Kaplitt / During Gene Therapy of the Central Nervous System: From Bench to Bedside

1. Auflage 2005
ISBN: 978-0-08-045437-5
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, 370 Seiten

Few areas of biomedical research provide greater opportunities for radically new therapies for devastating diseases that have evaded treatment so far than gene therapy. This is particularly true for the brain and nervous system, where gene transfer has become a key technology for basic research and has recently been translated to human therapy in several landmark clinical trials.
Gene Therapy of the Central Nervous System: From Bench to Bedside represents the first definitive volume on this subject. Edited by two pioneers of neurological gene therapy, this volume contains contributions by leaders who helped create this field and are expanding the promise of gene therapy for the future of basic and clinical neuroscience. Drawing upon this extensive collective experience, this book provides clear and informative reviews on a variety of subjects of interest to anyone exploring or using gene therapy for neurobiological applications in research and clinical praxis.
* Presents gene transfer technologies with particular emphases upon novel vehicles, immunological issues and the role of gene therapy in stem cells
* Discusses preclinical areas that are likely to translate into clinical studies in the near future, including epilepsy, pain and amyotrophic lateral sclerosis
* Includes 'insider' information on technological and regulatory issues which can often limit effective translation of even the most promising idea into clinical use

Zielgruppe

Academic/professional/technical: Research and professional

Autoren/Hrsg.

Kaplitt, Michael G.

