Gene Therapy for Autoimmune and Inflammatory Diseases (eBook)

Title Page 3
Copyright Page 4
Table of Contents 5
List of Contributors 7
Preface 10
Gene therapy for arthritis 11
Why gene therapy in arthritis? 11
Ex vivo strategy 12
In vivo strategy 12
Vectors for gene transfer in arthritis 13
The target genes 17
Different promoter to provide safe and targeted gene expression 19
What have we learnt from preclinical studies? 21
Clinical experience of gene therapy in RA 21
Conclusion 23
References 23
Gene therapy for the treatment of inflammatory bowel disease 29
Inflammatory Bowel Disease 29
Pathogenesis of IBD 30
Treatment of IBD – current clinical standards 31
Pharmacologic therapy 32
Surgical therapy 34
New approaches to the treatment of IBD 34
Blocking pro-inflammatory cytokine activity 35
Anti-inflammatory cytokine treatment 35
T cell inhibition 36
Promoting intestinal repair 37
Modifying the enteric microbiota 37
Applications of nucleic acid-based therapies in IBD treatment 38
Concluding remarks 42
References 43
Gene therapy for diabetes 48
Introduction 48
Approaches for treating Type 1 diabetes by gene transfer 49
Prevention of autoimmunity by gene therapy 49
Islet transplantation with immunoregulatory gene transfection 50
Induction of insulin-producing cells from stem/progenitor cells by gene transfection 51
Reversible immortalization of pancreatic ß cells by gene transfer and site specific recombination 51
Conclusions 52
References 53
Gene therapy for cystic fibrosis lung disease 56
Introduction 56
CFTR mutations 57
Pathophysiology of CF lung disease 57
The low volume hypothesis to explain CF lung disease 57
Pharmacological approaches to treat CF lung disease 58
Drugs that increase CFTR protein levels 58
CFTR correctors, drugs to increase trafficking of CFTR 59
CFTR potentiators, drugs that increase conductance at the apical membrane 60
Modulation of other ion channels 60
Gene therapy clinical trials 61
Adenovirus and Adeno-Associated Virus 61
Negative strand RNA viruses 62
Lentiviruses 63
Non-viral vectors for CF gene therapy 63
Cationic polymers as mediators for CF plasmid DNA gene therapy 64
Modifier genes and future directions 64
Conclusion 66
References 66
Gene therapy of multiple sclerosis 74
Introduction 74
Modulation of T cells by cytokines 76
Interferon-ß 76
Interleukin-4 78
Interleukin-10 79
Th17-Treg cytokines family 79
Decoy receptors 80
Immunotoxins 80
Induction of tolerance 81
Innate immune system 82
Angiogenesis 82
Antioxidative therapy 82
Stem cell mediated gene therapy 83
Conclusions 83
References 83
Gene therapy for myositis 88
Introduction 88
Diagnosis 89
Immunopathogenesis 90
Conventional therapies 93
Gene therapy 94
Gene therapy in inflammatory muscle disorders 95
Targets for gene therapy 95
Conclusion and outlook 96
References 97
Gene therapy for osteoarthritis 100
Introduction: osteoarthritis a disease of eroding cartilage 100
Current approaches to treatment 101
Articular cartilage matrix composition and OA 102
Mediators of disease in OA 103
Gene therapy approaches 104
Chondroprotection: inhibition of IL-1 106
Cartilage repair and regeneration 107
Tissue engineering: Ex vivo delivery of genetically modified chondrocytes 108
Tissue engineering: genetically modified mesenchymal progenitors 109
Persistence of intra-articular transgene expression 111
Self-complementary adeno-associated virus for gene delivery in OA 111
Future directions 114
References 115
Gene therapy: Sjögren’s syndrome 122
Sjögren’s syndrome 122
The salivary gland in SS 123
Current treatment for SS 125
Gene therapy for SS 125
The use of local gene therapy 126
Experience with local gene therapy 126
Future therapeutic targets 128
Immunological targets 128
Chemokines 128
The co-stimulatory pathway 129
Non-immunological targets 129
Neuro-stimulatory pathway 130
