1 Introduction to Neurobiotechnology ........................... 1
Definitions and History ...................................... 1
Molecular Neurology .......................................... 2
Molecular Neuroscience ....................................... 2
Relationships of Biotechnologies to Neurology ................ 3
References ................................................... 4
2 Neurogenetics and Neurogenomics .............................. 7
Introduction ................................................. 7
Neurogenetics ................................................ 7
Neurogenomics ............................................. 8
Variations in the Human Genome ............................ 8
Technologies Used in Neurogenomics ........................ 9
Applications of Neurogenomics ............................... 12
References .................................................. 15
3 Neuroproteomics ............................................. 17
Introduction ................................................ 17
Proteomic Technologies ...................................... 17
Application of Proteomics for the Study of Nervous
System ...................................................... 18
Study of Synapses ........................................ 19
Study of Neurotransmitters ............................... 19
Study of Neuronal Receptors .............................. 20
Study of Regeneration and Degeneration of the Nervous
System ................................................... 20
Proteomics of Blood-Brain Barrier ........................ 20
Proteomics for Study of Neurological Disorders .............. 21
Proteomics of Prion Diseases ............................. 21
Protein Misfolding and Neurodegenerative Disorders ....... 23
Ion Channel Link for Protein-Misfolding Disease .......... 24
Detection of Misfolded Proteins v ....................... 24
Neurodegenerative Disorders with Protein Abnormalities ... 24
Proteomics and Glutamate Repeat Disorders ................ 30
Proteomics and Demyelinating Diseases .................... 32
Proteomics of Neurogenetic Disorders ..................... 32
Quantitative Proteomics and Familial Hemiplegic
Migraine ................................................. 34
Proteomics of Spinal Muscular Atrophy .................... 34
Proteomics of CNS Trauma ................................. 34
Neuroproteomics of Epilepsy .............................. 36
Proteomics of CNS Aging .................................. 36
Neuroproteomics of Psychiatric Disorders ................. 37
Neurodiagnosties Based on Proteomics ........................ 39
Disease-Specific Proteins in the Cerebrospinal Fluid ..... 39
CNS Tissue Proteomics .................................... 40
Diagnosis of CNS Disorders by Examination of Proteins
in Urine ................................................. 42
Diagnosis of CNS Disorders by Examination of Proteins
in the Blood ............................................. 42
Future Prospects of Neuroproteomics in Neurology ............ 44
HUPO 's Pilot Brain Proteome Project ..................... 45
References .................................................. 46
4 Biomarkers of Neurological Disorders ........................ 49
Introduction ................................................ 49
Biomarkers of Neurological Disorders ........................ 50
Discovery of Biomarkers for Neurological Disorders .......... 50
Biomarker Identification in the CSF Using Proteomics ..... 51
Biomarker Identification in the CSF Using Lipidomics ..... 52
Cerebral Microdialysis for the Study of Biomarkers
of Cerebral Metabolism ................................... 52
Detection of Protein Biomarkers of CNS Disorders in the
Blood .................................................... 53
Brain Imaging for Detection of Biomarkers ................ 53
Biomarkers of the Aging Brain ............................... 54
Cellular Biomarker of Aging of the Brain ................. 54
CSF F2-Isoprostanes as Biomarker of Aging Brain .......... 54
Protein Aggregation as a Biomarker of Aging Brain ........ 55
Data Mining for Biomarkers of Neurological Disorders ........ 55
Antibodies as Biomarkers in Disorders of the Nervous
System ...................................................... 56
Biomarkers of Neural Regeneration ........................... 56
Biomarkers of Disruption of Blood-Brain Barrier ............. 57
Biomarkers of Neurotoxicity ................................. 57
Glial Fibrillary Acidic Protein as Biomarker of
Neurotoxicity ............................................ 58
Single-Stranded DNA as a Biomarker of Neuronal
Apoptosis ................................................ 58
Biomarkers of Neurogenetic Disorders ........................ 59
Charcot-Marie Tooth Disease .............................. 59
Duchenne and Becker Muscular Dystrophy ................... 60
Fragile X Syndrome ....................................... 61
Hereditary Neuropathy with Liability to Pressure
Palsies .................................................. 62
Hereditary Metabolic Storage Disorders with Neurologic
Manifestations ........................................... 62
Mitochondrial Disorders Affecting the Nervous System ..... 63
Spinal Muscular Atrophy .................................. 64
Biomarkers of Neurodegenerative Disorders ................... 64
Biomarkers of Alzheimer's Disease ........................... 65
The Ideal Biomarker for AD ............................... 68
Methods for Determining Biomarkers of AD ................. 69
Biomarkers of AD in CSF .................................. 76
Blood Biomarkers of AD ................................... 82
Urine Tests for AD ....................................... 85
A Biomarker-Based Skin Test for AD ....................... 86
Salivary Biomarkers of AD ................................ 86