During, Matthew

Inhaltsverzeichnis

1;Cover;1
2;Gene Therapy of the Central Nervous System: From Bench to Bedside;4
3;Contents;6
4;Contributors;10
5;Preface;14
6;Section I Gene Transfer Technology and Regulatory Issues;16
6.1;Design and Optimization of Expression Cassettes Including Promoter Choice and Regulatory Elements;18
6.1.1;Introduction;18
6.1.2;Design of the rAAV Cassette;18
6.1.3;Cell-Type-Specific Tropism of rAAV;19
6.1.4;Choice of Promoter;20
6.1.5;Regulatory Elements;25
6.1.6;Summary and Conclusion;27
6.2;Identification of Novel Adeno-Associated Virus Serotypes for Use as Vectors;32
6.2.1;Introduction;32
6.2.2;Identification and Isolation of Novel Primate AAVs;34
6.2.3;Classification of Novel Primate AAVs;35
6.2.4;Novel AAVs as Gene Transfer Vectors;37
6.2.5;Conclusions;37
6.3;HSV Amplicon Vectors for Gene Delivery to the Nervous System;40
6.3.1;Basics of HSV-1 Amplicon;40
6.3.2;Advantages of HSV-1 Amplicon;43
6.3.3;Uses in Nervous System;47
6.3.4;Perspectives;51
6.3.5;Acknowledgments;53
6.4;Influence of the Immune System on Central Nervous System Gene Transfer;60
6.4.1;Adaptive Immunity and Viral Vectors;62
6.4.2;Immunology of Transgenes;65
6.4.3;Conclusion;65
6.4.4;Acknowledgments;66
6.5;Targeted Induction of Endogenous Neural Stem and Progenitor Cells: A New Strategy for Gene Therapy of Neurological Disease;68
6.5.1;Neural Stem and Progenitor Cells of the Human Brain;68
6.5.2;Cell Genesis in the Adult CNS Shares Common Themes with that in other Solid Organs;70
6.5.3;Neural Progenitor Cells are widely Distributed in the Adult Human Brain;70
6.5.4;Progenitor Cells may be useful as both Engraftable and Inducible Substrates for Repair;71
6.5.5;Endogenous Progenitor Cells are Mobilized by Injury and Disease;71
6.5.6;Resident Progenitor Cells can be Mobilized Pharmacologically and Genetically;71
6.5.7;Induced Neurogenesis in the Adult Neostriatum;73
6.5.8;The Development of Glial Suppressive Strategies Enhancing Heterotopic Neurogenesis;73
6.5.9;Induced Neurogenesis as a Therapeutic Strategy in Huntington’s Disease;74
6.5.10;Progenitor Cell Targeting in Parkinson’s Disease;74
6.5.11;Induced Neurogenesis as a Restorative Strategy for the Hippocampal Atrophies;74
6.5.12;Parenchymal Glial Progenitors are Attractive Targets for Exogenous Mobilization;75
6.5.13;Transduced Neural Progenitors as Vectors for Enzymatic Repletion in the Storage Diseases;76
6.5.14;Overview;77
6.5.15;Acknowledgments;77
6.6;Neurosurgical Targeting, Delivery, and Infusion of Gene Therapy Agents in the Brain;82
6.6.1;Anatomical Targeting in Stereotactic Neurosurgery;83
6.6.2;Methods of Accessing the Central Nervous System;85
6.6.3;Methods for Enhancing Intracranial Gene Transfer;87
6.6.4;Conclusion;88
6.7;Gene Transfer for Neurological Disease: Agencies, Policies, and Process*;92
6.7.1;The Landscape of Gene Therapy;92
6.7.2;Oversight of Gene Therapy Protocols;93
6.7.3;Good Practice Requirements for Gene Therapy Protocols;96
6.7.4;Clinical Phases for Development of Biologics;96
6.7.5;Sequential Steps in Implementation of a Clinical Gene Transfer Trial;97
6.7.6;Limitations of the System;102
7;Section II Gene Therapy for Degenerative and Functional Disorders;104
7.1;Gene Therapy for Parkinson’s Disease;106
7.1.1;Introduction;106
7.1.2;Parkinson’s Disease;107
7.1.3;Current Pharmacological Therapy vs. Gene Therapy for PD;107
7.1.4;Animal Models of PD;108
7.1.5;Strategies for Gene Therapy Intervention in PD;108
7.1.6;Biochemical Augmentation: Gene Transfer of Enzymes Involved in Dopamine Synthesis;109
7.1.7;Gene Transfer of Growth Factors;112
7.1.8;Gene Therapy to Reset Neuronal Circuitry;114
7.1.9;Prevention of Apoptosis;115
7.1.10;Other Targets for PD Gene Therapy: The UPS;115
7.1.11;Remaining Hurdles in Gene Therapy for PD;116
7.1.12;Summary;116
7.2;Nonhuman Primate Models for Testing Gene Therapy for Neurodegenerative Disorders;124
7.2.1;Neurodegenerative Disorders;124
7.2.2;Why use Gene Therapy for Treatment of Neurodegenerative Disorders?;125
7.2.3;Methods of Delivery of Therapeutic Genes;125
7.2.4;Considerations for a Successful Gene Therapy Strategy;126
7.2.5;The Need for Nonhuman Primate Experimentation;127
7.2.6;Nonhuman Primate Models of Neurodegenerative Disorders and Gene Therapy;127
7.2.7;What makes a Gene Therapy Study in Monkeys Relevant?;131
7.2.8;A Final Comment;132
7.2.9;Acknowledgments;132
7.3;Delivery of Molecular Therapeutics into the CNS and their Distribution within the Brain;136
7.3.1;Bypassing the Blood–Brain Barrier (BBB);136
7.3.2;Local Methods of Drug Delivery to the CNS;138
7.3.3;Distribution of Molecular Therapeutics within the Brain;141
7.3.4;Brain Tumors;142
7.3.5;Acknowledgment;144
7.4;Gene Therapy for CNS Diseases Using Intrabodies;148
7.4.1;Introduction;148
7.4.2;Mechanisms of Intrabody Approaches to Neurodegeneration;151
7.4.3;Improving Intrabody Gene Delivery, Expression, and Function;158
7.4.4;Potential Intrabody Toxicity;158
7.4.5;Perspective;159
7.4.6;Acknowledgments;159
7.5;Gene Therapy for Epilepsy;166
7.5.1;Introduction;166
