Chernajovsky / Robbins Gene Therapy for Autoimmune and Inflammatory Diseases

1. Auflage 2011
ISBN: 978-3-0346-0165-8
Verlag: Springer
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 239 Seiten

Reihe: Milestones in Drug Therapy

In this monograph about gene therapy of autoimmune and inflammatory d- orders we have gathered international experts and leaders from different fields to review the state of the art advances on topics ranging from disease entities to vectors and engineered cells. The different approaches described in each chapter take into consideration the biomedical knowledge of these diseases and address the complexities of delivering long-term genetic interventions. Gene therapy also serves as a testing ground for new therapeutic entities and helps provide proof of principle for their potential therapeutic role in animal models of disease. Scaling up from mice to men still remains an important h- dle not only from the quantitative point of view, but also for currently unknown and unexpected secondary effects of the vector or the transgene. Some of these approaches have already been tested in the clinic, but much more needs to be done to understand the human conditions treated and the n- ural history of their pathology. We are indebted to the secretarial assistance of Ms. Lin Wells (Bone and Joint Research Unit, London, UK) and the help of Hans Detlef Klüber for his help in getting this book published. We hope this book will be of interest to c- nicians and scientists and inspiring to students of the subject who will use their own ingenuity and knowledge to further forward this discipline into clinical use.

Autoren/Hrsg.

Chernajovsky, Yuti

Robbins, Paul D.