Applications of Biomarkers of AD ......................... 87
Concluding Remarks About Biomarkers for AD and Future
Prospects ................................................ 89
Biomarkers of Parkinson's Disease ........................... 90
Biomarkers of PD Based on Gene Expression in Blood ....... 91
Cardiac Denervation as a Biomarker of PD ................. 91
Imaging Biomarkers of PD ................................. 92
Metabolic Brain Networks as Biomarkers ................... 93
Metabonomic Biomarker Profile for Diagnosis
and Monitoring of PD ..................................... 93
Protein Вiomarkers of PD ................................. 94
Serum Vitamin D as a Biomarker of PD ..................... 94
Future Prospects for Biomarkers of PD .................... 95
Biomarkers of Huntington's Disease .......................... 95
Quantitative MRI Measurement of Brain Atrophy
as Biomarker of HD ....................................... 97
Biomarkers of Wilson's Disease .............................. 97
Biomarkers of Amyotrophic Lateral Sclerosis ................. 98
Biomarkers of Neuroinflammation in ALS ................... 98
Detection of ALS Biomarkers in Blood vs CSF .............. 99
Ideal Biomarker of ALS ................................... 99
Imaging Biomarkers of ALS ............................... 100
Metabolomic Biomarkers of ALS ........................... 100
Proteomic Вiomarkers of ALS ............................. 101
Future Prospects of Biomarkers of ALS ................... 101
Biomarkers of Dementia in HIV-1 -Infected Patients ......... 102
Biomarkers of Prion Diseases ............................... 102
14-3-3 Protein and tTau/P-Tau Ratio ..................... 103
Bioluminescence Imaging as a Surrogate Biomarker
of Prion Infectivity .................................... 103
Biomarkers of Multiple Sclerosis ........................... 103
Antibodies in Multiple Sclerosis ........................ 104
CSF Cystatin С as a Biomarker of Multiple Sclerosis ..... 106
T Cells as Biomarkers of Multiple Sclerosis ............. 106
Matrix Metalloproteinases as Biomarkers in Multiple
Sclerosis ............................................... 107
Gelsolin as a Biomarker of Multiple Sclerosis ........... 107
Gene Expression Profiling of Biomarkers in Multiple
Sclerosis ............................................... 108
Serum Proteomic Pattern Analysis in Multiple Sclerosis .. 108
Brain Imaging Biomarkers of Multiple Sclerosis .......... 108
Biomarkers of Response to Therapy of Multiple
Sclerosis ............................................... 110
Concluding Remarks and Future Perspective for
Biomarkers of Multiple Sclerosis ........................... 110
Biomarkers of Cerebrovascular Disorders ................. 112
Biomarkers of Stroke .................................... 112
Biomarkers of Cerebral Vasospasm ........................ 120
Biomarkers of Intracerebral Hemorrhage .................. 120
Biomarkers of Hypoxic Brain Damage ...................... 121
D-dimer as a Biomarker of Cerebral Venous Thrombosis .... 121
Biomarkers of Traumatic Brain Injury ....................... 122
Technologies for Identification of Biomarkers of TBI .... 122
Biomarkers of TBI ....................................... 124
Biomarkers of Inflicted TBI in Infants .................. 127
Clinical Applications of Biomarkers of TBI .............. 128
Biomarkers of CNS Infections ............................... 129
Biomarkers of Вacterial Meningitis ...................... 129
Biomarkers of Viral Infections of CNS ................... 129
Biomarkers of Epilepsy ..................................... 131
Genetic Epilepsies ...................................... 131
Biochemical Markers of Epilepsy ......................... 131
Biomarkers of Temporal Lobe Epilepsy .................... 132
Imaging Biomarkers of Epilepsy .......................... 132
Biomarkers of Normal Pressure Hydrocephalus ................ 133
Biomarkers of Retinal Disorders ............................ 133
Biomarkers of Age-Related Macular Degeneration .......... 133
Biomarkers of Sleep Disorders .............................. 134
Biomarker of Excessive Daytime Sleepiness ............... 134
Biomarkers of Obstructive Sleep Apnea ................... 135
Biomarkers of Restless Legs Syndrome .................... 135
Biomarkers of Pain ......................................... 136
Biomarkers of Neuropathic Pain .......................... 136
Brain Insular Glutamate as Biomarker of Fibromyalgia .... 137
Biomarkers of Visceral Pain ............................. 137
Вiomarkers of Migraine .................................. 138
Biomarkers of Myalgic En cephalomyelitis/Chronic
Fatigue Syndrome ........................................... 138
Biomarkers of Psychiatric Disorders ........................ 139
Anorexia Nervosa ........................................ 139
Attention-Deficit Hyperactivity Disorder ................ 139
Biomarkers for Autism ................................... 140
Biomarkers of Depression ................................ 141
Biomarkers of Psychosis ................................. 142
Biomarkers of Schizophrenia ............................. 142
References ................................................. 145
5 Molecular Diagnostics for Neurological Disorders ........... 155
Introduction ............................................... 155
Technologies ............................................ 155
Molecular Brain Imaging ................................. 157
Applications of Sequencing in Molecular Diagnostics ..... 159
Clinical Applications ...................................... 160
Molecular Diagnosis of Neurogenetic Disorders .............. 160
Introduction ............................................ 160
Applications ............................................ 160
