
			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
		„ 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
	Upstream Processing
		■ Expression Systems
			General Considerations
			Transgenic Animals
		■ Cultivation Systems
			Single-Use Systems
			Fermentation Protocols
		■ Cultivation Medium
	Downstream Processing
		■ Introduction
		■ Filtration/Centrifugation
		■ Precipitation
		■ Chromatography
			Chromatographic Stationary Phases
			Adsorption Chromatography
			Ion-Exchange Chromatography
			(Immuno)Affinity Chromatography
				Affinity Chromatography
				Immunoaffinity Chromatography
			Hydrophobic Interaction Chromatography
			Gel-Permeation Chromatography
			Expanded Beds
		■ Viruses
		■ Bacteria
		■ Cellular DNA
		■ Protein Contaminants and Product Variants
			N- and C-Terminal Heterogeneity
			Conformational Changes/Chemical Modifications
			Proteolytic Processing
	Bacteria: Protein Inclusion Body Formation
	Commercial-Scale Manufacturing and Innovation
	Self-Assessment Questions
4: Formulation of Biotech Products, Including Biopharmaceutical Considerations
	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
5: Pharmacokinetics and Pharmacodynamics of Peptide and Protein Therapeutics
	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
			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
	Self-Assessment Questions
		Further Reading
6: Immunogenicity of Therapeutic Proteins
	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
	Self-Assessment Questions
		Further Reading
7: Monoclonal Antibodies: From Structure to Therapeutic Application
	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
	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
8: Genomics, Other “Omic” Technologies, Personalized Medicine, and Additional Biotechnology-Related Techniques
	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
	Self-Assessment Questions
9: Dispensing Biotechnology Products: Handling, Professional Education, and Product Information
	Pharmacist Readiness
		■ Types of Information Needed by Pharmacists
		■ Sources of Information for Pharmacists
		■ The Pharmacist and Handling of Biotech Drugs
		■ Temperature Requirements
		■ Storage in Dosing and Administration Devices
		■ Storage in IV Solutions
		■ Light Protection
		■ Mixing and Shaking
		■ Travel Requirements
		■ Routes of Administration
		■ Filtration
		■ Flushing Solutions
		■ Prophylaxis to Prevent Infusion Reactions
	Biosimilars: Almost to Market
	Outpatient/Home Care Issues
		■ Patient Assessment and Education
		■ Monitoring
	Educational Materials
		■ Educational Materials for Health Professionals
		■ Educational Materials for Patients
		■ The Internet and Biotech Information
	Concluding Remarks
	Self-Assessment Questions
		Further Reading
10: Economic Considerations in Medical Biotechnology
	The Value of a New Medical Technology
	An Overview of Economic Analysis for New Technologies
		■ 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)
		Further Reading
11: Regulatory Framework for Biosimilars
	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
12: Insulin
	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
			Extemporaneous Mixing
	Self-Assessment Questions
		Recommended Reading
13: Follicle-Stimulating Hormone
	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
		Further Reading
14: Human Growth Hormone
	hGH Structure and Isohormones
		■ 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
		Further Reading
15: Recombinant Coagulation Factors and Thrombolytic Agents
	Factor VIII
		„ Structure
		„ Pharmacology
	Recombinant Factor VIII
		„ Pharmaceutical Considerations
		„ Clinical Usage
	Factor VIIa
		„ Structure
		„ Pharmacology
	Recombinant Factor VIIa
		„ Pharmacokinetics and Pharmacodynamics
		„ Pharmaceutical Considerations
		„ Clinical Usage
		„ Recent Developments
	Factor IX
	Recombinant Coagulation Factor IX
		„ Pharmacology
		„ Pharmaceutical Considerations
		„ Clinical Usage
		„ 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
	Self-Assessment Questions
16: Recombinant Human Deoxyribonuclease I
		„ Historical Perspective and Rationale
	Protein Chemistry, Enzymology, and Structure
		„ 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
	Self-Assessment Questions
17: Monoclonal Antibodies in Cancer
	Classes of Monoclonal Antibodies: CD Antigens
		■ Alemtuzumab
			Pharmacology and Pharmacokinetics
			Indications and Clinical Efficacy
		■ 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
		■ Brentuximab Vedotin
			Pharmacology and Pharmacokinetics
			Indications and Clinical Efficacy
	Classes of Monoclonal Antibodies: Vascular Endothelial Growth Factor (VEGF) Inhibitors
		■ Bevacizumab
			Pharmacology and Pharmacokinetics
			Indications and Clinical Efficacy
	Classes of Monoclonal Antibodies: Endothelial Growth Factor Receptor (EGFR) Inhibitors
		■ Trastuzumab
			Pharmacology and Pharmacokinetics
			Indications and Clinical Efficacy
		■ Pertuzumab
			Pharmacology and Pharmacokinetics
			Indications and Clinical Efficacy
		■ Cetuximab
			Pharmacology and Pharmacokinetics
			Indications and Clinical Efficacy
		■ Panitumumab
			Pharmacology and Pharmacokinetics
			Indications and Clinical Efficacy
	Classes of Monoclonal Antibodies: Antihuman Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4)
		■ Ipilimumab
			Pharmacology and Pharmacokinetics
			Indications and Clinical Efficacy
	Classes of Monoclonal Antibodies: Receptor Activator of Nuclear Factor Kappa Beta Ligand Inhibitor
		■ Denosumab
			Pharmacology and Pharmacokinetics
			Indications and Clinical Efficacy
	Self-Assessment Questions
18: Hematopoietic Growth Factors: Focus on Erythropoiesis-Stimulating Agents
	Erythropoiesis-Stimulating Agents
		■ Regulation of Erythropoietin
		■ Pharmacokinetics
		■ 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
19: Monoclonal Antibodies in Solid Organ Transplantation
	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
		■ Alemtuzumab
		■ Rituximab
		■ Eculizumab
		■ Belatacept
	Self-Assessment Questions
20: Monoclonal Antibodies and Antibody-Based Biotherapeutics in Inflammatory Diseases
		■ Abatacept
		■ Adalimumab
		■ Certolizumab Pegol
		■ Etanercept
		■ Golimumab
		■ Infliximab
		■ Rituximab
		■ Tocilizumab
	Systemic Lupus Erythematosus
		■ Belimumab
		■ 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
	Self-Assessment Questions
21: Interferons and Interleukins
	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
		Further Reading
22: Vaccines
	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
		Further Reading
23: Oligonucleotides
	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
	Self-Assessment Questions
		Further Reading
24: Gene Therapy
	Vectors for Gene Transfer
		■ Basic Components of Plasmid (cf.Chap. 1)
			Bacterial Elements
			Transcription Regulatory Elements (TRE)
			Multiple Cloning Site (MCS)
			Untranslated Regions (UTR)
			Polyadenylation (polyA) Sequence
			Fusion Tag
	Viral Vectors
		■ Retrovirus
			Suitability of Retroviruses as Vectors for Gene Transfer
			Clinical Use of Retrovirus
		■ Lentivirus
			Suitability of Lentiviruses as Vectors for Gene Transfer
			Clinical Use of Lentiviral Vectors
		■ Adenovirus
			Suitability of Adenoviruses as Vectors for Gene Transfer
			Clinical Use of Adenoviral Vectors
		■ Adeno-Associated Virus (AAV)
			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
		■ 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
		Further Reading
25: Stem Cell Technology
		■ 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

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