Gene Delivery: Nanotechnology and Therapeutic Applications

Cover
Half Title
Series Page
Title Page
Copyright Page
Dedication
Table of Contents
Preface
Editor
List of Contributors
Chapter 1: Challenges in Delivering Gene Therapy
1.1 Introduction
1.2 Experimental Concepts of Gene Therapy
1.3 Aims of Gene Therapy
1.4 Delivery Systems of Gene Therapy
1.5 Vectors of Gene Therapy
1.6 Retroviral Vectors
1.7 Lentiviral Vectors
1.8 Adenoviral Vectors
1.9 Nonviral Vectors
1.10 Challenges in Delivery Systems
1.11 Challenges in Gene Delivery
1.12 Immune Response Challenges in Gene Delivery
1.13 Future Perspectives
1.14 Conclusion
References
Chapter 2: Advances in Genome Editing: The Technology of Choice for Precise and Efficient Disease Treatment, with Special Focus on Nano Delivery Systems
2.1 Introduction
2.2 Three Major Genome Editing Methods
2.2.1 Zinc-Finger Nucleases (ZFNs)
2.2.2 Transcription Activator-Like Effector Nucleases (TALEN)
2.3 Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR/CAS)
2.3.1 Applications of Genome Editing in Therapy
2.3.2 Nano Delivery Approaches in Genome Editing for Disease Treatment
2.3.2.1 Lipid Nanoparticles
2.3.2.2 Polymeric Nanoparticles
2.3.2.3 Extra-Cellular Vesicles
2.3.2.4 Miscellaneous Nanoparticles
2.4 Future Perspectives
Abbreviations
References
Chapter 3: Extracellular Vesicles for Nucleic Acid Delivery: Progress and Prospects for Safe RNA-Based Gene Therapy
3.1 Introduction
3.2 Extracellular Vesicles (EVs)
3.2.1 Origin and Biogenesis
3.2.2 RNA-Sorting Mechanisms
3.2.3 Composition of Extracellular Vesicles (EVs)
3.2.3.1 Proteins and Lipids
3.2.3.2 RNAs
3.2.4 Inherent Capacity of Extracellular Vesicles in Crossing Physical Barriers
3.3 Role of EVs in Nucleic Acid Transfer and Communication
3.3.1 EVs as Nucleic Acid Delivery Tool
3.3.2 Loading After EV Isolation
3.3.2.1 Simple Incubation
3.3.2.2 Electroporation
3.3.2.3 Sonication
3.3.3 Loading before EV isolation
3.4 Functionalized EVs for Targeted Delivery
3.5 Therapeutic Applications of EVs in Nucleic Acid Delivery
3.6 Conclusion
References
Chapter 4: Green Synthesis of Nanoparticles in Oligonucleotide Drug Delivery System
4.1 Introduction
4.2 Types of Oligonucleotides
4.2.1 Antisense oligonucleotides (ASO)
4.2.1.1 RNAse H-dependent oligonucleotide
4.2.2 Steric-blocker oligonucleotides
4.2.3 Small Interfering RNA or Silencing RNA (siRNA)
4.2.4 Micro RNA (miRNA)
4.2.5 Aptamer
4.2.6 CpG Oligonucleotides
4.3 Therapeutic Importance of Oligonucleotides
4.4 Drug Delivery Approaches for Oligonucleotides
4.5 Green Synthesis of Nanoparticles
4.6 Approaches Involved in the Green Synthesis of Nanoparticles
4.6.1 Green Synthesis of Nanoparticles
4.6.2 Bacteria-Mediated Nanoparticle Generation
4.6.3 Silver Nanoparticles
4.6.4 Gold Nanoparticle
4.6.5 Magnetite Nanoparticles
4.6.6 Palladium and Platinum Nanoparticles
4.6.7 Selenium and Tellurium Nanoparticles
4.6.8 Fungi-Mediated Nanoparticle Generation
4.6.9 Actinomycetes-Mediated Nanoparticle Generation
References
Chapter 5: Development of m-RNA Vaccines in Covid-19 Pandemic Scenario
5.1 Historical Landmarks Outlining the Development of mRNA Vaccines