Alzheimer Disease ....................................... 163
Familial Amyotrophic Lateral Sclerosis .................. 164
Down Syndrome ........................................... 165
Molecular Diagnosis of Wilson's Disease ................. 165
Neuromuscular Disorders ................................. 166
Triple Repeat Disorders ................................. 167
Mitochondrial Disorders Affecting the Nervous System .... 170
Epilepsy ................................................ 171
Hereditary Metabolic Disorders with Neurologic
Manifestations .......................................... 172
Hereditary Motor and Sensory Neuropathies ............... 173
Parkinson Disease ....................................... 175
Autism Spectrum Disorders ............................... 175
Attention Deficit Hyperactivity Disorder ................ 176
Advantages and Limitations of Molecular Diagnostics
of Genetic Disorders .................................... 177
Molecular Diagnosis of CNS Infections ...................... 177
Introduction ............................................ 177
Indications ............................................. 178
Detection of Viral Infections of the Nervous System ..... 179
Molecular Methods for Detection of Bacterial, Fungal
and Protozoal Infections ................................ 184
Neurocysticercosis ...................................... 188
Limitations and Pitfalls of Molecular Diagnosis of
Infections .............................................. 189
Molecular Diagnosis of Brain Tumors ........................ 189
Introduction ............................................ 189
Molecular Diagnostic Technologies Relevant to Brain
Tumors .................................................. 190
Genetic Alterations Underlying the Pathogenesis
of Brain Tumors ......................................... 196
Advantages and Limitations of Molecular Diagnostics
of Brain Tumors ......................................... 205
Concluding Remarks on Molecular Diagnosis of Brain
Tumors .................................................. 206
References ................................................. 206
6 Molecular Neuropharmacology ................................ 211
Introduction ............................................... 211
Impact of Biotechnology on Neuropharmacology ............... 211
Pharmacogenetics and Neuropharmacology .................. 212
Biotechnology and Pharmacokinetics ...................... 212
Biotechnology and Pharmacodynamics ...................... 214
Biomarkers and Neuropharmacology ........................ 214
Role of Genomics in Neuropharmacology ...................... 215
Pharmacogenomics ........................................ 215
Role of DNA Sequencing in Drug Discovery and
Development ............................................. 216
Application of Synthetic Biology in Drug Discovery ...... 216
Role of Antisense in Drug Discovery for Neurological
Disorders ............................................... 217
Role of RNAi in Drug Discovery for Neurological
Disorders ............................................... 218
Role of Proteomics in Neuropharmacology .................... 218
Proteomics for Drug Discovery ........................... 218
Proteins as Drug Targets ................................ 219
Pharmacoproteomics ...................................... 220
Global Proteomics for Pharmacodynamics .................. 220
Integration of Proteomics with Genomics for Drug
Discovery ............................................... 221
Cell-Based Drug Discovery .................................. 221
Advantages and Pitfalls of Cell-Based Assays for Drug
Discovery ............................................... 221
Stem Cells for Drug Discovery ........................... 222
References ................................................. 224
7 Ion Channels and Neurology ................................. 227
Introduction ............................................ 227
Historical Aspects ...................................... 227
Ion Channels in the Nervous System ......................... 228
Voltage-Gated Channels .................................. 228
Potassium Channels ...................................... 228
Sodium Channels ......................................... 229
Calcium Channels ........................................ 229
Chloride Channels ....................................... 230
Aquporins ............................................... 231
Gap Junctions ........................................... 231
Ligand-Gated and Transmitter-Gated Ion Channels ......... 231
Structure and Function of Ion Channels ..................... 232
Molecular Structure of Ion Channels ..................... 232
Physiology of Ion Channels .............................. 233
Role of Ion Channels in the Nervous System .............. 233
Genomics and Ion Channels .................................. 234
Role of Ion Channels in Pathophysiology of Neurologic
Disorders .................................................. 235
Inherited Neurologic Channelopathies .................... 235
Acquired or Secondary Neurologic Channelopathies ........ 236
Pathomechanism of Disease Due to Mutated Proteins ....... 238
Channelopathies According to Channel Involved .............. 239
Potassium Channelopathies ............................... 239
Calcium Channelopathies ................................. 240
Sodium Channelopathies .................................. 240
Chloride Channelopathies ................................ 241
Ion Channels and Pain ...................................... 241
Role of Ion Channels in Pathomechanism of Pain .......... 241
Ion Channels as Targets for Pain Therapeutics ........... 241
Role of Ion Channels in Management of Neurologic
Disorders .................................................. 242
Role of Ion Channels in Clinical Neuropharmacology ...... 242
