Challenges in Delivery of Therapeutic Genomics and Proteomics

Challenges in Delivery of Therapeutic Genomics and Proteomics, Second Edition is a complete reference on the biological principles involved in gene and protein delivery to cells and tissues. Highlighting the various chemical, physical, and biological approaches to protein and gene delivery, the book provides guidelines for pharmaceutical researchers in academia and corporate R&D. This new edition brings updates on the delivery of therapeutic proteomics and genomics in each chapter, and newly developed chapters on the regulatory aspects of related products, CRISPR/Cas9 gene editing, and computational tools in genomics and proteomics.

After an overview of the barriers to genomics and proteomics delivery, the book dives into physical, chemical, and biological methods of gene delivery. Further chapters extensively discuss the delivery of proteins and therapeutic peptides through the respiratory, oral, parenteral, transdermal, topical, uterine, and rectal pathways. This book is the ideal reference for pharmaceutical scientists dealing with gene and protein/peptide delivery. Regulators and corporate researchers can also benefit from the wide coverage of delivery methods presented.

Challenges in Delivery of Therapeutic Genomics and Proteomics
Cover image
Title page
Table of Contents
Copyright
Dedication
Contributors
Preface
Chapter 1 Barriers to gene and protein delivery
Abstract
Keywords
1.1 Introduction
1.2 Transcription and translation: DNA to mRNA to protein
1.3 Therapeutic role of genes and proteins
1.4 Barriers to delivery of therapeutic genes and proteins
1.5 Extracellular barriers
1.5.1 Extracellular barriers to naked DNA delivery
1.5.2 Extracellular barriers for vector-mediated DNA delivery
1.6 Intracellular barriers for naked DNA and DNA delivery systems
1.6.1 Endosomal escape of DNA from the DNA-DNA-polycation complex
1.6.2 Cytosolic transport of DNA
1.6.3 Nuclear transport of plasmid DNA
1.6.4 Transgene expression and posttranslational changes in proteins
1.7 Biological and immune response as barriers
1.8 Scale-up barriers and FDA approval
1.9 Barriers to delivery of therapeutic proteins
1.10 Conclusion
References
Chapter 2 Gene delivery using physical methods
Abstract
Keywords
2.1 Introduction
2.2 Electroporation (EP)
2.3 Hydrodynamic gene therapy
2.4 Particle bombardment using gene gun
2.5 Microinjection
2.6 Sonoporation ultrasound-mediated gene delivery
2.7 Iontophoresis
2.8 Magnetofection
2.9 Laser beam gene transduction
2.10 Impalefection
2.11 Conclusion
References
Chapter 3 Gene delivery using chemical methods
Abstract
Keywords
3.1 Introduction
3.2 Polymeric vectors
3.2.1 Condensing polymers
3.2.2 Noncondensing polymers
3.3 Lipidic vectors
3.3.1 Ammonium salt lipids
3.3.2 Lipoamines
3.3.3 Cationic lipids containing both quaternary ammonium salt and lipoamines
3.3.4 Amidinium salt lipids and miscellaneous cationic entities
3.4 Lipid polymer hybrid systems or lipopolymers
3.5 Peptides
3.5.1 Poly-l-lysines
3.5.2 Arginine-rich peptides
3.5.3 Poly-l-ornithine
3.5.4 Cell-targeting peptides
3.5.5 Cell-penetrating peptides
3.5.6 Endosomal escape peptides
3.6 Dendrimers
3.6.1 Factors affecting dendrimer-based gene delivery
3.6.2 Strategies to overcome challenges in dendrimer-based gene delivery
3.7 Biopolymers
3.7.1 Chitosan
3.7.2 Cyclodextrin
3.7.3 Dextran
3.7.4 Gelatin
3.7.5 Albumin
3.8 Conclusion
References
Chapter 4 Gene delivery using viral vectors
Abstract
Keywords
4.1 Introduction
4.2 Adenovirus
