Translational Neuroscience : Fundamental Approaches for Neurological Disorders

Contents
Editor Bio
Contributors
Chapter 1: Introduction
	Introduction
	References
Part I: Molecular Approaches
	Chapter 2: Gene Therapy of CNS Disorders Using Recombinant AAV Vectors
		Introduction
		Recombinant AAV Vectors
		Gene Therapy of CNS Disorders Arising from Metabolic Defects
		Gene Therapy of Movement Disorders
		Summary
		References
	Chapter 3: NGF and BDNF Gene Therapy for Alzheimer’s Disease
		Introduction
		Alzheimer’s Disease
			Background
			Symptoms and Neuropathology
		AD Gene Therapy
		NGF Gene Therapy for Alzheimer’s Disease
			Discovery and Effects of NGF
			NGF Gene Therapy: Phase I Ex Vivo Clinical Trial
			NGF Gene Therapy: Phase 1 and 2 In Vivo Clinical Trials
		BDNF Gene Therapy for Alzheimer’s Disease
			Rationale
			Preclinical Studies of BDNF Gene Therapy
			Improved Tools for Gene Delivery to the Brain: Real-Time Imaging and Convection Enhanced Delivery of AAV2-BDNF in AD
		Gene Therapy in AD: Delivery of Other Therapeutic Genes
			Gene Therapy and Amyloid Degradation
			RNA Interference in AD
			Other Gene Therapy in AD
		Future Gene Therapy for AD
		Summary
		References
	Chapter 4: GDNF and AADC Gene Therapy for Parkinson’s Disease
		Introduction
		AAV Delivery to the Putamen
		Axonal Transport
		Clinical Experience with AAV2-hAADC for PD
		Neurotrophin Gene Therapy
		Conclusion
		References
	Chapter 5: GAD Gene Therapy for Parkinson’s Disease
		Background
		Preclinical Data
		Phase I Study
		Phase II Study
		Summary
		References
	Chapter 6: Antisense Oligonucleotides for Amyotrophic Lateral Sclerosis
		SOD1
		C9ORF72
		miRNAs and ALS
		Pharmacodynamics Biomarkers for ASO in ALS
		Conclusion
		References
	Chapter 7: Gene Therapy for Inborn Errors of Metabolism: Batten Disease
		Introduction
		Identifying the Target Disease
		Developing the Gene Therapy Approach
		Vectors
		Delivery to the CNS
		Strategy for Preclinical Development
		Strategy for Second Generation Preclinical Development
		Translation to Clinic: Safety and Toxicology Studies
		Regulatory Hurdles and Strategies
		Clinical Strategy
		Safety Parameters
		Efficacy Parameters
		Assembling the Clinical Team
		Identifying Inclusion/Exclusion Criteria
		Funding for Clinical Translation
		Lessons Learned
		Summary
		References
	Chapter 8: Gene Therapy for Spinal Cord Injury
		Introduction
		Gene Delivery for Axonal Growth Using Ex Vivo Modified Cells
		In Vivo Gene Delivery to the Spinal Cord
		Temporal Regulation of Gene Expression
		Directional Growth of Axons and Target Innervation
		Activating the Intrinsic Regenerative Program by Gene Delivery
		Nonneuronal Targets for SCI Gene Therapy
		Conclusions
		References
	Chapter 9: Gene Therapy for Epilepsy
		Introduction
		Modulatory Neuroactive Peptides
		Neurotrophic Factors
		Adenosine
		Ion Channels
		DREADD Receptors
		Conclusion
		References
	Chapter 10: Translating Gene Therapy for Pain from Animal Studies to the Clinic
		Introduction
		Animal Studies of Gene Transfer for Pain
			DRG Transduction by Skin Inoculation
			Gene Transfer by Intrathecal or Intraneural Delivery
			Gene Delivery by Intraparenchymal Injection
		Translation to Clinical Trial
			General Considerations
			Preproenkephalin for Inflammatory Pain
			Characterization of the Vector
			Clinical Trials of the Enkephalin-Expressing Vector
			Clinical Trial of HSV-GAD in Neuropathic Pain
		Future Directions
		Concluding Thoughts
		References
Part II: Cellular Approaches
	Chapter 11: Stem Cells for Parkinson’s Disease
		Introduction
		History of Cell Therapy
		Fetal Nigral Transplants
		Stem Cell Differentiation of DA Neurons
		Current Approaches to Stem Cell Therapy
		Conclusions and Future Directions
		References
	Chapter 12: Could Stem Cells Be Used to Treat or Model Alzheimer’s Disease?