Concluding Remarks and Future Prospects .................... 245
References ................................................. 246
8 Role of Nitric Oxide in Neurological Disorders ............. 249
Introduction ............................................... 249
Role of NO in the Nervous System ........................... 250
Neurovascular Coupling of COX-2 and nNOS ................ 251
Neuroglobin ............................................. 251
Acute Actions of NO in the CNS Pathways ................. 252
Role of NO in Memory and Learning ....................... 252
Role of NO in Synaptic Plasticity ....................... 253
Role of NO in the Peripheral Nervous System ............. 253
NO and Neuroendocrine Function .......................... 253
NO-Based Therapies for Neurological Disorders .............. 254
Role of NO in Neurodegenerative Disorders .................. 254
NO-induced Mitochondrial Dysfunction in
Neurodegeneration ....................................... 254
White Matter Disorders .................................. 255
Alzheimer's Disease ..................................... 256
Role of NO in Pathophysiology of AD ..................... 256
Role of ApoE Genotype ................................... 257
NO-based Therapies for AD ............................... 259
Parkinson Disease ....................................... 260
Potential of NO-based Therapies for PD .................. 262
NO and Amyotrophic Lateral Sclerosis .................... 262
Stroke ..................................................... 263
Pathophysiology of Cerebral Ischemia ....................... 263
Role of NO in Cerebral Ischemia ............................ 263
Basis of Use of NO-based Treatment in Cerebrovascular
Ischemia ................................................... 265
Use of NO Donors in Cerebral Ischemia ...................... 266
Use of NO Donors in Cerebral Reperfusion Injury ............ 267
Attenuation of NO for Neuroprotection in Cerebral
Ischemia ................................................... 267
Role of NO in Neuroprotection in Cerebral Ischemia ......... 268
eNOS Gene Polymorphisms as Predictor of Cerebral
Aneurysm Rupture ........................................... 268
Role of NO in Assessment of Cerebral and Retinal Blood
Flow .................................................... 269
Stroke and Heart Disease ................................ 269
Cerebral Vasospasm and NO ............................... 269
NOS Gene Therapy for Cerebral Vasospasm ................. 270
NO and Traumatic Brain Injury .............................. 271
Role of NO in Pathophysiology of TBI .................... 272
Role of NO in the Treatment of Traumatic Brain Injury ... 273
NO and Epilepsy ............................................ 273
Role of NO in Peripheral Neuropathy ..................... 274
iNOS Induction in Experimental Allergic Neuritis ........ 274
Role of NO in Sciatica ..................................... 275
Neuroinflammatory Disorders ................................ 275
NO and Muscular Dystrophy ............................... 276
Basis for the Use of NO in Muscular Dystrophies ......... 276
NO and Duchenne Muscular Dystrophy ...................... 276
NO and Vestibulotoxicity ................................... 277
NO and Blood-Brain Barrier ................................. 277
Role of NO in the BBB ................................... 277
NO for Opening the BBB .................................. 278
Role of NO in Pain ......................................... 278
NO-Based Therapies for Pain ............................. 278
Treatment of Diabetic Neuropathy with Isosorbide
Dinitrate Spray ......................................... 279
NO-Based Therapies for Migraine ......................... 279
Concluding Remarks ......................................... 280
References ................................................. 280
9 Nanoneurology .............................................. 283
Introduction ............................................... 283
Nanobiotechnology for Neurophysiological Studies ........... 283
Use of Nanoelectrodes in Neurophysiology ................ 283
Gold Nanoparticles for In Vivo Study of Neural
Function ................................................ 284
Nanodiagnosis and Nanoparticle-Based Brain Imaging ......... 284
Applications of Nanotechnology in Molecular Imaging
of the Brain ............................................ 284
Nanoparticles and MRI for Macrophage Tracking in the
CNS ..................................................... 285
Nanoparticles for Tracking Stem Cells for Therapy
of CNS Disorders ........................................ 286
Multifunctional NPs for Diagnosis and Treatment
of Brain Disorders ...................................... 287
Nanotechnology-Based Drug Delivery to the CNS .............. 287
Nanoencapsulation for Delivery of Vitamin E for CNS
Disorders ............................................... 287
Nanoparticle Technology for Drug Delivery Across BBB .... 288
Nanobiotechnology and Neuroprotection ...................... 289
Nanotechnology-Based Devices and Implants for CNS .......... 290
Nanowire Neuroprosthetics with Functional Membrane
Proteins ................................................ 291
Nanotube-Neuron Electronic Interface .................... 291
Nanobiotechnology-Based Devices for Restoration
of Neural Function ...................................... 292
Concluding Remarks and Future Prospects of Nanoneurology ... 292
References ................................................. 293
10 Neurotrophic Factors ....................................... 295
Introduction ............................................... 295
Historical Aspects of Neurotrophic Factors .............. 295
Classification of Neurotrophic Factors .................. 295