4.2.1 Structure and genome of adenovirus
4.2.2 Adenovirus replication cycle
4.2.3 Pathogenesis
4.2.4 Design and construction of adenoviral vectors
4.2.5 Application of adenoviral vectors
4.3 Adeno-associated virus (AAV)
4.3.1 Structure and genome of adeno-associated virus
4.3.2 Adeno-associated virus replication cycle
4.3.3 Pathogenesis
4.3.4 Application of adeno-associated viral vectors
4.4 Retrovirus
4.4.1 Structure and genome of retrovirus
4.4.2 Retrovirus replication cycle
4.4.3 Pathogenesis
4.4.4 Application of retroviral vectors
4.5 Herpes simplex virus
4.5.1 Structure and genome of herpes simplex virus
4.5.2 Herpes simplex virus replication cycle
4.5.3 Pathogenesis
4.5.4 Application of herpes viral vectors
4.6 Other viral vectors
4.6.1 Baculovirus
4.6.2 Lentivirus
4.6.3 Influenza virus
4.6.4 Human papillomavirus
4.6.5 Hepatitis B virus
4.6.6 Vaccinia virus vectors
4.6.7 Mammalian orthoreovirus vectors
4.6.8 Measles virus vectors
4.6.9 Vesicular stomatitis virus (VSV) vectors
4.6.10 Sendai virus vectors
4.7 Immune response to viral vectors
4.8 Biodistribution of viral gene delivery systems
4.9 Conclusion
References
Chapter 5 RNA-based therapeutics—Mechanisms and challenges
Abstract
Keywords
5.1 Introduction
5.2 Types of RNA-based therapeutics and modes of action
5.2.1 Antisense oligonucleotides (ASOs)
5.2.2 Types of antisense agents
5.2.3 RNA interference (RNAi)
5.2.4 MicroRNAs (miRNAs)
5.2.5 RNA activation (RNAa)
5.2.6 RNA aptamers
5.2.7 Ribozymes
5.2.8 RNA decoys
5.2.9 Small interfering RNAs (siRNAs)
5.2.10 MicroRNAs
5.3 Pharmacokinetics
5.4 Formulation considerations for RNA therapeutics
5.5 Delivery method for RNA-based therapeutics
5.5.1 Viral vectors
5.5.2 Nonviral delivery techniques
5.6 Conclusions and future perspectives
References
Chapter 6 Protein and peptide delivery through respiratory pathway
Abstract
Keywords
6.1 Introduction
6.2 Respiratory system
6.2.1 Anatomy of the human respiratory tract
6.2.2 Physiology of the respiratory system
6.3 Biophysical issues in peptide drug delivery
6.3.1 Physiological and biomechanical factors relevant to inhaled drug delivery
6.3.2 Biophysics of inhaled drug particles
6.3.3 Critical factors for determining particle deposition in lungs
6.3.4 Chemical and physical properties of peptide and protein drugs
6.3.5 Characterization of peptide and protein drugs
6.3.6 Absorption and bioavailability of inhaled peptides and proteins
6.4 Pharmaceutical issues in peptide drug delivery
6.4.1 Drug delivery systems
6.5 Intranasal delivery of peptides and proteins
6.5.1 Use of the nasal cavity for drug administration
6.5.2 Structure and function of the human nasal cavity
6.5.3 Barriers to nasal drug delivery
6.5.4 Methods of overcoming the barriers to absorption
6.5.5 Therapeutic inhalation aerosols
6.5.6 Rational therapy with inhalation aerosols
6.5.7 Airway deposition of inhaled particles
6.5.8 Aerosolization of pharmaceutical particles
6.5.9 Other factors affecting performance of inhalation aerosols
6.5.10 Intranasal delivery of peptides and proteins
6.6 Delivery of proteins and peptides by inhalation
6.6.1 Localized delivery of peptides and proteins
6.6.2 Systemic delivery of peptides and proteins
6.6.3 Innovative strategies for delivery of peptides and proteins through the respiratory route
6.7 Conclusion
References
Chapter 7 Oral delivery of proteins and peptides: Concepts and applications
Abstract
Keywords
7.1 Introduction
7.2 Anatomy and physiology of oral mucosa
7.2.1 Oral cavity
7.2.2 Gastrointestinal tract other than oral cavity
