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Reportlinker Adds Drug Delivery in Central Nervous System Diseases - technologies,markets and companies

NEW YORK, Sept. 7 /PRNewswire/ -- announces that a new market research report is available in its catalogue:

Drug Delivery in Central Nervous System Diseases - technologies,markets and companies

SummaryThe delivery of drugs to central nervous system (CNS) is a challenge in the treatment of neurological disorders. Drugs may be administered directly into the CNS or administered systematically (e.g., by intravenous injection) for targeted action in the CNS. The major challenge to CNS drug delivery is the blood-brain barrier (BBB), which limits the access of drugs to the brain substance.

Advances in understanding of the cell biology of the BBB have opened new avenues and possibilities for improved drug delivery to the CNS. Several carrier or transport systems, enzymes, and receptors that control the penetration of molecules have been identified in the BBB endothelium. Receptor-mediated transcytosis can transport peptides and proteins across the BBB. Methods are available to assess the BBB permeability of drugs at the discovery stage to avoid development of drugs that fail to reach their target site of action in the CNS.

Various strategies that have been used for manipulating the blood-brain barrier for drug delivery to the brain include osmotic and chemical opening of the blood-brain barrier as well as the use of transport/carrier systems. Other strategies for drug delivery to the brain involve bypassing the BBB. Various pharmacological agents have been used to open the BBB and direct invasive methods can introduce therapeutic agents into the brain substance. It is important to consider not only the net delivery of the agent to the CNS, but also the ability of the agent to access the relevant target site within the CNS. Various routes of administration as well as conjugations of drugs, e.g., with liposomes and nanoparticles, are considered. Some routes of direct administration to the brain are non-invasive such as transnasal route whereas others involve entry into the CNS by devices and needles such as in case of intrathecal and intracerebroventricular delivery. Systemic therapy by oral and parenteral routes is considered along with sustained and controlled release to optimize the CNS action of drugs. Among the three main approaches to drug delivery to the CNS - systemic administration, injection into CSF pathways, and direct injection into the brain - the greatest developments is anticipated to occur in the area of targeted delivery by systemic administration.

Many of the new developments in the treatment of neurological disorders will be biological therapies and these will require innovative methods for delivery. Cell, gene and antisense therapies are not only innovative treatments for CNS disorders but also involve sophisticated delivery methods. RNA interference (RNAi) as a form of antisense therapy is also described.

The role of drug delivery is depicted in the background of various therapies for neurological diseases including drugs in development and the role of special delivery preparations. Pain is included as it is considered to be a neurological disorder. Cell and gene therapies will play an important role in the treatment of neurological disorders in the future.

The method of delivery of a drug to the CNS has an impact on the drug's commercial potential. The market for CNS drug delivery technologies is directly linked to the CNS drug market. Values are calculated for the total CNS market and the share of drug delivery technologies. Starting with the market values for the year 2009, projections are made to the years 2014 and 2019. The markets values are tabulated according to therapeutic areas, technologies and geographical areas. Unmet needs for further development in CNS drug delivery technologies are identified according to the important methods of delivery of therapeutic substances to the CNS. Finally suggestions are made for strategies to expand CNS delivery markets. Besides development of new products, these include application of innovative methods of delivery to older drugs to improve their action and extend their patent life.

Profiles of 71 companies involved in drug delivery for CNS disorders are presented along with their technologies, products and 69 collaborations. These include pharmaceutical companies that develop CNS drugs and biotechnology companies that provide technologies for drug delivery. A number of cell and gene therapy companies with products in development for CNS disorders are included. References contains over 400 publications that are cited in the report. The report is supplemented with 51 tables and 9 figures.