Description of Neurotrophic Factors ........................ 295
Neurotrophin Family ..................................... 295
Neurotrophic Factor Receptors ........................... 305
Axonal Transport of Nerve Growth Factors ................ 306
Role of Neurotrophic Factors in Neuronal Development,
Maturation, and Survival ................................ 306
Role of Neurocytokines and Neurotrophic Factors
in Cell Signaling ....................................... 308
Hedgehog Family of Inducing Proteins .................... 310
Proteins Involved in Neuromuscular Development .......... 311
Neuroimmunophilins ...................................... 311
Role of Neurotrophic Factors in Action of
Antidepressants ......................................... 312
Role of Neurotrophic Factors in Brain Inflammation ...... 312
Effect of Exercise on Serum Neurotrophic Factors ........ 313
Methods of Delivery of Neurotrophic Factors ................ 313
Clinical Applications of NTFs .............................. 314
Neurotrophic Factors as Neuroprotective Agents .......... 315
Neurotrophic Factors and Oxidative Stress ............... 317
Neurotrophic Factors for Seizures ....................... 317
NTFs for Neurodegenerative Disorders ....................... 317
Scientific Basis of Effect of NTFs in
Neurodegenerative Disorders ............................. 317
Alzheimer Disease ....................................... 318
Parkinson Disease ....................................... 320
Amyotrophic Lateral Sclerosis ........................... 323
Huntington Disease ...................................... 325
NTFs for Treatment of Stroke ............................ 326
Molecular Mechanisms in Ischemic Stroke ................. 327
Role of Neurotrophic Factors in Central Nervous System
Injury .................................................. 328
Changes in Neurotrophic Factor Associated with
Cerebral Ischemia ....................................... 328
Potential Role of Neurotrophic Factors in the Treatment
of Cerebral Ischemia .................................... 329
Method of Administration of Neurotrophic Factors
for Cerebral Ischemia ................................... 332
Use of Neurotrophic Factors as Neuroprotective Agents ...... 332
Other Agents Mimicking Neurotrophic Factors ................ 333
Role of NTFs in Action of Stem Cell Therapy
for Cerebral Ischemia ................................... 333
oncluding Remarks About Use of NTFs in Stroke ........... 334
Role of NTFs in Traumatic Injuries to the Nervous
System ..................................................... 334
Traumatic Brain Injury .................................. 335
Spinal Cord Injury ...................................... 338
Peripheral Nerve Injuries ............................... 342
Treatment of Peripheral Neuropathies with NTFs ............. 344
Diabetic Neuropathy ..................................... 345
Antineoplastic Agents-Induced Neuropathy ................ 349
Motor Neuropathies ...................................... 350
Neurotrophic Factors and Neuropathic Pain ............... 350
Delivery of NTFs for Peripheral Neuropathies ............ 351
Contraindications for Use of NTFs in Peripheral
Neuropathies ............................................ 351
Future Prospects of NTFs for the Treatment
of Peripheral Neuropathies ................................. 352
Adverse Effects of NTFs .................................... 352
Concluding Remarks and Future Prospects .................... 353
References ................................................. 354
11 Cell Therapy of Neurological Disorders ..................... 361
Introduction ............................................... 361
Historical Landmarks in Cell Therapy of Neurological
Disorders .................................................. 362
Rationale of Cell Therapy for Neurologic Disorders ......... 362
Sources of Cells ........................................... 362
Types of Cells that Are Used for Cell Implantation for
in CNS .................................................. 364
Stem Cell Transplantation ............................... 365
Indications for Cell Therapy of Neurological Disorders .. 366
Cell Therapy of Neurodegenerative Disorders ................ 367
Cell Therapy of Amyotrophic Lateral Sclerosis ........... 367
Cell Therapy for Parkinson Disease ...................... 368
Cell Therapy for Huntington Disease ..................... 368
Cell Therapy for Alzheimer Disease ...................... 370
Cell Transplants for Demyelinating Disorders ............... 370
Cell Therapy for Stroke .................................... 371
Cell Therapy of Epilepsy ................................... 372
Management of Chronic Intractable Pain by Cell Therapy ..... 373
Implantation of Chromaffin Cells ........................ 373
Role of Stem Cells in Management of Pain ................ 374
Implantation of Astrocytes Secreting Enkephalin ......... 374
Cells for Delivery of Antinociceptive Molecules ......... 374
Implantation of Genetically Engineered Cells ............ 375
Clinical Trials of Cell Therapy of Neurological Disorders .. 375
Adverse Effects of Cell Therapy ............................ 375
Future Prospects for Cell Therapy of CNS Disorders ......... 379
References ................................................. 380
12 Gene Therapy of Neurological Disorders ..................... 383
Introduction ............................................... 383
Historical Evolution of Gene Therapy ....................... 383
Indications ................................................ 385
Methods of Gene Therapy .................................... 385
Classification .......................................... 385
Techniques of Gene Therapy Relevant to the Nervous
System .................................................. 385
Viral Vectors for Gene Therapy .......................... 389