Inhaltsverzeichnis

1;Title Page;3
2;Copyright Page;4
3;Table of Contents;5
4;List of Contributors;7
5;Preface;10
6;Gene therapy for arthritis;11
6.1;Why gene therapy in arthritis?;11
6.2;Ex vivo strategy;12
6.3;In vivo strategy;12
6.4;Vectors for gene transfer in arthritis;13
6.5;The target genes;17
6.6;Different promoter to provide safe and targeted gene expression;19
6.7;What have we learnt from preclinical studies?;21
6.8;Clinical experience of gene therapy in RA;21
6.9;Conclusion;23
6.10;References;23
7;Gene therapy for the treatment of inflammatory bowel disease;29
7.1;Inflammatory Bowel Disease;29
7.1.1;Pathogenesis of IBD;30
7.2;Treatment of IBD – current clinical standards;31
7.2.1;Pharmacologic therapy;32
7.2.2;Surgical therapy;34
7.3;New approaches to the treatment of IBD;34
7.3.1;Blocking pro-inflammatory cytokine activity;35
7.3.2;Anti-inflammatory cytokine treatment;35
7.3.3;T cell inhibition;36
7.3.4;Promoting intestinal repair;37
7.3.5;Modifying the enteric microbiota;37
7.4;Applications of nucleic acid-based therapies in IBD treatment;38
7.5;Concluding remarks;42
7.6;References;43
8;Gene therapy for diabetes;48
8.1;Introduction;48
8.2;Approaches for treating Type 1 diabetes by gene transfer;49
8.2.1;Prevention of autoimmunity by gene therapy;49
8.2.2;Islet transplantation with immunoregulatory gene transfection;50
8.2.3;Induction of insulin-producing cells from stem/progenitor cells by gene transfection;51
8.2.4;Reversible immortalization of pancreatic ß cells by gene transfer and site specific recombination;51
8.3;Conclusions;52
8.4;References;53
9;Gene therapy for cystic fibrosis lung disease;56
9.1;Introduction;56
9.2;CFTR mutations;57
9.3;Pathophysiology of CF lung disease;57
9.4;The low volume hypothesis to explain CF lung disease;57
9.5;Pharmacological approaches to treat CF lung disease;58
9.6;Drugs that increase CFTR protein levels;58
9.7;CFTR correctors, drugs to increase trafficking of CFTR;59
9.8;CFTR potentiators, drugs that increase conductance at the apical membrane;60
9.9;Modulation of other ion channels;60
9.10;Gene therapy clinical trials;61
9.11;Adenovirus and Adeno-Associated Virus;61
9.12;Negative strand RNA viruses;62
9.13;Lentiviruses;63
9.14;Non-viral vectors for CF gene therapy;63
9.15;Cationic polymers as mediators for CF plasmid DNA gene therapy;64
9.16;Modifier genes and future directions;64
9.17;Conclusion;66
9.18;References;66
10;Gene therapy of multiple sclerosis;74
10.1;Introduction;74
10.2;Modulation of T cells by cytokines;76
10.2.1;Interferon-ß;76
10.2.2;Interleukin-4;78
10.2.3;Interleukin-10;79
10.2.4;Th17-Treg cytokines family;79
10.2.5;Decoy receptors;80
10.2.6;Immunotoxins;80
10.2.7;Induction of tolerance;81
10.2.8;Innate immune system;82
10.2.9;Angiogenesis;82
10.2.10;Antioxidative therapy;82
10.2.11;Stem cell mediated gene therapy;83
10.3;Conclusions;83
10.4;References;83
11;Gene therapy for myositis;88
11.1;Introduction;88
11.2;Diagnosis;89
11.3;Immunopathogenesis;90
11.4;Conventional therapies;93
11.5;Gene therapy;94
11.6;Gene therapy in inflammatory muscle disorders;95
11.6.1;Targets for gene therapy;95
11.7;Conclusion and outlook;96
11.8;References;97
12;Gene therapy for osteoarthritis;100
12.1;Introduction: osteoarthritis a disease of eroding cartilage;100
12.2;Current approaches to treatment;101
12.3;Articular cartilage matrix composition and OA;102
12.4;Mediators of disease in OA;103
12.5;Gene therapy approaches;104
12.6;Chondroprotection: inhibition of IL-1;106
12.7;Cartilage repair and regeneration;107
12.8;Tissue engineering: Ex vivo delivery of genetically modified chondrocytes;108
12.9;Tissue engineering: genetically modified mesenchymal progenitors;109
12.10;Persistence of intra-articular transgene expression;111
12.11;Self-complementary adeno-associated virus for gene delivery in OA;111
12.12;Future directions;114
12.13;References;115
13;Gene therapy: Sjögren’s syndrome;122
13.1;Sjögren’s syndrome;122
13.2;The salivary gland in SS;123
13.3;Current treatment for SS;125
13.4;Gene therapy for SS;125
13.5;The use of local gene therapy;126
13.5.1;Experience with local gene therapy;126
13.6;Future therapeutic targets;128
13.6.1;Immunological targets;128
13.6.2;Chemokines;128
13.6.3;The co-stimulatory pathway;129
13.6.4;Non-immunological targets;129
13.6.5;Neuro-stimulatory pathway;130
13.7;Future directions and limitations;130