5.2 Challenges Towards Rationale Design of mRNA Vaccines
5.3 Clinical Trials Evaluating the Safety and Immunogenicity of mRNA Vaccines
5.4 mRNA Vaccines in Adolescents and Older Adults
5.5 mRNA Technology: A Promising Alternative for Future Implications and Supporting Data Review
5.6 Safety and Efficacy of mRNA-1273 and BNT162b2 Vaccines (Phase III Clinical Trial)
5.7 Conclusion
References
Chapter 6: Gene Therapy for Cardiovascular Diseases: Clinical Evidences
6.1 Introduction
6.2 Targets for Cardiovascular Gene Therapy
6.2.1 Ischemic Heart Diseases
6.2.2 Atherogenesis and Thrombosis
6.2.3 Restenosis, In-Stent Restenosis, Graft Failure
6.2.4 Systemic Hypertension
6.2.5 Pulmonary Hypertension
6.2.6 Heart Failure
6.2.6.1 Ca 2+ Protein Cycling as a Target
6.2.6.2 Targeting of Beta-Adrenergic System
6.3 Clinical Studies on Gene Therapy for CVDs
6.4 Conclusion and Future Perspective
References
Chapter 7: Current Application of CRISPR/Cas9 Gene-Editing Technique to Eradication of HIV/AIDS
7.1 Introduction
7.2 Overview of CRISPR/Cas9 Technology
7.3 Application of CRISPR/Cas9 System to HIV/AIDS Prevention and Treatment
7.3.1 Inactivation and Elimination of HIV-1 Provirus by CRISPR/Cas9 Technology
7.3.2 Disruption of Co-receptors CCR5 and CXCR4 by CRISPR/Cas9 Technology
7.3.3 Reactivation of Latent HIV-1 Virus by CRISPR/Cas9 Technology
7.3.4 Reactivation of Host Restriction Factors During HIV-1 Infection
7.3.5 CRISPR/CAS9 System Delivery Approach
7.4 Conclusion
References
Chapter 8: siRNA Delivery for Therapeutic Applications Using Nanoparticles
8.1 Introduction
8.2 Mechanism of Gene Silencing
8.3 Nanoparticles in siRNA Delivery
8.4 siRNA Conjugation with Peptides or Polymers (Less Than 10 nm in Size)
8.5 Polyethylene Amine and Cationic Based Peptides and Proteins (100 to 300 nm in Size)
8.6 Cationic Based Lipid Nanoparticles (100 to 300 nm in Size)
8.7 Neutral Liposomes (<200 nm in Size)
8.8 Liposomes and Lipoplexes
8.9 Other Nanoparticles
8.10 Polyplexes
8.11 Nanomicelles
8.12 Carbon-Based Nanomaterials
8.13 Dendrimers
8.14 Metal Based Nanoparticles
8.15 Mesoporous Silica and Silicon-Based Nanoparticles
8.16 Hybrid Nanoparticles
8.17 Gold Nanoparticles
8.18 Iron Oxide Nanoparticles
References
Chapter 9: Clinical Perspectives on Gene Therapy for Retinal and Eye Diseases
9.1 Introduction
9.1.1 Age Related Macular Degeneration (AMD or ARMD)
9.1.2 Retinitis Pigmentosa (RP)
9.1.3 Leber’s congenital amaurosis (LCA)
9.2 Categories of Gene Therapy
9.3 Eye as a Lucrative Target for Gene Therapy
9.3.1 Ocular Gene Delivery Vectors
9.3.2 Ocular Routes of Administration
9.3.3 Outcome Measures in Clinical Trials for Study of Effectivity of Gene Therapy in Eye Diseases
9.4 Current Therapies for Retinal Diseases Under Investigation
9.4.1 Leber’s Congenital Amaurosis (LCA)
9.4.2 Achromatopsia
9.4.3 Retinitis Pigmentosa (RP)
9.4.4 Leber’s Hereditary Optic Neuropathy (LHON)
9.4.5 AMD
9.4.6 Retinoblastoma
9.4.7 Other Retinal Diseases
9.5 Gene Therapy in Other Eye Diseases
9.6 Future Directions
9.7 Conclusion
Acknowledgement
References
Chapter 10: Herpesvirus microRNAs for Use in Gene Therapy Immune-Evasion Strategies
