Gene Therapy of the Central Nervous System: From Bench to Bedside (eBook)

Cover 1
Gene Therapy of the Central Nervous System: From Bench to Bedside 4
Contents 6
Contributors 10
Preface 14
Section I Gene Transfer Technology and Regulatory Issues 16
Design and Optimization of Expression Cassettes Including Promoter Choice and Regulatory Elements 18
Introduction 18
Design of the rAAV Cassette 18
Cell-Type-Specific Tropism of rAAV 19
Choice of Promoter 20
Regulatory Elements 25
Summary and Conclusion 27
Identification of Novel Adeno-Associated Virus Serotypes for Use as Vectors 32
Introduction 32
Identification and Isolation of Novel Primate AAVs 34
Classification of Novel Primate AAVs 35
Novel AAVs as Gene Transfer Vectors 37
Conclusions 37
HSV Amplicon Vectors for Gene Delivery to the Nervous System 40
Basics of HSV-1 Amplicon 40
Advantages of HSV-1 Amplicon 43
Uses in Nervous System 47
Perspectives 51
Acknowledgments 53
Influence of the Immune System on Central Nervous System Gene Transfer 60
Adaptive Immunity and Viral Vectors 62
Immunology of Transgenes 65
Conclusion 65
Acknowledgments 66
Targeted Induction of Endogenous Neural Stem and Progenitor Cells: A New Strategy for Gene Therapy of Neurological Disease 68
Neural Stem and Progenitor Cells of the Human Brain 68
Cell Genesis in the Adult CNS Shares Common Themes with that in other Solid Organs 70
Neural Progenitor Cells are widely Distributed in the Adult Human Brain 70
Progenitor Cells may be useful as both Engraftable and Inducible Substrates for Repair 71
Endogenous Progenitor Cells are Mobilized by Injury and Disease 71
Resident Progenitor Cells can be Mobilized Pharmacologically and Genetically 71
Induced Neurogenesis in the Adult Neostriatum 73
The Development of Glial Suppressive Strategies Enhancing Heterotopic Neurogenesis 73
Induced Neurogenesis as a Therapeutic Strategy in Huntington’s Disease 74
Progenitor Cell Targeting in Parkinson’s Disease 74
Induced Neurogenesis as a Restorative Strategy for the Hippocampal Atrophies 74
Parenchymal Glial Progenitors are Attractive Targets for Exogenous Mobilization 75
Transduced Neural Progenitors as Vectors for Enzymatic Repletion in the Storage Diseases 76
Overview 77
Acknowledgments 77
Neurosurgical Targeting, Delivery, and Infusion of Gene Therapy Agents in the Brain 82
Anatomical Targeting in Stereotactic Neurosurgery 83
Methods of Accessing the Central Nervous System 85
Methods for Enhancing Intracranial Gene Transfer 87
Conclusion 88
Gene Transfer for Neurological Disease: Agencies, Policies, and Process* 92
The Landscape of Gene Therapy 92
Oversight of Gene Therapy Protocols 93
Good Practice Requirements for Gene Therapy Protocols 96
Clinical Phases for Development of Biologics 96
Sequential Steps in Implementation of a Clinical Gene Transfer Trial 97
Limitations of the System 102
Section II Gene Therapy for Degenerative and Functional Disorders 104
Gene Therapy for Parkinson’s Disease 106
Introduction 106
Parkinson’s Disease 107
Current Pharmacological Therapy vs. Gene Therapy for PD 107
Animal Models of PD 108
Strategies for Gene Therapy Intervention in PD 108
Biochemical Augmentation: Gene Transfer of Enzymes Involved in Dopamine Synthesis 109
Gene Transfer of Growth Factors 112
Gene Therapy to Reset Neuronal Circuitry 114
Prevention of Apoptosis 115
Other Targets for PD Gene Therapy: The UPS 115
Remaining Hurdles in Gene Therapy for PD 116
Summary 116
Nonhuman Primate Models for Testing Gene Therapy for Neurodegenerative Disorders 124
Neurodegenerative Disorders 124
Why use Gene Therapy for Treatment of Neurodegenerative Disorders? 125
Methods of Delivery of Therapeutic Genes 125
Considerations for a Successful Gene Therapy Strategy 126
The Need for Nonhuman Primate Experimentation 127
Nonhuman Primate Models of Neurodegenerative Disorders and Gene Therapy 127
What makes a Gene Therapy Study in Monkeys Relevant? 131
A Final Comment 132
Acknowledgments 132
Delivery of Molecular Therapeutics into the CNS and their Distribution within the Brain 136
Bypassing the Blood–Brain Barrier (BBB) 136
Local Methods of Drug Delivery to the CNS 138
Distribution of Molecular Therapeutics within the Brain 141
Brain Tumors 142
Acknowledgment 144
Gene Therapy for CNS Diseases Using Intrabodies 148
Introduction 148
Mechanisms of Intrabody Approaches to Neurodegeneration 151
Improving Intrabody Gene Delivery, Expression, and Function 158
Potential Intrabody Toxicity 158
Perspective 159