TABLE OF CONTENTS0.Executive Summary 15

1.Basics of Drug Delivery to the Central Nervous System 17

Introduction 17

Historical evolution of drug delivery for CNS disorders 17

Neuroanatomical and neurophysiological basis of drug delivery 18

The cerebrospinal fluid 18

The extracellular space in the brain 19

Neurotransmitters 19

Neuropharmacology relevant to drug delivery 21

Introduction to neuropharmacology 21

Pharmacokinetics 21

Absorption and distribution of drugs 21

Drug metabolism and elimination 22

Pharmacodynamics 22

Receptors 22

Sites of drug action in the CNS 22

Receptors coupled to guanine nucleotide binding proteins 23

Acetylcholine receptor channels 23

Dopamine receptors 23

GABA receptor channels 24

Glutamate receptor channels 24

Non-competitive NMDA antagonists 24

Serotonin receptors 25

G-protein coupled receptors 25

In vivo study of drug action in the CNS in human patients 25

Electroencephalography 25

Brain imaging 26

Chronopharmacology as applied to the CNS 26

2.Blood Brain Barrier 29

Introduction 29

Features of the blood-brain barrier relevant to CNS drug delivery 29

The neurovascular unit 29

Functions of the BBB 30

BBB as an anatomical as well as physiological barrier 30

BBB as a biochemical barrier 31

Genomics and proteomics of BBB 31

Other neural barriers 32

Blood-cerebrospinal fluid barrier 32

Blood nerve barrier 32

Blood-retinal barrier 32

Blood-labyrinth barrier 32

Passage of substances across the blood-brain barrier 33

Transporters localized in the BBB 33

Glucose transporter 34

Amino acid transporters 35

Ionic transporter 35

Efflux transport systems 35

BBB-specific enzymes 36

Receptor-mediated transcytosis 37

Lysophosphatidic acid-mediated increade in BBB permeability 37

Folate transport system 38

Molecular biology of the BBB 38

Transport of peptides and proteins across the BBB 38

Passage of leptin across the BBB 38

Passage of cytokines across the BBB 39

Passage of hormones across the BBB 39

Passage of enzymes across the BBB 40

Drugs that cross the BBB by binding to plasma proteins 40

Current concepts of the permeability of the BBB 40

Factors that increase the permeability of the BBB 41

BBB disruption as adverse effect of vaccines for CNS disorders 41

CNS disorders that affect the permeability of BBB 42

Neurodegenerative disorders 43

Mitochondrial encephalopathies 44

Multiple sclerosis 44

Central nervous system injuries 44

Epilepsy 45

Cerebrovascular disease 45

Infections 46

Autoimmune disorders 46

BBB and primary brain tumors 46

BBB and cerebral metastases 47

Testing permeability of the BBB 47

In vitro models of BBB 47

In vivo study of BBB 48

Brain imaging 48

In silico prediction of BBB 49

Relevance of the BBB penetration to pharmacological action 50

BBB penetration and CNS drug screening 51


Transthyretin monomer as a marker of blood-CSF barrier disruption 51

Evaluation of BBB permeability by brain imaging 51

Biomarkers of disruption of blood-brain barrier 52

Future directions for research on the BBB 52

Application of genomics and proteomics to the study of BBB 53

Use of neural stem cells to construct the blood brain barrier 53

Strategies to cross the BBB 54

3.Methods of Drug Delivery to the CNS 55

Introduction 55

Routes of drug delivery to the brain 56

Delivery of drugs to the brain via the nasal route 56

Nasal delivery of insulin-like growth factor-I 57

Nasal delivery of midazolam 57

Nasal delivery of hypocretin 58

Intranasal administration of IFN beta-1b 58

Nasal delivery of thyrotropin-releasing hormone by nanoconstructs 58

Nasal delivery of neuroprotective drugs for stroke 59

Transdermal drug delivery for neurological disorders 59

Drug delivery to the brain via inner ear 60

Invasive neurosurgical approaches 60

Intraarterial drug delivery to the brain 60

Direct injection into the CNS substance or CNS lesions 61

Intraventricular injection of drugs 61

Intrathecal drug delivery 62

Retrograde delivery to the brain via the epidural venous system 63

Devices for drug delivery to the CNS 63

Strategies for drug delivery to the CNS across the BBB 64

Increasing the permeability (opening) of the BBB 65

Osmotic opening of the BBB 65