		Introduction
		AD Neuropathology and the Amyloid Cascade Hypothesis
		Properties and Sources of Neural Stem Cells
		Transplantation of Stem Cells for AD
			Cell Replacement
			Neurotrophic Mechanisms
			Delivery of Disease-Modifying Proteins
			Modulation of Neuroinflammation
		Unique Challenges to Clinical Translation
		Stem Cells Self-Renew
		The Challenges of Scale and Delivery
		Could Induced Pluripotent Stem Cells Be Used to Treat or Model AD?
		Transplantation of iPSC-Derived Cells
		Modeling AD with iPSCs
		Conclusions
		References
	Chapter 13: Stem Cells for Amyotrophic Lateral Sclerosis
		Introduction
			Stem Cell Types
			Autologous Versus Allogenic Transplantation
			Animal Models
		Neural Stem Cells
			Evidence from Animal Studies
			Clinical Trials of Neural Stem Cells
			The Future of Neural Stem Cells
		Mesenchymal Stem Cells
			Evidence from Animal Studies
			Differentiation and Survival
			Clinical Trials of MSCs
			The Future of MSC Therapy
		Bone Marrow Stem Cells
			Evidence from Animal Studies
			Clinical Trials of Bone Marrow Stem Cells
			The Future of Bone Marrow Stem Cells
		Olfactory Ensheathing Cells
			Evidence from Animal Studies
			Clinical Trials of Olfactory Ensheathing Cells
		Umbilical Cord Blood
		Closing Thoughts
		References
	Chapter 14: Stem Cells for Multiple Sclerosis
		Introduction
		“Classical” Stem Cell Therapy: Replacing Lost Oligodendrocytes for Myelin Repair (Fig. 14.1)
		Immune Reconstitution: Hematopoietic Stem Cell Therapy
		“Restorative” Cell Therapy
			Remyelination
			Suppressing Inflammation, Modulating Immunity
			Neuroprotection
			Cell Fusion
			Diffuse Damage
			Clinical Translation
		Conclusion
		References
	Chapter 15: Cell Therapy for Pediatric Disorders of Glia
		Cell Types for Cell Replacement
		Disease Targets for Glial Cell Therapy
		Approaches to Cell-Based Therapy
		Neural stem and Progenitor Cell-Based Treatment of Enzymatic Disorders
		Clinical Considerations in the Use of Cell Transplantation for Developmental Myelin Disorders
		Conclusion
		References
	Chapter 16: Neural Stem Cells for Spinal Cord Injury
		Introduction
		Isolation and Characteristics of Neural Stem Cells
			Neural Stem Cells Directly Isolated from the Developing Spinal Cord
			Embryonic Stem Cells Driven to Neural Stem Cells
			Induced Pluripotent Stem Cells Driven to Neural Stem Cells
			Direct Differentiation of Somatic Cells into Neural Stem Cells
		In Vivo Studies of Neural Stem Cell Therapy for Spinal Cord Injury
			Formation of Novel Synaptic Relays Across Sites of Injury
			Grafts of Human ESC- or iPSC-Derived NSCs to Sites of SCI
			Mechanistic Studies of Neural Stem Cell-Induced Axonal Growth
			The Path of Neural Stem Cell Translation to the Clinic
			Other Neural Stem Cell Approaches for SCI
		Future Perspectives
		References
	Chapter 17: Marrow-Derived Mesenchymal Stromal Cells in the Treatment of Stroke
		Stroke Is a Major Cause of Human Disability
		MSC Have Multiple Mechanisms of Action
		Issues Related to MSC Generation and Transport
		Preclinical Data
		Clinical Trials of MSC in Human Subjects with Stroke
		Principles of Brain Repair and MSC Therapy After Stroke
		Summary
		References
	Chapter 18: Glioma Stem Cells
		Introduction
		Cerebellar Neuron and Glia Development
		Cell of Origin in Glioma
		Stem Cell Hypotheses
		Characteristics of a Stem Cell
		Identification of CSCs
		CD133
		L1CAM and CD133+ Cells
		CD15
		CD44/Id1
		Nestin
		Integrin α6
		Musashi-1
		EphA2 and EphA3
		Embryonic Stem Cell Markers
		Therapeutic and Prognostic Implications from Stem Cell Markers
		CSC Radio and Chemotherapy Resistance
		Possible Treatment Options to Target Glioma Stem Cells
		Immunotherapy and Stem Cells
		Gene Therapy and Stem Cells
		Final Summary
		References
Part III: Novel Pharmacological Approaches
