Handbook of Innovations in CNS Regenerative Medicine

Handbook of Innovations in Central Nervous System Regenerative Medicine
Copyright
Contents
List of Contributors
Preface
1 Insights on nervous system biology and anatomy
	1.1 Introduction
	1.2 Development of the vertebrate nervous system
		1.2.1 Development of the trilaminar embryo
		1.2.2 Neural induction
		1.2.3 Neurulation
		1.2.4 Development of brain vesicles
	1.3 General organization of the nervous system
		1.3.1 Spinal cord
		1.3.2 Brain
			1.3.2.1 Brainstem
			1.3.2.2 Cerebellum
			1.3.2.3 Diencephalon
			1.3.2.4 Basal ganglia
			1.3.2.5 Cortex
				1.3.2.5.1 Neocortex
				1.3.2.5.2 Hippocampal formation
				1.3.2.5.3 Olfactory cortex
				1.3.2.5.4 Amygdala
		1.3.3 Meninges and the ventricular system
			1.3.3.1 Meninges
			1.3.3.2 Ventricular system
	1.4 Cells of the nervous system
		1.4.1 Neurons
		1.4.2 Glial cells
			1.4.2.1 Oligodendrocytes and Schwann cells
			1.4.2.2 Astrocytes
			1.4.2.3 Microglia
		1.4.3 Ependymal cells
	1.5 Technical approaches to study the nervous system
	1.6 Conclusions
	References
2 Overview of Alzheimer's and Parkinson's diseases and the role of protein aggregation in these neurodegenerative diseases
	2.1 Alzheimer’s disease
	2.2 Prevalence of Alzheimer’s disease
	2.3 Diagnosis of Alzheimer’s disease
	2.4 Neurodegeneration and neurobiology of Alzheimer’s disease
	2.5 Progression of amyloid deposition throughout the brain
	2.6 Genetic influences
	2.7 The amyloid cascade hypothesis
	2.8 Parkinson’s disease
	2.9 Prevalence of Parkinson’s disease
	2.10 Diagnosis of Parkinson’s disease
	2.11 Neurodegeneration and neurobiology of Parkinson’s disease
	2.12 Progression of α-synuclein deposition throughout the brain
	2.13 Genetic and environmental causes
	2.14 Common cellular mechanisms in neurodegenerative diseases
	2.15 Conclusions
	2.16 Acknowledgments
	References
3 Introduction to trauma in the central nervous system
	3.1 Introduction
	3.2 The current landscape of central nervous system trauma
	3.3 Stages of central nervous system injury
		3.3.1 Primary injury
		3.3.2 Secondary injury: an overview of acute, subacute, and chronic phases
	3.4 Traumatic spinal cord injury pathophysiology
		3.4.1 Acute injury
			3.4.1.1 Patterns of injury
			3.4.1.2 Hypotension and ischemia
			3.4.1.3 Spinal shock
			3.4.1.4 Glutamate excitotoxicity and ion imbalance
			3.4.1.5 Free radical formation and oxidative stress
			3.4.1.6 Inflammation and angiogenesis
			3.4.1.7 Edema
		3.4.2 Subacute injury
			3.4.2.1 Cellular apoptosis
			3.4.2.2 Neurite growth-inhibitory factors
			3.4.2.3 Endogenous stem cell response
			3.4.2.4 Glial scar formation
		3.4.3 Chronic injury
			3.4.3.1 Altered neural circuitry
			3.4.3.2 Syrinx formation
	3.5 Traumatic brain injury
		3.5.1 Classification
		3.5.2 Cerebral perfusion and ischemia
		3.5.3 Excitotoxicity and oxidative stress
		3.5.4 Inflammation
		3.5.5 Long-term sequelae
	3.6 Guidelines for the management of neurotrauma
	3.7 Conclusion
	Acknowledgments
	References
4 Current clinical approaches in neurodegenerative diseases
	4.1 Alzheimer’s disease and Parkinson’s disease in a clinical context
		4.1.1 Epidemiology of Parkinson’s disease
		4.1.2 Epidemiology of Alzheimer’s disease
		4.1.3 Clinical diagnosis and the natural history of Parkinson’s disease
		4.1.4 Clinical diagnosis and the natural history of Alzheimer’s disease
		4.1.5 Neuropathology and etiopathogenesis of Parkinson’s disease
		4.1.6 Neuropathology and etiopathogenesis of Alzheimer’s disease
		4.1.7 Genetics of Parkinson’s disease
		4.1.8 Genetics of Alzheimer’s disease
	4.2 Current pharmacotherapies used in Alzheimer’s and Parkinson’s diseases