Focal disruption of BBB by ultrasound 65

Chemical opening of the BBB 66

Cerebral vasodilatation to open the BBB 66

Use of nitric oxide donors to open the BBB 66

Manipulation of the sphingosine 1-phosphate receptor system 67

Pharmacological strategies to facilitate transport across the BBB 67

2B-Trans™ technology 67

ABC afflux transporters and penetration of the BBB 68

Carrier-mediated drug delivery across the BBB 68

G-Technology® 69

Glycosylation Independent Lysosomal Targeting 70

Inhibition of P-glycoprotein to enhance drug delivery across the BBB 70

Modification of the drug to enhance its lipid solubility 70

Monoclonal antibody fusion proteins 71

Neuroimmunophilins 72

Peptide-mediated transport across the BBB 72

Prodrug bioconversion strategies and their CNS selectivity 73

Role of the transferrin-receptor system in CNS drug delivery 74

Transport of small molecules across the BBB 74

Transport across the BBB by short chain oligoglycerolipids 74

Transvascular delivery across the BBB 75

Trojan horse approach 75

Use of receptor-mediated transocytosis to cross the BBB 76

Cell-based drug delivery to the CNS 77

Activated T lymphocytes 78

Microglial cells 78

Neural stem cells 78

Drug delivery to the CNS by using novel formulations 78

Crystalline formulations 78

Liposomes 79

Monoclonal antibodies 80

Microspheres 80

Microbeads 81

Brain-targeted chemical delivery systems 81

Nanotechnology-based drug delivery to CNS 82

Nanoparticles for drug delivery across the BBB 82

Penetration of BBB by nanoparticles coated with polysorbate 80 83

NanoDel? technology for crossing the BBB 83

Masking BBB-limiting characteristics by nanotechnology 83

Peptide-nanoparticle conjugates for crossing the BBB 84

Nanovesicles for transport across BBB 84

Nanotechnology-based devices and implants for CNS 84

Biochip implants for drug delivery to the CNS 85

Controlled-release microchip 85

Retinal implant chip 85

Convection-enhanced delivery to the CNS 86

Systemic administration of drugs for CNS effects 86

Sustained and controlled release drug delivery to the CNS 86

Fast dissolving oral selegiline 88

Choice of the route of systemic delivery for effect on the CNS disorders 88

Methods of delivery of biopharmaceuticals to the CNS 89

Delivery of biopharmaceuticals across the BBB 89

Methods of delivery of peptides for CNS disorders 89

Challenges for delivery of peptides across the BBB 90

Transnasal administration of neuropeptides 90

Direct delivery of neuropeptides into the brain 90

Alteration of properties of the BBB for delivery of peptides 91

Molecular manipulations of peptides to facilitate transport into CNS 91

CNS delivery of peptides via conjugation to biological carriers 92

Delivery of conopeptides to the brain 92

Delivery of neurotrophic factors to the nervous system 93

Systemic administration of NTFs 94

Delivery systems to facilitate crossing of the BBB by NTFs 95

Use of microspheres for delivery of neurotrophic factors 96

Intracerebroventricular injection 96

Direct application of NTFs to the CNS 97

Intrathecal administration 97

Implants for delivery of neurotrophic factors 97

Use of neurotrophic factor mimics 98

Use of microorganisms for therapeutic entry into the brain 99

Bacteriophages as CNS therapeutics 99

Intracellular drug delivery in the brain 100

Local factors in the brain affecting drug action 100

Methods for testing drug delivery to the CNS 100

Animal models for testing drug delivery 100

Screening for drug-P-gp interaction at BBB 101

4.Delivery of Cell, Gene and Antisense Therapies to the CNS 103

Introduction 103

Cell therapy of neurological disorders 103

Methods for delivering cell therapies in CNS disorders 103

Encapsulated cells 104

Genetically modified stem cells for metachromatic leukodystrophy 105

CNS neotissue implant 105

CNS delivery of cells by catheters 105

Subarachnoid delivery of stem cells 106

Intravascular administration 106

Gene therapy techniques for the nervous system 107

Introduction 107

Methods of gene transfer to the nervous system 108

AAV vector mediated gene therapy for neurogenetic disorders 109

Ideal vector for gene therapy of neurological disorders 109