	Chapter 19: Discovery of Potent Gamma Secretase Modulators for the Treatment of Alzheimer’s Disease
		References
	Chapter 20: Blocking the Nogo-A Signaling Pathway to Promote Regeneration and Plasticity After Spinal Cord Injury and Stroke
		Introduction: Myelin Associated Neurite Growth Inhibitors—Focus on Nogo-A
			The Central Nervous System Is a Hostile Environment for Axonal Regeneration: History of Discovery
			The Neurite Growth Inhibitory Protein Nogo-A: Description of Nogo Signaling and Possible Pharmacological Interventions
			Physiological Functions of Nogo-A
		Regeneration and Plasticity after CNS Injury and in CNS Disease
			Stimulation of Regeneration by Upregulating Intrinsic Neuronal Growth Mechanisms
			Nogo-A Neutralization Improves Regeneration and Promotes Plasticity in Animal Models of Spinal Cord Injury and Stroke
			Suppression of the Nogo-A Pathway in Animal Models of Spinal Cord Injury
				Nogo-A Neutralization by Antibodies
				Blockade of Nogo-A Receptors and Signaling
			Suppression of Nogo-A Signaling in Animal Models of Stroke
				Nogo-A Neutralization by Antibodies
				Suppression of Nogo-A Receptor Activation and Signaling
			Nogo-A in Amyotrophic Lateral Sclerosis (ALS)
			Nogo-A in Multiple Sclerosis (MS)
		Preparing Translation: Preclinical Studies for Nogo-A Blocking Agents
		Interventions Blocking Nogo-A Signaling in Clinical Trials
			Spinal Cord Injury
			Ischemic Stroke
			Amyotrophic Lateral Sclerosis (ALS)
			Multiple Sclerosis (MS)
		Conclusions
		References
	Chapter 21: Intrinsic Neuronal Mechanisms in Axon Regeneration After Spinal Cord Injury
		Introduction
		Why Exploring the Intrinsic Mechanisms?
		Loss of Intrinsic Axon Growth Ability in Mammalian CNS Neurons
			Development-Dependent Mechanisms
				KLFs
				cAMP
				mTOR
			Injury-Induced Mechanisms
		“Preconditioning” Effect in Sensory Neurons
		Strategies that Enhancing the Intrinsic Axon Regenerative Ability
			“Rejuvenating” Adult CNS Neurons with Transcription Factors
			Reactivating Trophic Responses with Growth Factors and cAMP
			Modulating PTEN/mTOR Pathway
			Modulating SOCS3/STAT Pathway
			Triggering Axon Regeneration by Inflammation
		Perspectives
		References
	Chapter 22: Voltage-Gated Ion Channels as Molecular Targets for Pain
		Introduction
		Sodium Channels as Molecular Targets for Pain
			“Peripheral” Sodium Channels
			NaV1.7
			NaV1.8
			NaV1.9
			NaV1.3
		Voltage-Gated Calcium Channels
			N-type Calcium Channels
			T-type Calcium Channels
		Voltage-Gated Potassium Channels
		Horizons and Prospects
		References
	Part IV: Activity-Dependent Plasticity and Neurorehabilitation
	Chapter 23: Rehabilitation-Dependent Neural Plasticity After Spinal Cord Injury
		Neuronal Control of Normal and Impaired Locomotion
			Physiological Basis of Human Locomotion
			Gait Disorder Following Spinal Cord Injury
				Reflexes and Muscle Tone
				Biomechanical Muscle Transformations
				Therapeutic Approaches
		Recovery of Locomotor Function in Human SCI
			Neurological and Functional Recovery
			Therapeutic Approaches
			Contributors to Recovery
		Conclusion
		References
	Chapter 24: Neural Prostheses for Neurotrauma
		Introduction
			Delivery of Electrical Stimulation
			Properties of Pulse Trains
		Types of NPs
			Surface NPs That Enhance Gait
			Surface NPs That Enhance Upper Limb Function
			Therapeutic Carry-Over Effects
			Implanted NPs
			Implanted NPs That Enhance Gait
			Epidural and Intraspinal Stimulators
			Implanted NPs That Enhance Upper Limb Function
			NPs for Bladder Control
			NPs for Overactive Bladder
			NPs That Block Nerve Conduction to Reduce Spastic Hypertonus
		Concluding Remarks
		References
	Chapter 25: Why Is Functional Electrical Stimulation Therapy Capable of Restoring Motor Function Following Severe Injury to the Central Nervous System?