10.1 Introduction
10.1.1 What is Gene Therapy?
10.1.1.1 Importance of Gene Therapy in Transplantation Biology
10.1.1.2 Transplantation and Graft Rejection
10.2 What are miRNAs
10.3 What are Herpes Viruses
10.4 Epstein Barr Virus and associated microRNAs
10.5 Human Cytomegalovirus and Associated microRNAs
10.6 Kaposi’s Sarcoma Associated Herpesvirus and Associated microRNAs
10.7 Herpes Simplex Virus and Associated microRNAs
References
Chapter 11: Gene Therapy and Small Molecules Used in the Treatment of Cystic Fibrosis
11.1 Introduction
11.2 History of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Gene
11.3 Pathophysiology of CFTR Gene
11.4 Ionic content and fluid on epithelial surfaces
11.5 Role of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)
11.6 Cystic fibrosis related lung disease
11.7 Signs and Symptoms of Cystic Fibrosis
11.7.1 Respiratory Symptoms
11.7.2 Gastro-enterologic Symptoms
11.7.3 Miscellaneous Symptoms
11.7.4 Symptoms that may Indicate the Presence of CFRD (Cystic Fibrosis Related Diabetes)
11.8 Diagnosis
11.8.1 Sweat Testing
11.8.1.1 Interpretation of Sweat Test
11.8.2 Genotyping
11.8.3 Semen Analysis
11.8.4 Sinus Radiographs
11.8.5 Tests of Exocrine Pancreatic Function
11.8.6 Nasal Potential Difference Measurements
11.8.7 Bronchoalveolar Lavage
11.8.8 Respiratory Tract Microbiology
11.8.9 Newborn Screening
11.9 National Registries: The Crucial Provision to Monitor Progress
11.10 Different Class Mutations of Cystic Fibrosis
11.11 Treatment options
11.11.1 Gene Therapy
11.11.1.1 Importance of Gene Therapy
11.11.1.2 Challenges for Gene Therapy
11.11.1.3 Gene Editing
11.11.1.4 Gene Transfer Involving Both Viral and Non-viral Gene Therapy
11.11.1.5 In-utero Gene Therapy for Cystic Fibrosis
11.11.2 Small Molecules Used in the Treatment of Cystic Fibrosis
11.11.2.1 Potentiator
11.11.2.2 Stabilizer
11.11.2.3 Corrector
11.11.2.4 Amplifier
11.11.3 Managing a Good Nutritional State in Older Children
11.11.4 Gastrointestinal Therapies
11.11.5 Pulmonary Therapies
11.11.6 Organ Transplantations
11.12 Common Issues Complicating Cystic Fibrosis and Its Treatment
11.13 Conclusion
References
Chapter 12: Non-Viral Delivery of Genome-Editing Nucleases for Gene Therapy
12.1 Introduction
12.2 Methods of Delivery and Nonviral Approaches for Gene Editing Nucleases
12.2.1 Electroporation
12.2.1.1 Selections of Cargoes for Gene Therapy
12.2.1.1.1 Plasmid DNA
12.2.1.1.2 mRNA
12.2.1.1.3 Proteins
12.3 Hydrodynamic Delivery
12.4 Lipid Nanoparticles
12.5 Polymer Based Nanoparticles
12.6 Cell Penetrating Peptides
12.7 DNA Origami
References
Chapter 13: CRISPER Gene Therapy Recent Trends and Clinical Applications
13.1 Introduction
13.2 CRISPR–Cas9 System
13.2.1 Structure of CRISPR Loci
13.3 The Mechanism Involved in the CRISPR–Cas System