7.3 Transport mechanisms in the GI tract
7.3.1 Paracellular transport
7.3.2 Transcellular absorption
7.3.3 Carrier-mediated transport
7.3.4 Receptor-mediated transport
7.4 Barriers to protein absorption
7.4.1 Mucus barrier
7.4.2 Extracellular and enzymatic barriers
7.4.3 Cellular barriers
7.5 Factors affecting peptides and proteins absorption
7.5.1 Molecular weight and size of molecule
7.5.2 Three-dimensional structure and immunogenicity
7.5.3 Charge distribution
7.5.4 Solubility, lipophilicity, and the partition coefficient
7.5.5 Aggregation
7.6 Approaches to improve oral protein and peptide delivery
7.6.1 Targeted delivery of peptides and proteins
7.6.2 Chemical alteration in the structure
7.6.3 Vehicles to improve absorption
7.6.4 Bioadhesive formulations
7.6.5 Penetration enhancers
7.6.6 Protease inhibitors
7.6.7 Specialized drug delivery systems
7.6.8 Other formulation approaches
7.7 Technique for oral absorption studies
7.7.1 In vitro studies
7.7.2 In vivo studies
7.8 Strategic use of oral route for immunization
7.9 Conclusion
References
Chapter 8 Parenteral delivery of peptides and proteins
Abstract
Keywords
8.1 Introduction
8.2 Pharmacological considerations of P/P drugs
8.2.1 Pharmacokinetic considerations of P/P drugs
8.2.2 Pharmacodynamic considerations of P/P drugs
8.2.3 Antibody induction
8.2.4 Interspecies scaling
8.2.5 Modulation of P/P disposition by chemical modifications of P/P drugs
8.2.6 P/P drug delivery across the blood-brain barrier
8.3 Techniques for stabilizing aqueous P/P formulation
8.3.1 Serum albumin
8.3.2 Amino acids
8.3.3 Carbohydrates
8.3.4 Cyclodextrin
8.3.5 Surfactants
8.3.6 Polyhydroxylated alcohols
8.3.7 Antioxidants and chelating agents
8.4 Polymers used in parenteral delivery of P/P
8.4.1 Nondegradable polymers
8.4.2 Biodegradable polymers
8.5 Parenteral delivery systems for P/P
8.5.1 Microspheres
8.5.2 Implants
8.5.3 Liposomes
8.5.4 Nanoparticles
8.5.5 Solid lipid nanoparticles
8.5.6 Hydrogels
8.5.7 Microemulsions
8.5.8 Vaccines adjuvants
8.5.9 Pulsatile delivery and self-regulated delivery of P/P
8.5.10 Pumps
8.6 New advances in the parenteral administration of P/P
8.6.1 Pegylated proteins
8.6.2 Protein crystals
8.6.3 Prefilled syringes
8.6.4 Needle-free injections
8.6.5 Intracellular delivery of P/P by cell-penetrating peptides
8.6.6 Miscellaneous delivery system
8.7 Conclusion
References
Chapter 9 Other routes of protein and peptide delivery: Transdermal, topical, uterine, and rectal
Abstract
Keywords
9.1 Transdermal delivery of proteins and peptides
9.1.1 Introduction
9.1.2 Structure of the skin
9.1.3 Penetration pathways through the skin
9.1.4 Approaches to enhance transdermal peptide delivery
9.2 Topical delivery of proteins and peptides
9.2.1 Antimicrobial peptides
9.2.2 Growth factors
9.2.3 Proteins and peptides as cosmeceuticals
9.2.4 Delivery systems
9.2.5 Iontophoresis and phonophoresis
9.3 Intrauterine delivery of proteins and peptides
9.3.1 Introduction
9.3.2 Delivery of proteins and peptides to the uterus
9.3.3 Intrauterine drug delivery systems
9.4 Rectal delivery of proteins and peptides
9.4.1 Introduction
9.4.2 Rectal absorption
9.4.3 Advantages and disadvantages of peptide and protein drug delivery through the rectal route
9.4.4 Approaches to improve rectal absorption of proteins and peptides
9.5 Conclusion
References
Chapter 10 Computational tools in genomics and proteomics
Abstract
Keywords
10.1 Introduction
10.1.1 Genomics
10.1.2 Proteomics
10.1.3 Bioinformatics and machine learning
10.1.4 Importance of computational tools in genomics and proteomics