Nonviral Vectors for Gene Therapy ....................... 393
Ideal Vector for Gene Therapy of Neurologic Disorders ... 396
Promoters of Gene Transfer .............................. 396
RNA Trans-Splicing ...................................... 397
Antisense Therapy ....................................... 397
RNA Interference and Gene Therapy ....................... 398
Delivery of Genes to the CNS ............................... 398
Routes of Delivery of Genes to the CNS .................. 398
Introduction of Antisense Compounds into the CSF
Pathways ................................................ 400
Delivery of Gene Therapy to the Peripheral Nervous
System .................................................. 400
Cell-Mediated Gene Therapy .............................. 401
Targeted and Controlled Gene Therapy .................... 404
Monitoring of Gene Therapy .............................. 404
Applications of Gene Therapy in Neurological Disorders ..... 405
Gene therapy for Injuries to the Nervous System ......... 405
Gene Therapy of Neurodegenerative Disorders ................ 406
Vectors for Gene Therapy of Neurodegenerative
Disorders ............................................... 406
Gene Therapy for Parkinson Disease ......................... 406
Rationale of Gene Therapy for PD ........................ 407
Techniques of Gene Therapy for PD ....................... 408
Ex Vivo Gene Therapy of PD Using Genetically
Engineered Cells ........................................ 411
Prospects of Gene Therapy for PD ........................ 413
Clinical Trials of Gene Therapy for PD .................. 414
Gene Therapy for Alzheimer Disease ......................... 415
Rationale of Gene Therapy for AD ........................ 415
Methods of Gene Therapy in AD ........................... 416
Development of Gene Therapy for Huntington Disease ......... 417
Encapsulated Genetically Engineered Cellular Implants
for HD .................................................. 418
Viral Vector Mediated Administration of Neurotrophic
Factors for HD .......................................... 418
Antisense Therapy for HD ................................ 418
RNAi Therapy of HD ...................................... 419
Gene Therapy of Amyotrophic Lateral Sclerosis .............. 419
Gene Therapy of ALS Using Neurotrophic Factors .......... 419
Delivery of Gene Therapy for ALS ........................ 420
RNAi Therapy for ALS .................................... 421
Gene Therapy of Neurogenetic Disorders ..................... 421
Scientific Basis of Gene Therapy of Neurogenetic
Disorders ............................................... 421
Gene Therapy of Hereditary Metabolic Disorders .......... 422
Gene Therapy of Lysosomal Storage Disorders ............. 427
Limitations of the Gene Therapy of Neurogenetic
Disorders ............................................... 432
Gene Therapy During Pregnancy ........................... 432
Scientific Basis for Gene Therapy of Trinucleotide
Repeat Disorders ........................................ 433
Gene Therapy for Muscular Dystrophy ........................ 433
Scientific Basis of Gene Therapy for Muscular
Dystrophies ............................................. 434
Animal Models of Muscular Dystrophy ..................... 434
Conventional Gene Therapy of Muscular Dystrophy ......... 435
Types of Dystrophin Constructs .......................... 435
Alternative Approaches to Gene Therapy .................. 436
Cell-Based Gene Therapy for Muscular Dystrophy .......... 437
Nonviral Vectors for DMD ................................ 439
Viral Vectors for DMD ................................... 439
Routes Gene Delivery for Muscular Dystrophy ............. 441
Clinical Trials of Gene Therapy of Muscular
Dystrophies ............................................. 443
Concluding Remarks About Gene Therapy of Muscular
Dystrophy ............................................... 443
Gene Therapy of Cerebrovascular Disease .................... 444
Technologies for Gene Therapy of Cerebrovascular
Disease .................................................... 445
Gene Transfer to Cerebral Blood Vessels ................. 445
Gene Therapy for Cerebral Vasospasm ..................... 445
Gene Therapy for Cerebral Ischemia ...................... 445
Delivery of Gene Therapy for Stroke ..................... 447
Gene Therapy for Prevention of Stroke by Control of
Risk Factors ............................................ 450
Clinical Trials of Gene Therapy for Stroke .............. 451
Concluding Remarks and Future of Gene Therapy for
Stroke .................................................. 451
Gene Therapy of Glioblastoma Multiforme .................... 452
Viral Vector-Mediated Gene Therapy of GBM ............... 452
Oncolytic Viruses for Treatment of GBM .................. 455
Suicide Gene Therapy: HSV-Thymidine Kinase .............. 456
Nonviral Vectors for Gene Therapy of GBM ................ 457
Antiangiogenic Gene Therapy ............................. 458
Stem Cell Gene Therapy .................................. 458
Immunogene Therapy ...................................... 459
Suppression of Growth of GBM ............................ 460
Vaccines for GBM ........................................ 463
Nanobiotechnology for Improving Delivery of Gene
Therapy ................................................. 463
Concluding Remarks on Gene Therapy of GBM ............... 463
Combination of Gene Therapy with Other Anticancer
Strategies .............................................. 464
Overview of Clinical Trials of Gene Therapy ................ 465
Adverse Effects of Gene Therapy ............................ 465
Adverse Effects of Viral Vectors ........................ 465
Adenoviral Vectors ...................................... 466