Promoters of gene transfer 109

Routes of delivery of genes to the nervous system 110

Direct injection into CNS 110

Introduction of the genes into cerebral circulation 111

Introduction of genes into cerebrospinal fluid 111

Intravenous administration of vectors 111

Delivery of gene therapy to the peripheral nervous system 112

Cell-mediated gene therapy of neurological disorders 112

Neuronal cells 112

Neural stem cells and progenitor cells 112

Astrocytes 112

Cerebral endothelial cells 113

Implantation of genetically modified encapsulated cells into the brain 113

Genetically modified bone marrow cells 113

Nanoparticles as non-viral vectors for CNS gene therapy 114

Applications of gene therapy for neurological disorders 114

Companies involved in cell/gene therapy of neurological disorders 115

Antisense therapy of CNS disorders 116

Delivery of antisense oligonucleotides to the CNS 117

Delivery of oligonucleotides cross the BBB 118

Cellular delivery systems for oligonucleotides 118

High-flow microinfusion into the brain parenchyma 119

Systemic administration of peptide nucleic acids 119

Introduction of antisense compounds into the CSF Pathways 119

Intrathecal administration of antisense compounds 120

Intracerebroventricular administration of antisense oligonucleotides 120

Nanoparticle-based delivery of antisense therapy to the CNS 121

Methods of delivery of ribozymes 121

Delivery aspects of RNAi therapy of CNS disorders 122

Delivery of siRNA to the CNS 122

Future drug delivery strategies applicable to the CNS 122

5.Drug Delivery in the Treatment of CNS Disorders 125

Parkinson's disease 125

Drug delivery systems for Parkinson's disease 126

Duodenal levodopa infusion 128

Transdermal drug delivery for PD 128

Transdermal dopamine agonists for Parkinson's disease 128

Transdermal administration of other drugs for Parkinson's disease 130

Intracerebral administration of GDNF 130

Cell therapy for Parkinson's disease 130

Human dopaminergic neurons for PD 132

Graft survival-enhancing drugs 132

Xenografting porcine fetal neurons 132

Encapsulated cells for PD 133

Stem cells for PD 133

Engineered stem cells for drug delivery to the brain in PD 135

Human retinal pigment epithelium cells for PD 135

Delivery of cells for PD 136

Gene therapy for Parkinson disease 136

Rationale 136

Techniques of gene therapy for PD 137

Prospects of gene therapy for Parkinson's disease 140

Companies developing gene therapy for PD 141

RNAi therapy of Parkinson's disease 141

Alzheimer disease 142

Drug delivery for Alzheimer disease 142

Blood-brain partitioning of an AMPA receptor modulator 143

Clearing amyloid through the BBB 143

Delivery of the passive antibody directly to the brain 143

Delivery of thyrotropin-releasing hormone analogs by molecular packaging 144

Intranasal delivery of nerve growth factor to the brain 144

Nanoparticle-based drug delivery for Alzheimer's disease 144

Perispinal etanercept 145

Slow release implant of an AChE inhibitor 145

Transdermal drug delivery in Alzheimer's disease 145

Trojan-horse approach to prevent build-up of A? aggregates 146

Cell and gene therapy for Alzheimer disease 146

NGF gene therapy 146

Neprilysin gene therapy 147

RNAi therapy of Alzheimer's disease 148

Huntington's disease 148

Treatment of Huntington's disease 148

Drug delivery in Huntington's disease 149

Gene therapy of Huntington's disease 149

Encapsulated genetically engineered cellular implants 149

Viral vector mediated administration of neurotrophic factors 149

RNAi therapeutics for the treatment of HD 149

Amyotrophic lateral sclerosis 149

Treatment of ALS 150

Drug delivery in ALS 150

Gene and antisense therapy of amyotrophic lateral sclerosis 151

Neurotrophic factor gene therapies of ALS 151

Antisense therapy of ALS 153

RNAi therapy of amyotrophic lateral sclerosis 153

Drug delivery for CNS involvement in Hunter syndrome 153

Cerebrovascular disease 154

Treatment of stroke 154

Drug delivery in stroke 155

Intraarterial administration of tissue plasminogen activator in stroke 155

Drug delivery for prevention of restenosis of carotid arteries 156

Modified NO donors 157

In-stent restenosis 157