		4.2.1 Current therapeutics in Parkinson’s disease
		4.2.2 Current therapeutics in Alzheimer’s disease
	4.3 Pitfalls of the clinical trials
		4.3.1 Pitfalls in Parkinson’s disease
			4.3.1.1 Dopaminergic targets
			4.3.1.2 Nondopaminergic targets
			4.3.1.3 Other failed therapies in Parkinson’s disease
		4.3.2 Pitfalls in Alzheimer’s disease
			4.3.2.1 Therapies targeted at amyloid
			4.3.2.2 Reducing Aβ generation
			4.3.2.3 Accelerating Aβ clearance
	4.4 New drugs currently being developed
		4.4.1 New drugs in Parkinson’s disease
			4.4.1.1 Cellular therapies
			4.4.1.2 Gene therapy
			4.4.1.3 Iron-targeting agents
			4.4.1.4 α-Synuclein active immunotherapy
			4.4.1.5 LRRK2 inhibition
			4.4.1.6 Incrementing the lysosomal system
		4.4.2 New drugs in Alzheimer’s disease
			4.4.2.1 Therapies targeted at tau
			4.4.2.2 Tau stabilizers and aggregation inhibitors
			4.4.2.3 Therapies targeted at tau posttranslational modifications
			4.4.2.4 Anti-tau immunotherapy
			4.4.2.5 Therapies targeted at ApoE
			4.4.2.6 Neurotrophic factors
			4.4.2.7 Neuroinflammation and oxidative stress
	4.5 Conclusion and future challenges
	References
5 Neuroprotection in the injured spinal cord
	5.1 Spinal cord injury in a clinical context
		5.1.1 Current spinal cord injury clinical management
	5.2 Behind spinal cord injury
		5.2.1 Permeability and vascular alterations
		5.2.2 Metabolic alterations
		5.2.3 Ionic disruption and excitotoxicity
		5.2.4 Inflammatory response
		5.2.5 Spinal cord scarring
	5.3 Current neuroprotective therapies in spinal cord injury
		5.3.1 Nimodipine
		5.3.2 Glibenclamide (glyburide, DiaBeta)
		5.3.3 Progesterone
		5.3.4 Estrogen
		5.3.5 Magnesium
		5.3.6 Sygen (GM1)
		5.3.7 Riluzole
		5.3.8 Minocycline
		5.3.9 IL-4 cytokine
		5.3.10 Erythropoietin
		5.3.11 Ibuprofen
		5.3.12 Atorvastatin
		5.3.13 Hypothermia
	5.6 Final remarks
	References
6 The therapeutic potential of exogenous adult stem cells for the injured central nervous system
	6.1 Introduction
	6.2 Adult stem cells and their sources
		6.2.1 Neural stem cells
		6.2.2 Mesenchymal stem/stromal cells
		6.2.3 Induced pluripotent stem cells
		6.2.4 Directly induced neural stem cells
	6.3 Differentiation along neural lineages
		6.3.1 Chemical differentiation
		6.3.2 RNAi-mediated differentiation
		6.3.3 Genetic reprogramming
		6.3.4 Mechanical differentiation
	6.4 Challenges in expansion and transplantation
		6.4.1 Stability under long-term passaging
		6.4.2 Immunogenicity
		6.4.3 Timing
		6.4.4 Administration routes
		6.4.5 Complementary methods
	6.5 Adult stem cells in preclinical models of central nervous system diseases
		6.5.1 Spinal cord injury
		6.5.2 Traumatic brain injury
		6.5.3 Stroke
		6.5.4 Multiple sclerosis
		6.5.5 Amyotrophic lateral sclerosis
		6.5.6 Parkinson’s disease
		6.5.7 Alzheimer’s disease
		6.5.8 Retinal degenerative diseases
		6.5.9 Huntington’s disease
	6.6 Clinical trials of adult stem cells in the central nervous system
		6.6.1 Spinal cord injury
		6.6.2 Traumatic brain injury
		6.6.3 Stroke
		6.6.4 Multiple sclerosis
		6.6.5 Amyotrophic lateral sclerosis
		6.6.6 Parkinson’s disease
		6.6.7 Alzheimer’s disease
		6.6.8 Retinal degenerative diseases
		6.6.9 Huntington’s disease
	6.7 Conclusions
	6.8 Acknowledgements
	References
7 Biomaterial-based systems as biomimetic agents in the repair of the central nervous system
	7.1 Introduction
	7.2 Considerations on the pathology of spinal cord trauma
		7.2.1 The lesion site: cavitation, connective tissue scarring, and Schwannosis
		7.2.2 Beyond the lesion site: Wallerian degeneration and synaptic remodeling