7.5.2;Therapeutic Targets in Epilepsy;167
7.5.3;Delivery Methods for Gene Therapy;168
7.5.4;Studies in Experimental Models of Seizures;170
7.5.5;Therapeutic Implications and Conclusions;176
8;Section III Psychiatric and Behavioral Gene Therapy;180
8.1;Genetic Manipulation of Learning and Memory;182
8.1.1;Introduction;182
8.1.2;Techniques for Studying, Learning, and Memory;182
8.1.3;Aspects of Memory Formation;183
8.1.4;Conclusion;191
8.2;Psychiatric Applications of Viral Vectors;196
8.2.1;Recombinant Vectors;196
8.2.2;Application to the Study of Behavior;199
8.2.3;Example of the Utility of Viral Vectors in Psychiatry: Modulation of Cre-Dependent Transcription Alters Behavior;201
8.2.4;Novel uses for Viral Vectors;203
8.2.5;Conclusions;206
8.2.6;Acknowledgment;206
8.3;Use of Viral Vectors to Influence Behavior;210
8.3.1;Viral-Mediated RNA Interference for Behavioral Neuroscience;211
8.3.2;Silencing Estrogen-Receptor Expression in Mouse Hypothalamus using AAV Vectors;211
8.3.3;Restoration of Estrogen Receptor Expression in Transgenic Knockouts using AAV Vectors;216
8.3.4;Conclusion;219
9;Section IV Gene Therapy for Pain and Spinal Cord Diseases;222
9.1;Herpes Simplex Vector Mediated Gene Transfer to the Peripheral Nervous System for the Treatment of Polyneuropathy and Chronic Pain;224
9.1.1;Biology of HSV;225
9.1.2;HSV Vector Construction and Propagation;226
9.1.3;HSV-Mediated Gene Transfer in the Treatment Sensory Polyneuropathy;227
9.1.4;HSV-Mediated Gene Transfer in the Treatment of Chronic Pain;229
9.1.5;Summary;233
9.1.6;Acknowledgments;234
9.2;Characterization of Pain Receptors in the Spinal Cord Using a Viral Vector for Spatial–Temporal Gene Targeting;238
9.2.1;Introduction;238
9.2.2;Acknowledgments;243
9.3;Viral Vector Mediated Gene Therapy of Pain;246
9.3.1;Introduction;246
9.3.2;Opiate-Based Strategy;247
9.3.3;Growth Factor-Based Strategy;248
9.3.4;Gaba-Based Strategies;250
9.3.5;Forebrain Targets;250
9.3.6;Non-Pain Directed Strategies;250
9.3.7;Other Considerations;251
9.3.8;Acknowledgment;251
9.4;VEGF, an Angiogenic Factor with Neurotrophic Activity, Useful for Treatment of ALS?;254
9.4.1;VEGF „ A Key Angiogenic Player;254
9.4.2;Angiogenic Role of VEGF in Neural Development and Disease;255
9.4.3;A Neural Role for VEGF in Neural Development and Disease;255
9.4.4;VEGF and ALS;257
9.4.5;Finding a Therapy for ALS;258
9.4.6;Gene Therapy Approaches for ALS;258
9.4.7;The Therapeutic Potential of VEGF for ALS;262
9.5;Viral Vector Axonal Uptake and Retrograde Transport: Mechanisms and Applications;268
9.5.1;Neuronal Axonal Transport;268
9.5.2;Mechanisms of Uptake and Retrograde Transport of Neurotropic Viruses;269
9.5.3;Current Data on Uptake and Retrograde Transport of Viral Vectors;271
9.5.4;Neurotropic Viruses as Gene Transfer Vectors;273
9.5.5;Tetanus Toxin HC as a Protein Carrier Targeting CNS;274
9.5.6;Vector Pseudotyping;275
9.5.7;Application of Retrograde Transport of Viral Vectors;276
9.5.8;Conclusion;282
9.6;Gene Therapy for Spinal Cord Injury;288
9.6.1;Introduction;288
9.6.2;The Pathophysiology of SCI;289
9.6.3;Rat Models for Experimental SCI;290
9.6.4;What is Required to Elict Successful Regeneration after SCI?;291
9.6.5;Direct Viral Vector-Mediated Gene Transfer in the Injured Spinal Cord;291
9.6.6;Combining Transplantation and Gene Therapy;294
9.6.7;Future Perspective;297
10;Section V Gene Therapy for Brain Tumors and Neurogenetic Diseases;304
10.1;Prodrug-Activation Gene Therapy;306
10.1.1;Herpes Simplex Virus Type 1 Thymidine Kinase (HSVtk)/ Ganciclovir;306
10.1.2;Cytosine Deaminase (CD)/5-Fluorocytosine (5-FC);309
10.1.3;Cytochrome P450 (CYP)/Cyclophosphamide (CPA) or Ifosfamide (IFA);309
10.1.4;Guanine Phosphoribosyl-Transferase/ 6-Thioxanthine;311
10.1.5;Nitroreductase/CB1954;311
10.1.6;Carboxylesterase (CE)/CPT-11;312
10.1.7;E. Coli Purine Nucleoside Phosphorylase (PNP)/Purine Analogs;312
10.1.8;Conclusions;314
10.2;Clinical Trials of Gene Therapy for Canavan Disease;318
10.2.1;The Nosology of Canavan Disease;318
10.2.2;The NAA Metabolic Cycle;319
10.2.3;Animal Models of CD;322
10.2.4;ASPA Gene Therapy;324
10.2.5;Future Prospects;328
10.2.6;Acknowledgments;328
10.3;Gene Therapy for the Late Infantile Form of Batten Disease;332
10.3.1;Introduction;332
10.3.2;LINCL;332
10.3.3;CLN2 Gene and Protein;334
10.3.4;Therapeutic Options for Treating the CNS Manifestations of LINCL;335
10.3.5;Challenges for Effective Gene Therapy of LINCL;336
10.3.6;Pre-Clinical Efficacy Studies;337
10.3.7;Pre-Clinical Toxicology Studies;339
10.3.8;Manufacturing the Clinical Grade AAV2CU HCLN2 Vector;341
10.3.9;Clinical Protocol Design;343
10.3.10;Conclusion;345
10.3.11;Acknowledgments;345
10.4;Molecular Imaging of Gene Therapy for Neurogenetic Diseases;350
10.4.1;Genetic Diseases of the CNS;350
10.4.2;Imaging Modalities;351
10.4.3;Animal Models;351
10.4.4;Gene Transfer in the CNS;352
10.4.5;Radioisotope Methods (PET and SPECT);353
10.4.6;Magnetic Resonance Methods;355
10.4.7;Optical Imaging;359
10.4.8;Summary;360
10.4.9;Acknowledgments;360
11;Index;366