Targeted local anti-restenotic drug delivery 158

Catheter-based drug delivery for restenosis 158

Stents for prevention of restenosis 158

Drug-eluting stents 159

Antisense approach to prevent restenosis 160

Drug-eluting stents for the treatment of intracranial atherosclerosis 160

Tissues transplants for stroke 160

Transplant of encapsulated tissue secreting neurotrophic factors 161

Cell therapy for stroke 161

Stem cell transplant into the brain 161

Immortalized cell grafts for stroke 162

Intravenous infusion of marrow stromal cells 162

Intravenous infusion of umbilical cord blood stem cells 162

Future of cell therapy for stroke 163

Gene therapy of cerebrovascular diseases 163

Gene transfer to cerebral blood vessels 163

NOS gene therapy for restenosis 164

Gene therapy for cerebral ischemia 165

Gene therapy of strokes with a genetic component 166

Drug delivery to intracranial aneurysms 166

Drug delivery for vasospasm following subarachnoid hemorrhage 167

Intrathecal tissue plasminogen activator 168

Gene therapy for vasospasm 168

Drug delivery in multiple sclerosis 169

An electronic device for self injection of interferon beta-1a 170

Oral therapies for MS 170

Antisense and RNAi approaches to MS 170

Cell therapy for multiple sclerosis 171

Hematopoietic stem cell transplantation for multiple sclerosis 171

Embryonic stem cells and neural precursor cells for MS 171

Gene therapy for multiple sclerosis 172

Drug delivery in epilepsy 172

Routes of administration of antiepileptic drugs 173

Controlled-release preparations of carbamazepine 173

Intravenous carbamazepine 173

Various methods of delivery of diazepam 174

Methods of delivery of novel antiepileptic therapies 174

Regulated activation of prodrugs 174

Use of neuronal membrane transporter 174

Delivery of the antiepileptic conopeptides to the brain 174

Nasal administration of AEDs 175

Intracerebral administration of phenytoin 175

The role of drug delivery in status epilepticus 175

Cell therapy of epilepsy 176

Gene therapy for epilepsy 177

Gene therapy for neuroprotection in epilepsy 177

Concluding remarks on drug delivery in epilepsy 178

Drug delivery for pain 178

Intranasal delivery of analgesics 179

Intranasal administration of morphine 179

Intranasal morphine derivatives 180

Intranasal fentanyl 180

Intranasal buprenorphine 181

Intranasal ketamine 181

Intranasal ketorolac 181

Delivery of analgesics by inhalation 182

Spinal delivery of analgesics 183

Epidural dexamethasone 185

Epidural morphine 185

Relief of pain by intrathecal ziconotide 185

Intrathecal neostigmine 186

Intrathecal prostaglandin antagonists 186

Intrathecal fadolmidine 186

Intrathecal siRNA for relief of neuropathic pain 187

Concluding remarks on intrathecal delivery of analgesic agents 187

Intracerebroventricular drug delivery for pain 187

Delivery of analgesics to the CNS across the BBB 187

Drug delivery for migraine 188

Management of migraine 188

Novel drug delivery methods for migraine 189

Nasal formulations for migraine 190

Sublingual spray for migraine 191

Needle-free drug delivery for migraine 191

Relief of spasticity by intrathecal baclofen 191

Drug delivery for brain tumors 192

Methods for evaluation of anticancer drug penetration into brain tumor 192

Innovative methods of drug delivery for glioblastoma multiforme 192

Anticancer agents with increased penetration of BBB 193

Local delivery of chemotherapeutic agents into the tumor 194

Carmustine biodegradable polymer implants 194

Fibrin glue implants containing anticancer drugs. 194

Biodegradable microspheres containing 5-FU 195

Nanoparticles for delivery of drugs to brain tumors across BBB 195

Convection-enhanced delivery 196

Delivery of antibody-based anticancer therapy by ultrasound BBB disruption 196

Targeted monoclonal antibodies conjugated with liposomes 197

Immunoliposomes 197

Lipid-coated microbubbles as a delivery vehicle for taxol 197

Thermoliposomes containing cytotoxic drugs 197

Introduction of the chemotherapeutic agent into the CSF pathways 197

Intrathecal chemotherapy 197

Intraventricular chemotherapy for meningeal cancer 198

Increasing the permeability of blood-tumor barrier to anticancer drugs 198