	7.3 Positioning biomaterials for central nervous system regenerative medicine
	7.4 Biofunctionalized electroconducting microfibers as biomimetic agents in central nervous system repair
	7.5 Central nervous system regeneration: decomposing the needs to recompose the strategy
		7.5.1 Crossing the gap versus closing the gap
		7.5.2 Promoting axonal growth and synaptic reconnection beyond the lesion site
	7.6 Translational research on biomaterials for central nervous system repair
	7.7 Acknowledgments
	References
8 Tissue engineering and regenerative medicine in spinal cord injury repair
	8.1 Introduction
		8.1.1 Pathophysiology of spinal cord injury
	8.2 Experimental models of spinal cord injury: methodology, advantages, disadvantages, and behavioral testing
		8.2.1 Animal models of spinal cord injury
		8.2.2 Behavioral testing of the animal spinal cord injury
			8.2.2.1 Locomotor tests
			8.2.2.2 Sensory tests
			8.2.2.3 Sensory-motor tests
			8.2.2.4 Autonomic tests
			8.2.2.5 Training of the animals
	8.3 Treatment strategies
		8.3.1 Axon growth in spinal cord injury
	8.4 Cell therapy: overview, comparison of various types of stem cells, methods of application
		8.4.1 Mesenchymal stem cells
		8.4.2 Neural stem and progenitor cells
		8.4.3 Oligodendrocyte precursor cells
		8.4.4 Schwann cells
		8.4.5 Olfactory ensheathing cells
		8.4.6 Cell transplantation route
	8.5 Antioxidant treatment
		8.5.1 Epigallocatechin-3-gallate
		8.5.2 Curcumin
	8.6 Biomaterials in spinal cord injury
		8.6.1 Synthetic scaffolds for spinal cord injury
		8.6.2 Natural scaffolds
		8.6.3 Biomaterials in clinical applications
		8.6.4 Combinatory therapies
	8.7 Low-level laser therapy
	8.8 Future perspectives
	8.9 Acknowledgements
	8.10 Contribution
	References
9 Toward the therapeutic application of small interfering RNA bioconjugates in the central nervous system
	9.1 Considerations on therapeutic drug delivery for neurological disorders
	9.2 Small interfering RNA
	9.3 Barriers for siRNA delivery
	9.4 Chemical modifications
	9.5 Ribose modifications
		9.5.1 Backbone modifications
	9.6 Structural modifications
	9.7 Bioconjugates
		9.7.1 Lipids
		9.7.2 Cell-penetrating peptides and polymers
		9.7.3 Receptor-ligand conjugates
		9.7.4 Antibodies
		9.7.5 Aptamers
	9.8 Dynamic polyconjugates
	9.9 Other delivery systems: nanocarriers
	9.10 Future perspectives
	Acknowledgements
	References
10 Gene therapy approaches in central nervous system regenerative medicine
	10.1 Gene therapy
	10.2 Gene therapy vectors
		10.2.1 Adenovirus
		10.2.2 Retrovirus
		10.2.3 Lentivirus
		10.2.4 Adenoassociated virus
		10.2.5 Herpes simplex virus
		10.2.6 Nonviral vectors
	10.3 Gene therapy for nervous system
		10.3.1 Gene therapy vectors for central nervous system
		10.3.2 Gene therapy clinical assays for neurodegenerative diseases
		10.3.3 Gene therapy approaches for spinal cord injury
		10.3.4 Gene therapy approaches for traumatic brain injury
	References
11 Gene editing and central nervous system regeneration
	11.1 Introduction
	11.2 Targeted nucleases for efficient genome editing
	11.3 Nuclease-mediated alterations: resolving double-strand breaks
	11.4 CRISPR-Cas9 technology
		11.4.1 From the natural bacterial system to the engineered nuclease
		11.4.2 Dealing with challenges: Cas9 variants and orthologs
		11.4.3 CRISPR-Cas9 as means for therapeutic genome editing: evidence in brain disorders
		11.4.4 Generation of cellular and animal models for brain disorders
		11.4.5 Employing CRISPR-Cas beyond genome editing: gene expression regulation in neurological disorders
		11.4.6 Clinical translation
	Acknowledgment
	References