Acknowledgments 159
Gene Therapy for Epilepsy 166
Introduction 166
Therapeutic Targets in Epilepsy 167
Delivery Methods for Gene Therapy 168
Studies in Experimental Models of Seizures 170
Therapeutic Implications and Conclusions 176
Section III Psychiatric and Behavioral Gene Therapy 180
Genetic Manipulation of Learning and Memory 182
Introduction 182
Techniques for Studying, Learning, and Memory 182
Aspects of Memory Formation 183
Conclusion 191
Psychiatric Applications of Viral Vectors 196
Recombinant Vectors 196
Application to the Study of Behavior 199
Example of the Utility of Viral Vectors in Psychiatry: Modulation of Cre-Dependent Transcription Alters Behavior 201
Novel uses for Viral Vectors 203
Conclusions 206
Acknowledgment 206
Use of Viral Vectors to Influence Behavior 210
Viral-Mediated RNA Interference for Behavioral Neuroscience 211
Silencing Estrogen-Receptor Expression in Mouse Hypothalamus using AAV Vectors 211
Restoration of Estrogen Receptor Expression in Transgenic Knockouts using AAV Vectors 216
Conclusion 219
Section IV Gene Therapy for Pain and Spinal Cord Diseases 222
Herpes Simplex Vector Mediated Gene Transfer to the Peripheral Nervous System for the Treatment of Polyneuropathy and Chronic Pain 224
Biology of HSV 225
HSV Vector Construction and Propagation 226
HSV-Mediated Gene Transfer in the Treatment Sensory Polyneuropathy 227
HSV-Mediated Gene Transfer in the Treatment of Chronic Pain 229
Summary 233
Acknowledgments 234
Characterization of Pain Receptors in the Spinal Cord Using a Viral Vector for Spatial–Temporal Gene Targeting 238
Introduction 238
Acknowledgments 243
Viral Vector Mediated Gene Therapy of Pain 246
Introduction 246
Opiate-Based Strategy 247
Growth Factor-Based Strategy 248
Gaba-Based Strategies 250
Forebrain Targets 250
Non-Pain Directed Strategies 250
Other Considerations 251
Acknowledgment 251
VEGF, an Angiogenic Factor with Neurotrophic Activity, Useful for Treatment of ALS? 254
VEGF „ A Key Angiogenic Player 254
Angiogenic Role of VEGF in Neural Development and Disease 255
A Neural Role for VEGF in Neural Development and Disease 255
VEGF and ALS 257
Finding a Therapy for ALS 258
Gene Therapy Approaches for ALS 258
The Therapeutic Potential of VEGF for ALS 262
Viral Vector Axonal Uptake and Retrograde Transport: Mechanisms and Applications 268
Neuronal Axonal Transport 268
Mechanisms of Uptake and Retrograde Transport of Neurotropic Viruses 269
Current Data on Uptake and Retrograde Transport of Viral Vectors 271
Neurotropic Viruses as Gene Transfer Vectors 273
Tetanus Toxin HC as a Protein Carrier Targeting CNS 274
Vector Pseudotyping 275
Application of Retrograde Transport of Viral Vectors 276
Conclusion 282
Gene Therapy for Spinal Cord Injury 288
Introduction 288
The Pathophysiology of SCI 289
Rat Models for Experimental SCI 290
What is Required to Elict Successful Regeneration after SCI? 291
Direct Viral Vector-Mediated Gene Transfer in the Injured Spinal Cord 291
Combining Transplantation and Gene Therapy 294
Future Perspective 297
Section V Gene Therapy for Brain Tumors and Neurogenetic Diseases 304
Prodrug-Activation Gene Therapy 306
Herpes Simplex Virus Type 1 Thymidine Kinase (HSVtk)/ Ganciclovir 306
Cytosine Deaminase (CD)/5-Fluorocytosine (5-FC) 309
Cytochrome P450 (CYP)/Cyclophosphamide (CPA) or Ifosfamide (IFA) 309
Guanine Phosphoribosyl-Transferase/ 6-Thioxanthine 311
Nitroreductase/CB1954 311
Carboxylesterase (CE)/CPT-11 312
E. Coli Purine Nucleoside Phosphorylase (PNP)/Purine Analogs 312
Conclusions 314
Clinical Trials of Gene Therapy for Canavan Disease 318
The Nosology of Canavan Disease 318
The NAA Metabolic Cycle 319
Animal Models of CD 322
ASPA Gene Therapy 324
Future Prospects 328
Acknowledgments 328
Gene Therapy for the Late Infantile Form of Batten Disease 332
Introduction 332
LINCL 332
CLN2 Gene and Protein 334
Therapeutic Options for Treating the CNS Manifestations of LINCL 335
Challenges for Effective Gene Therapy of LINCL 336
Pre-Clinical Efficacy Studies 337
Pre-Clinical Toxicology Studies 339
Manufacturing the Clinical Grade AAV2CU HCLN2 Vector 341
Clinical Protocol Design 343
Conclusion 345
Acknowledgments 345
Molecular Imaging of Gene Therapy for Neurogenetic Diseases 350
Genetic Diseases of the CNS 350
Imaging Modalities 351
Animal Models 351
Gene Transfer in the CNS 352
Radioisotope Methods (PET and SPECT) 353
Magnetic Resonance Methods 355
Optical Imaging 359
Summary 360
Acknowledgments 360
Index 366