Toxicity of Lipopolysaccharides ......................... 467
Measures to Improve Safety and Efficacy of Gene
Therapy ................................................. 467
Gene Therapy of Glioblastoma Multiforme .................... 468
References ................................................. 468
13 Role of Biotechnology in Drug Delivery to the Nervous
System ..................................................... 477
Introduction ............................................... 477
Historical Evolution of Drug Delivery for CNS Disorders .... 478
The Neurovascular Unit ..................................... 478
Passage of Substances Across the Blood-Brain Barrier ....... 480
Receptor-Mediated Peptide and Protein Transcytosis ...... 482
Molecular Biology of the BBB ............................ 482
Damage to BBB Manifested as Increased Permeability ...... 484
Strategies to Cross the BBB ............................. 486
Use of Nanobiotechnology for Therapeutic Delivery
Across the BBB .......................................... 496
Delivery of Cell Therapy to the Brain ...................... 496
Intravenous Delivery of Stem Cells ...................... 497
Intraarterial Delivery of Stem Cells .................... 497
Pharmacologically Active Microcarriers .................. 497
Targeted Delivery of Engineered Cells to Specific
Tissues via Circulation ................................. 498
Devices for Delivery of Cell Therapy .................... 499
Cell Encapsulation ...................................... 499
Encapsulated Cell Biodelivery ........................... 500
Therapeutic Applications of Encapsulated Cells in
Neurological Disorders .................................. 500
Implantation of Microencapulated Genetically Modified
Cells ................................................... 501
Ferrofluid Microcapsules for Tracking with MRI .......... 502
Delivery of Gene Therapy to the Brain ...................... 502
Clinical Applications of Biotechnology for CNS Drug
Delivery ................................................... 502
Introduction of Therapeutic Substances into the CSF ..... 503
Osmotic Opening of the Blood-Brain Barrier .............. 503
Intraarterial Administration of Therapeutic Substances
for CNS Disorders ....................................... 504
Drug Delivery to the Brain in PD ........................ 504
Drug Delivery to the Brain in AD ........................ 504
Drug Delivery in Epilepsy ............................... 505
Innovative Methods of Drug Delivery for Glioblastoma
Multiforme .............................................. 505
References ................................................. 509
14 Vaccines for Neurological Disorders ........................ 513
Introduction ............................................... 513
A Brief History of Vaccines ............................. 513
Application of Vaccines in Neurology ....................... 514
Scientific Basis of Vaccination ......................... 514
Indications for Vaccination ............................. 514
Construction of Vaccines ................................... 516
DNA Vaccines ............................................ 516
Delivery Systems and Adjuvants for Vaccines ............. 517
Vaccines for Infections .................................... 517
Lyme Disease Vaccine .................................... 517
Herpes Zoster Vaccine ................................... 517
Cytomegalovirus Vaccine ................................. 518
Japanese Encephalitis Vaccine ........................... 520
Tick-Borne Encephalitis Vaccine ......................... 520
Neuroprotective Vaccine in Neurodegenerative Disorders ..... 520
Alzheimer Disease Vaccine ............................... 521
Amyotrophic Lateral Sclerosis ........................... 521
Vaccines for Miscellaneous Neurological Disorders .......... 522
Multiple Sclerosis Vaccine .............................. 522
Vaccines for Addiction .................................. 522
Brain Tumor Vaccine ..................................... 523
Central Nervous System Trauma ........................... 523
Adverse Effects of Vaccines ................................ 524
Precautions in Use of Vaccines .......................... 525
References ................................................. 525
15 Biotechnology for Neuroprotection .......................... 529
Introduction ............................................... 529
Neuroprotection and Neuroregeneration ................... 529
Intrinsic Neuroprotective Factors ....................... 530
Neuroprotective Gene Expression ......................... 530
Neurotrophic Factors .................................... 532
Intrinsic Nonenzymatic Antioxidants ..................... 533
Activation of Transcription Factor Nrf2 ................. 533
Intrinsic Neuroprotective Proteins ...................... 534
Stem Cell Factor ........................................ 537
Role of the Immune System in Neuroprotection ............ 537
Induction of DNA Repair Enzymes for Neuroprotection ..... 538
Microtubule-Based Neuroprotective Response to Axonal
Injury .................................................. 539
Biotechnology-Based Neuroprotective Agents ................. 539
Concluding Remarks ......................................... 539
References ................................................. 542
16 Biotechnology in Neuroregeneration ......................... 545
Introduction ............................................... 545
Historical Aspects of Neuroregeneration ................. 545
Basic Aspects of Neuroregeneration ......................... 546
Neuroprotection and Neuroregeneration ................... 547
Intrinsic Factors that Influence Regeneration in the
CNS ..................................................... 547
Causes of Lack of regeneration in the CNS ............... 547