12 Molecular therapeutic strategies in neurodegenerative diseases and injury
	12.1 Introduction
	12.2 Spinal cord injury
		12.2.1 Neurotrophins and growth factors
		12.2.2 Inflammation
		12.2.3 Promoting axonal growth
		12.2.4 Modulation of excitotoxicity
		12.2.5 Future directions
	12.3 Traumatic brain injury
		12.3.1 Growth factors
		12.3.2 Modulation of free radicals
		12.3.3 Inflammation
		12.3.4 Excitotoxicity
		12.3.5 Mir-23b, apolipoprotein-E, and Nav1.3 in the preclinical setting
		12.3.6 Future directions
	12.4 Amyotrophic lateral sclerosis
		12.4.1 Excitotoxicity
		12.4.2 Neuroprotective and neurotrophic approaches
		12.4.3 Antisense-oligonucleotides and RNA interference
		12.4.4 Mitochondrial dysfunction and oxidative stress
		12.4.5 Neuroinflammation
		12.4.6 Aggregation
		12.4.7 Future directions
	12.5 Multiple sclerosis
		12.5.1 Strategies modulating B-lymphocytes
		12.5.2 Strategies promoting remyelination
		12.5.3 Modulation of T cell response
		12.5.4 Modulation of natural killer cells and dendritic cells
		12.5.5 Tyrosine-kinase inhibitors
		12.5.6 Future directions
	12.6 Alzheimer’s disease
		12.6.1 AchE inhibition
		12.6.2 BACE-1
		12.6.3 GSK-3B
		12.6.4 MAOs
		12.6.5 Metal ions
		12.6.6 NMDA receptor
		12.6.7 5-HT receptors
		12.6.8 Phosphodiesterases
		12.6.9 Antiaggregation
		12.6.10 Angiotensin system in Alzheimer’s disease
		12.6.11 Antiviral therapy in Alzheimer’s disease
		12.6.12 Antibody therapy
		12.6.13 Flavonoids
		12.6.14 Future directions
	12.7 Parkinson’s disease
		12.7.1 Nucleic acid therapeutics targeting alpha-synuclein
		12.7.2 Targeted small molecule inhibitors
		12.7.3 Iron chelators
		12.7.4 GLP-1 receptor agonists
		12.7.5 Viral vector mediated gene therapy
		12.7.6 Immunotherapy therapy using vaccines or antibodies against alpha-synuclein
		12.7.7 Dihydropyridine calcium channel blockers
		12.7.8 Substrate reduction therapies: chaperone-mediated autophagy
		12.7.9 Future directions
	References
13 Spinal cord stimulation for the recovery of function following spinal cord injury
	13.1 Introduction
	13.2 A brief history into electricity induced neuromodulation
	13.3 Modulation of spinal circuits
		13.3.1 Stimulation site and parameters
		13.3.2 Functional electrical stimulation: don’t be confused
	13.4 Neuromodulation of motor circuits
		13.4.1 Locomotor function through epidural stimulation
			13.4.1.1 Animal models
			13.4.1.2 Human studies
		13.4.2 Control of arms and hands
		13.4.3 Other developments in neuromodulation of motor control
		13.4.4 Autonomic modulation through spinal cord stimulation
		13.4.5 Recovery of bladder function
		13.4.6 Modulation of breathing
		13.4.7 Animal models of spinal cord stimulation
	13.5 Conclusion
	Acknowledgements
	References
14 Electroceutical therapies for injuries of the nervous system
	14.1 Introduction
	14.2 Effects of electrical fields on neural growth in vitro
	14.3 Electrical stimulation for peripheral nerve injuries and regeneration
	14.4 Electrical stimulation in spinal cord injuries
		14.4.1 Electrical stimulation improves axonal regeneration in the spinal cord
		14.4.2 Spinal cord neuromodulation
			14.4.2.1 Intraspinal stimulation
			14.4.2.2 Epidural spinal stimulation
			14.4.2.3 Transcutaneous spinal stimulation
			14.4.2.4 Mechanisms of action
	14.5 Electrical stimulation in brain injuries
		14.5.1 Electrical stimulation for stroke
		14.5.2 Techniques for noninvasive brain stimulation
		14.5.3 Effects of noninvasive brain stimulation on brain ischemic injury
	References
15 Role of mesenchymal stem cells in central nervous system regenerative medicine: past, present, and future
	15.1 Mesenchymal stem cells: origins