13.3.1 Adaptation of CRISPR–Cas Spacer Sequences
13.3.2 Expression and Maturation of CRISPR–Cas System
13.3.3 Interference of CRISPR–Cas System
13.4 Biology of Type II CRISPR–Cas9
13.5 Recent Trends in CRISPER Gene Therapy
13.5.1 CRISPR System Accurately Cut Target DNA
13.5.2 Non-Homologous End Joining (NHEJ) and (Homology Directed Repair) HDR
13.5.3 On-Target Activity and Off-Target Activity
13.5.4 CRISPR Tools
13.5.5 CRISPR in Gene Editing
13.6 Clinical Application of CRISPER Gene Therapy
13.6.1 Gene Disruption
13.6.2 In vivo CRISPR Gene Therapy
13.6.3 CRISPR Editing in Human Embryos and Ethical Considerations
13.7 Conclusion
References
Chapter 14: Clinical Applications of Gene Therapy for Immuno-Deficiencies
14.1 Primary Immunodeficiencies (PIDS)
14.1.1 Severe Combined Immunodeficiencies
14.1.1.1 Adenosine Deaminase-Deficient Severe Combined Immunodeficiency (ADA-SCID)
14.1.1.2 X-linked Severe Combined Immunodeficiency (X-SCID)
14.1.1.3 Artemis SCID and Recombinase-activating Gene 1 (RAG1) Deficiency
14.1.2 Combined Immunodeficiencies
14.1.2.1 Wiskott–Aldrich Syndrome (WAS)
14.1.3 Disorders of Phagocyte Number and Function
14.1.3.1 Chronic Granulomatous Disease (CGD)
14.1.3.2 Leucocyte Adhesion Defect Type 1 (LAD-1)
14.1.4 Diseases of Immune Dysregulation
14.1.4.1 Familial Hemophagocytic Lymphohistiocytosis (FLH)
14.1.4.2 X-Linked Lymphoproliferative Disease 1 (XLP1)
14.1.4.3 Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked (IPEX) Syndrome
14.2 Acquired Immunodeficiencies (AIDS)
14.3 Conclusion
References
Chapter 15: Regulatory Challenges for Gene Delivery
15.1 Introduction
15.1.1 Gene Delivery
15.1.1.1 Somatic Gene Editing
15.1.1.2 Genome Editing Technologies: Viral Vectors and Nonviral Vectors
15.1.2 Clinical Trials in Gene Therapy
15.1.2.1 Clinical Trials in Liver
15.1.2.2 Clinical Trials in Rare Diseases
15.1.2.3 Clinical Trials in Cancer
15.1.3 Ethical Considerations for Gene Therapy
15.1.3.1 Regulations for Somatic Gene Editing in United States
15.1.3.2 Regulations for Somatic Gene Editing in United Kingdom
15.1.3.3 Current Regulatory Framework: Is It Fit for Purpose?
15.2 The Legal and Regulatory Landscape in Gene Therapy
15.2.1 EU Guidelines on Quality, Non-Clinical, and Clinical Aspects of Medicinal Products Containing Genetically Modified Cells
15.2.2 EU (Draft) Guideline on Quality, Non-Clinical, and Clinical Requirements for Investigational Gene Therapy in Clinical Trials
15.2.3 EU (Draft) Guideline on Safety and Efficacy Follow-Up and Risk Management of Gene Therapy Products
15.2.4 Gene Editing Regulations
15.2.4.1 Human Gene Editing Regulations
15.2.4.2 Animal Gene Editing Regulations
15.2.4.3 Plant Gene Editing Regulations
15.3 Conclusion and Future Trends
References
Index