10.2 Fundamentals of genomics and proteomics
10.2.1 Basic terminology for genomics and proteomics
10.2.2 Proteomics
10.2.3 Bioinformatics and computational tools
10.2.4 Key techniques in genomics and proteomics
10.2.5 Bioinformatics and role of computational tools
10.2.6 Applications of bioinformatics
10.3 Databases in genomics and proteomics
10.3.1 Genomic databases
10.3.2 Proteomic databases
10.4 Computational tools commonly used in the genomic and proteomic studies
10.5 Structural bioinformatics
10.5.1 Predicting protein structures
10.5.2 Molecular docking and simulation
10.6 Machine learning applications in genomics
10.7 Functional genomics
10.8 Integration of genomics and proteomics data
10.9 Challenges and future perspectives
10.10 Conclusion
10.10.1 Implications for future research
References
Chapter 11 CRISPR/Cas9 gene editing for treating gene and protein disorders
Abstract
Keywords
11.1 Introduction to the CRISPR/Cas9 tool kit
11.2 Operation of CRISPR/Cas9 genetic engineering
11.3 Optimization of CRISPR/Cas9 genome engineering
11.4 Innovative physical and chemical delivery strategies for CRISPR/Cas9 system
11.4.1 Use of virus
11.4.2 Use of microinjection
11.4.3 Use of liposomes
11.4.4 Use of proteins
11.4.5 Electroporation method
11.4.6 Use of exosomes
11.4.7 Use of polymeric nanoparticles
11.4.8 Plasmid-based method
11.4.9 mRNA method
11.4.10 Hydrodynamic approach
11.5 Harnessing the advantages of CRISPR/Cas9 technology
11.5.1 Application in Down syndrome
11.5.2 Application in ankylosing spondylitis
11.5.3 Application in Alzheimer's disease
11.5.4 Application in cystic fibrosis
11.5.5 Application in Duchenne muscular dystrophy
11.5.6 Application in phenylketonuria
11.5.7 Application in hemophilia
11.5.8 Application in Huntington's disease
11.5.9 Application in Parkinson's disease (PD)
11.5.10 Application in thalassemia
11.5.11 Application in sickle cell disease
11.5.12 Application in amyloidosis
11.6 Challenges of using CRISPR/Cas9 gene editing in genetic and protein disorders
11.7 Ethics and regulation of CRISPR/Cas9 technology
11.8 Conclusion and future concerns
References
Chapter 12 Regulatory guidance on therapeutic proteomics and genomics
Abstract
Keywords
12.1 Introduction
12.2 Marketing authorization procedures
12.2.1 Regulatory landscape for protein therapeutics
12.2.2 Conventional marketing authorization paradigm at USFDA, EMA, and PMDA
12.2.3 Fast-track marketing authorization paradigm
12.2.4 Marketing authorization procedure for biosimilars and interchangeable
12.2.5 Marketing authorization procedure for synthetic peptide therapeutics
12.3 Quality considerations for regulatory compliance
12.3.1 Control of drug substance and drug product
12.3.2 Stability study requirements
12.3.3 Container-closure system
12.4 Guidance on preclinical and clinical development
12.4.1 Preclinical assessment of therapeutic protein products
12.4.2 Immunogenicity assessment of therapeutic protein products
12.4.3 Clinical development of therapeutic protein products
12.4.4 Considerations for drug-drug interactions (DDI)
12.4.5 Preclinical and clinical considerations of gene therapy
12.4.6 Postmarket surveillance and patient safety of gene therapy
12.5 Conclusion
References
Index

Life Sciences

Physical Sciences & Engineering

Social Sciences & Humanities

Health

Challenges in Delivery of Therapeutic Genomics and Proteomics

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Aliasgar Shahiwala

Naazneen Surti

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