Role of Neurotrophic Factors in Neuronal Regeneration ... 549
Role of Synapses in CNS Regeneration .................... 550
Role of Neural Stem Cells in Regeneration ............... 550
Various Factors that Influence Plasticity in the CNS .... 551
Neurotrophic Factors and Cortical Plasticity ............ 551
Approaches to Regeneration and Repair of the CNS ........... 551
Bioharmaceutical Approaches to Facilitate Regeneration
of the CNS .............................................. 552
Role of Nanobiotechnology in Regeneration and Repair
Following CNS Trauma .................................... 554
Integrated Approaches to Repair and Regeneration of
CNS Disorders .............................................. 557
Repair Strategies for Demyelinating Diseases ............ 557
Spinal Cord Injury ...................................... 557
Traumatic Brain Injury .................................. 558
Stroke .................................................. 559
Concluding Remarks and Future Prospects .................... 559
References ................................................. 560
17 Role of Biotechnology in Neurosurgery ...................... 563
Introduction ............................................... 563
Neuroprotection and Neurosurgery ........................... 563
Neuroprotective Measures Prior to Surgery ............... 563
Cerebral Protection During Surgery of Brain Tumors ...... 565
Applications of Cell Therapy in Neurosurgery ............... 565
Biotechnology Approaches to Intervertebral Disc
Degeneration ............................................ 565
Cell Therapy for CNS Trauma ............................. 567
Applications of Nanobiotechnology in Neurosurgery .......... 568
Nanomaterials for Neural Implants ....................... 569
Mimimally Invasive Surgery Using Nanocatheters .......... 570
Femtolaser Neurosurgery ................................. 571
Nanoparticles as an Aid to Neurosurgery ................. 571
Quantum Dots for Molecular Imaging in Cerebrovascular
Disorders ............................................... 572
Nanorobots for Neurosurgery ............................. 572
Future Prospects of Applications of Biotechnology in
Neurosurgery ............................................... 573
References ................................................. 573
18 Personalized Neurology ..................................... 575
Introduction ............................................... 575
Role of Molecular Diagnostics in the Development
of Personalized Medicine ................................ 576
Integration of Diagnostics and Therapeutics ............. 577
Role of Biomarkers in Development of Personalized
Neurology ............................................... 577
Role of Systems Biology in Development of Personalized
Neurology ............................................... 578
Role of Sequencing in Development of Personalized
Medicine ................................................ 578
Synthetic Biology and Development of Personalized
Medicines ............................................... 579
Personalized Management of Alzheimer Disease ............... 580
Role of Molecular Diagnosis and Genomics in AD .......... 580
Guiding Therapy of AD ................................... 584
Assessment of Conventional Therapies for AD ............. 585
Assessment of New Therapies for AD ...................... 586
Personalized Management of Parkinson Disease ............... 587
Discovery of Subgroup-Selective Drug Targets in PD ...... 588
Personalized Management of Epilepsy ........................ 588
Choice of the Right AED ................................. 588
Pharmacogenetics of Epilepsy ............................ 589
Pharmacogenomics of Epilepsy ............................ 590
Drug Resistance in Epilepsy ............................. 591
Future Prospects for Management of Epilepsy ................ 592
Personalized Management of Migraine ..................... 593
Individualization of Use of Triptans for Migraine ....... 594
Personalized Treatment of Multiple Sclerosis ............ 594
Personalizing Mitoxantrone Therapy of MS ................ 596
Fusokine Method of Personalized Cell Therapy of MS ...... 596
MBP8298 ................................................. 597
Pharmacogenomics of IFN-Я Therapy in MS ................. 597
T Cell-Based Personalized Vaccine for MS ................ 598
Personalized Management of Brain Cancer .................... 599
Role of Genetics and Genomics of GBM
in Personalized Management .............................. 599
Prognosis of GBM Based on Its Genetic Landscape ......... 600
Combined Neuroimaging and DNA Microarray Analysis of
GBM ..................................................... 601
Multigene Predictor of Outcome in GBM ................... 601
Companion Diagnostic for Viral Gene Therapy of Brain
Cancer .................................................. 602
Biosimulation Approach to Personalizing Treatment of
GBM ..................................................... 602
Personalized Chemotherapy of GBM ........................ 602
Supratentorial Hemispheric Diffuse Low-Grade Gliomas .... 604
Personalized Therapy of Oligodendroglial Tumors (OTs) ... 605
Personalized Therapy of Medulloblastomas ................ 606
Personalized Management of Germ Cell Brain Tumors ....... 607
Personalized Treatment of Miscellaneous Neurological
Disorders .................................................. 607
Personalized Management of Stroke ....................... 607
Narcolepsy .............................................. 608
Chronic Fatigue Syndrome ................................ 608
Concluding Remarks and Future Prospects .................... 608
References ................................................. 609
Index ......................................................... 613
|