Future directions and limitations 130
References 130
Disease mechanisms, genetic susceptibility and therapeutic approaches in lupus disease 135
Introduction 135
Immunological abnormalities in lupus 136
Defective T lymphocyte responses 136
Defective B lymphocyte responses 137
Defective removal of apoptotic bodies 138
Defects in the production and response to cytokines 138
Genetic factors in lupus susceptibility 140
MHC genes and variants on chromosome 6 140
Variants for adhesion molecules and membrane co-receptors 141
Variants of cytokine associated transcription factors 142
Genes encoding signalling proteins 142
Genes for proteins with incompletely defined functions 143
Biological agents for the treatment of lupus 143
Biological agents targeting B lymphocytes 144
Biological agents targeting cognate T–B lymphocyte interactions 145
Biological anti-cytokine agents 145
Biological agents targeting complement components 146
Enzyme replacement 147
Gene therapy 147
Modulation of T lymphocyte responses 148
Gene therapy to modulate cognate interaction 148
Gene therapy to suppress B lymphocyte activation and responses 149
Gene therapy to target cytokines and chemokines 149
References 150
Regulated promoters 155
Disadvantages of constitutively active promoters 155
Transcriptional targeting 157
Acute phase gene promoters 157
Pro-inflammatory cytokine and enzyme gene promoters 158
Bioinformatics-driven promoter design 160
Transcriptional amplification strategy 161
Conditional RNA interference-based gene therapy 162
Future perspectives 163
References 164
Development of AAV vectors for the therapy of autoimmune and inflammatory diseases 168
Introduction 168
AAV biology 169
Improvement of AAV vector transduction 171
Development of double-stranded AAV cassettes 171
AAV packaging capacity/AAV split vectors 172
AAV serotypes 172
AAV mosaic and chimeric capsids 173
Development of targeted AAV vectors 174
Receptor targeting via chemical linker 174
Receptor targeting via genetic modification 175
Receptor targeting via the combination of a chemical linker and genetic modification 176
Directed evolution 176
Insertion of a peptide derived from a phage library into the AAV capsid 177
Insertion of random peptides into the AAV capsid 177
Cellular immune response to AAV vectors 178
Therapy of autoimmune diseases by AAV-mediated gene delivery 179
Arthritis 179
Diabetes 180
Inflammatory bowel diseases 181
Other autoimmune diseases 182
Conclusion 182
References 183
Delivery and application of plasmid DNA in arthritis gene therapy 188
Introduction 188
Chemical delivery of plasmids 189
Physical delivery of plasmids 190
Genetic immunisation 190
Therapeutic gene expression from skeletal muscle 191
Expression of therapeutic genes by electroporation 192
Hydrodynamic delivery 193
Hydrodynamic delivery to liver 193
Massage delivery 194
Ballistic delivery 194
Sonoporation 195
Plasmid delivery to joints 195
How efficient are plasmid delivery methods? 196
Conclusion 196
References 197
Helper-dependent adenoviral vectors 200
Introduction 200
HDAd 201
In vivo studies with HDAd 203
Liver directed gene therapy 203
Gene therapy for cystic fibrosis 205
Brain gene therapy 209
Concluding remarks 210
References 210
Cells as carriers of gene therapy 215
Concept and rationale of cells as carriers of gene therapy 215
Tissue cells 216
Lymphocytes 219
Antigen-presenting cells 221
Cell-derived particles 223
Stem cells 224
Conclusions 225
References 226
Perspectives for the future developments of gene therapy for autoimmune and inflammatory therapy 229
New findings from genome-wide association studies 229
MicroRNAS 230
Epigenetics 231
Mechanisms of resistance to therapies 232
Improving on delivery vectors for autoimmune inflammatory disease 232
Conclusion 233
References 234
Index 238