		Introduction
		Functional Electrical Stimulation
		Functional Electrical Stimulation Therapy
			FES Therapy for Lower Limb in Stroke
			FES Therapy for Lower Limb in SCI
			FET for Restoration of Upper Limb Function Following Stroke
			FES Therapy for Restoration of Upper Limb Function following SCI
			Our Contributions to FES Therapy
		Selected Processes in the Healthy Central Nervous System Pertinent to Neurorecovery following an Injury to the Central Nervous System
			Neuroplasticity and the Healthy Adult Brain
			The Healthy Neurological System and Exercise
			The Injured Neurological System, Neurogenesis, and Exercise
		The Injured Neurological System and Functional Electrical Stimulation Therapy
		Conclusion
		References
	Chapter 26: Deep Brain Stimulation for Neuropsychiatric Disorders
		Introduction
		Limbic System
		Obsessive-Compulsive Disorder
		Depression
		Addiction
		PTSD and Anxiety
		Anorexia Nervosa
		Conclusions
		References
	Chapter 27: Novel Interventions for Stroke: Nervous System Cooling
		Introduction
		Optimized Stroke Modeling Using Conventional Models
			Optimized Stroke Modeling with the Rodent Filament Model
			Optimized Stroke Modeling Advantages
		Therapeutic Hypothermia
		Conclusions
		References
	Chapter 28: Rehabilitation Strategies for Restorative Approaches After Stroke and Neurotrauma
		Substrates for Rehabilitation Strategies
		Neurorehabilitation Strategies
			Strengthening and Aerobic Fitness Exercise
			Task-Oriented Training
			Robotic-Assisted Upper Extremity Training
			Mobility Training
			Noninvasive Brain Stimulation
			Other CNS and PNS Stimulation Adjuncts
			Brain–Machine Interfaces
			Other Possibly Complementary Interventions
			Pharmacologic Agents
			Tele-rehabilitation
			Combinational Strategies
		Outcomes
		Conclusion
		References
	Chapter 29: Bridging the Chasm Between Scientific Discovery and a Pivotal Clinical Trial for a CNS Disorder: A Checklist
		Challenges Common to CNS Disorders
		Preclinical Validation Prior to Entering Human Study
		Good Laboratory Practice Reduces Experimental Bias
		Preclinical Therapeutic Development After Validation of Experimental Efficacy
		General Requirements for Clinical Trials and the Goals of Various Study Phases
		Establishing Clinical Trial Guidelines
		Consideration in Planning a Clinical Trial Program
			Protocol Concern #1: What Is the Most Appropriate Type of Participant to Enroll in Each Phase of a Trial Program?
			Protocol Concern #2: What Would Be the Most Accurate, Sensitive, and Reliable Outcome Measure for the Chosen Clinical Target?
			Protocol Concern #3: How Is a Clinical Endpoint Threshold Selected to Determine Whether the Therapeutic Provides a Meaningful Clinical Benefit to the Experimental Arm in Comparison to an Appropriate Control Group?
		Conclusions
		References
	Chapter 30: Conclusion