	15.2 The paradigm shift: from differentiation to secretome
	15.3 In vivo veritas
		15.3.1 Spinal cord injury
		15.3.2 Parkinson’s disease
	15.4 What lies ahead
		15.4.1 Secretome-based approaches
		15.4.2 Modulation of mesenchymal stem cells secretome profile
		15.4.3 New sources for mesenchymal stem cells
	15.5 Conclusion
	Acknowledgments
	References
16 Three-dimensional culture systems in central nervous system research
	16.1 Introduction
		16.1.1 Traditional methods of central nervous system culture
		16.1.2 Shifting to three-dimensional systems
		16.1.3 Introduction to three-dimensional systems used in central nervous system research
	16.2 Organoids
		16.2.1 Definition of organoids
		16.2.2 Development of organoids
		16.2.3 Disease-specific organoid models
		16.2.4 Strengths and limitations of organoids
	16.3 Spheroid systems
		16.3.1 Definition of spheroids
		16.3.2 Development of spheroids
		16.3.3 Disease-specific spheroid models
		16.3.4 Strengths and limitations of spheroids
	16.4 Scaffold-based models
		16.4.1 Hydrogels
			16.4.1.1 Natural hydrogel scaffolds
				16.4.1.1.1 Collagen
				16.4.1.1.2 Matrigel
				16.4.1.1.3 Fibrin
			16.4.1.2 Hybrid hydrogel scaffolds
				16.4.1.2.1 Chitosan
				16.4.1.2.2 Synthetic peptide-based hydrogels
				16.4.1.2.3 Alginate
		16.4.2 Solid porous scaffolds
			16.4.2.1 Polystyrene
			16.4.2.2 Graphene
		16.4.3 Fibrous scaffolds
		16.4.4 Summary
	16.5 Challenges and future directions
		16.5.1 Key challenges of advanced central nervous system culture models
	16.6 Concluding remarks
	Acknowledgments
	References
17 Scaffolds for spinal cord injury repair: from proof of concept to first in-human studies and clinical trials
	17.1 Scaffold-based strategies to facilitate spinal cord injury repair
		17.1.1 Scaffolds combined with neurotrophic factor transplantation to facilitate spinal cord injury repair
		17.1.2 Transplantation of stem cells combined with scaffolds to facilitate spinal cord injury repair
	17.2 The mechanisms of motor function recovery in complete transected spinal cord injury animals
		17.2.1 Complete transected animal models for evaluating neural regeneration
		17.2.2 Mechanisms of motor function recovery in complete spinal cord injury animals
			17.2.2.1 Corticospinal tract regeneration for complete spinal cord injury repair
			17.2.2.2 Neuronal relay formation with transplanted or endogenous neural stem cells for complete spinal cord injury repair
	17.3 Clinical study of stem cells and scaffold transplantation for spinal cord injury repair
	17.4 Perspectives and challenges
	Acknowledgments
	References
18 Animal models of central nervous system disorders
	18.1 Introduction
		18.1.1 Caenorhabditis elegans as a model system of central nervous system disorders
		18.1.2 Caenorhabditis elegans as a model for spinal cord injury
		18.1.3 C. elegans as a model for Parkinson’s disease
			18.1.3.1 Chemical models
			18.1.3.2 Genetic models
	18.2 Naturally regenerating animal models
		18.2.1 Xenopus laevis
		18.2.2 Salamander
		18.2.3 Zebrafish
	18.3 Rodents as a model of central nervous system disorders
	18.4 Rodents as a model for spinal cord injury
		18.4.1 Types of injury in rodent models
	18.5 Rodents as a model for Parkinson’s disease
	Acknowledgments
	References
19 Bioethics in translation research and clinical trials
	19.1 Introduction
		19.1.1 Core ethical principles for guiding both basic and clinical (stem cell) research
		19.1.2 The need for regulations and ethical guidelines
		19.1.3 The need for prioritizing rigorous and safe clinical trials
	19.2 The role of research ethics committees
	19.3 Conclusion
	References
Index