13.8;References;130
14;Disease mechanisms, genetic susceptibility and therapeutic approaches in lupus disease;135
14.1;Introduction;135
14.2;Immunological abnormalities in lupus;136
14.2.1;Defective T lymphocyte responses;136
14.2.2;Defective B lymphocyte responses;137
14.2.3;Defective removal of apoptotic bodies;138
14.2.4;Defects in the production and response to cytokines;138
14.3;Genetic factors in lupus susceptibility;140
14.3.1;MHC genes and variants on chromosome 6;140
14.3.2;Variants for adhesion molecules and membrane co-receptors;141
14.3.3;Variants of cytokine associated transcription factors;142
14.3.4;Genes encoding signalling proteins;142
14.3.5;Genes for proteins with incompletely defined functions;143
14.4;Biological agents for the treatment of lupus;143
14.4.1;Biological agents targeting B lymphocytes;144
14.4.2;Biological agents targeting cognate T–B lymphocyte interactions;145
14.4.3;Biological anti-cytokine agents;145
14.4.4;Biological agents targeting complement components;146
14.4.5;Enzyme replacement;147
14.5;Gene therapy;147
14.5.1;Modulation of T lymphocyte responses;148
14.5.2;Gene therapy to modulate cognate interaction;148
14.5.3;Gene therapy to suppress B lymphocyte activation and responses;149
14.5.4;Gene therapy to target cytokines and chemokines;149
14.6;References;150
15;Regulated promoters;155
15.1;Disadvantages of constitutively active promoters;155
15.2;Transcriptional targeting;157
15.3;Acute phase gene promoters;157
15.4;Pro-inflammatory cytokine and enzyme gene promoters;158
15.5;Bioinformatics-driven promoter design;160
15.6;Transcriptional amplification strategy;161
15.7;Conditional RNA interference-based gene therapy;162
15.8;Future perspectives;163
15.9;References;164
16;Development of AAV vectors for the therapy of autoimmune and inflammatory diseases;168
16.1;Introduction;168
16.2;AAV biology;169
16.3;Improvement of AAV vector transduction;171
16.3.1;Development of double-stranded AAV cassettes;171
16.3.2;AAV packaging capacity/AAV split vectors;172
16.3.3;AAV serotypes;172
16.3.4;AAV mosaic and chimeric capsids;173
16.4;Development of targeted AAV vectors;174
16.4.1;Receptor targeting via chemical linker;174
16.4.2;Receptor targeting via genetic modification;175
16.4.3;Receptor targeting via the combination of a chemical linker and genetic modification;176
16.4.4;Directed evolution;176
16.4.5;Insertion of a peptide derived from a phage library into the AAV capsid;177
16.4.6;Insertion of random peptides into the AAV capsid;177
16.5;Cellular immune response to AAV vectors;178
16.6;Therapy of autoimmune diseases by AAV-mediated gene delivery;179
16.6.1;Arthritis;179
16.6.2;Diabetes;180
16.6.3;Inflammatory bowel diseases;181
16.6.4;Other autoimmune diseases;182
16.7;Conclusion;182
16.8;References;183
17;Delivery and application of plasmid DNA in arthritis gene therapy;188
17.1;Introduction;188
17.2;Chemical delivery of plasmids;189
17.3;Physical delivery of plasmids;190
17.3.1;Genetic immunisation;190
17.3.2;Therapeutic gene expression from skeletal muscle;191
17.3.3;Expression of therapeutic genes by electroporation;192
17.3.4;Hydrodynamic delivery;193
17.3.5;Hydrodynamic delivery to liver;193
17.3.6;Massage delivery;194
17.3.7;Ballistic delivery;194
17.3.8;Sonoporation;195
17.3.9;Plasmid delivery to joints;195
17.4;How efficient are plasmid delivery methods?;196
17.5;Conclusion;196
17.6;References;197
18;Helper-dependent adenoviral vectors;200
18.1;Introduction;200
18.2;HDAd;201
18.3;In vivo studies with HDAd;203
18.4;Liver directed gene therapy;203
18.5;Gene therapy for cystic fibrosis;205
18.6;Brain gene therapy;209
18.7;Concluding remarks;210
18.8;References;210
19;Cells as carriers of gene therapy;215
19.1;Concept and rationale of cells as carriers of gene therapy;215
19.2;Tissue cells;216
19.3;Lymphocytes;219
19.4;Antigen-presenting cells;221
19.5;Cell-derived particles;223
19.6;Stem cells;224
19.7;Conclusions;225
19.8;References;226
20;Perspectives for the future developments of gene therapy for autoimmune and inflammatory therapy;229
20.1;New findings from genome-wide association studies;229
20.2;MicroRNAS;230
20.3;Epigenetics;231
20.4;Mechanisms of resistance to therapies;232
20.5;Improving on delivery vectors for autoimmune inflammatory disease;232
20.6;Conclusion;233
20.7;References;234
21;Index;238