Disruption of BBB 198

Nanoparticle-based targeted delivery of chemotherapy across the BBB 199

Modulating efflux transporters to enhance chemotherapy penetration 200

PDE5 inhibitors for enhancing tumor permeability to chemotherapy 200

Intraarterial chemotherapy 201

Interstitial delivery of dexamethasone for reduction of peritumor edema 201

Photodynamic therapy for chemosensitization 201

Boron neutron capture therapy 202

Gene therapy for glioblastoma multiforme. 203

Single-chain antibody-targeted adenoviral vectors 204

Peptides targeted to glial tumor cells 204

Antiangiogenic gene therapy 204

RNAi gene therapy of brain cancer 205

Drug delivery for traumatic brain injury 205

Cell therapy of traumatic brain injury 205

Gene therapy for traumatic brain injury 206

Drug delivery for spinal cord injury 206

Administration of neurotrotrophic factors for spinal cord injury 207

Cell therapy for spinal cord injury 207

Transplantation of glial cells for SCI 207

Fetal neural grafts for SCI 207

Embryonic stem cells for SCI 208

Schwann cell transplants for SCI 208

Olfactory glial cells for SCI 208

Marrow stromal cells for SCI 209

Intravenous injection of stem cells for spinal cord repair 209

Combinatorial approach for regeneration in SCI 209

Cell therapy of syringomyelia 210

Gene therapy of spinal cord injury 210

Drug delivery for retinal disorders 210

Age-related macular degeneration 211

TheraSight ocular brachytherapy system for wet AMD 211

Combretastatin A4P for myopic macular degeneration 211

Gene therapy for AMD 212

Anti-VEGF approach to AMD 212

Delivery of aptamers for treatment of AMD 212

Stem cell therapy for retinitis pigmentosa 213

Proliferative retinopathies 213

Drug delivery in CNS infections 214

Drug delivery in neuroAIDS 214

6.Markets for Drug Delivery in CNS Disorders 215

Introduction 215

Methods of calculation of CNS drug delivery markets 215

Markets for CNS drug delivery technologies 215

Drug delivery share in selected CNS markets 216

CNS share of drug delivery technologies 216

Geographical distribution of CNS drug delivery markets 217

Impact of improved drug delivery on CNS drug markets 217

Neurodegenerative disorders 217

Alzheimer's disease 217

Parkinson's Disease 218

Huntington's disease 218

Amyotrophic lateral sclerosis 218

Epilepsy 219

Migraine and other headaches 219

Stroke 219

Spinal cord injury 220

Multiple sclerosis 220

Brain tumors 220

Limitations of the current drug delivery technologies for CNS 220

Unmet needs in CNS drug delivery technologies 221

Future strategies for expanding CNS drug delivery markets 222

Education of neurologists 222

Demonstration of the advantages of the newer methods of delivery 222

Rescue of old products by novel drug delivery methods 223

Facilitation of the approval process of new drugs 223

7. Companies 225

Introduction 225

Profiles 225

Collaborations 300

8.References 303

TablesTable 1 1: Landmarks in the development of drug delivery to the CNS 17

Table 2 1: Proteins expressed at the neurovascular unit 30

Table 2 2: Transporters that control penetration of molecules across the BBB 34

Table 2 3: Enzymes that control the penetration of molecules across the BBB 36

Table 2 4: Factors that increase the permeability of the BBB 41

Table 2 5: Diseases that affect the BBB 42

Table 3 1: Various methods of drug delivery to the central nervous system 55

Table 3 2: Drugs available for intrathecal administration 62

Table 3 3: Strategies for drug delivery to the CNS across the BBB 65

Table 3 4: Specific inhibitors of P-glycoprotein in clinical development 70

Table 3 5: Molecules attached to Trojan horses injected intravenously for CNS effect 75

Table 3 6: Examples of controlled and sustained release drug delivery for CNS disorders 87

Table 3 7: Novel methods of delivery of drugs for CNS disorders 89

Table 3 8: Indications for the clinical applications of NTFs in neurologic disorders 93

Table 3 9: Methods for delivery of neurotrophic factors to the CNS 94

Table 4 1: Methods for delivering cell therapies in CNS disorders 104

Table 4 2: Classification of methods of gene therapy 107

Table 4 3: Methods of gene transfer as applied to neurologic disorders 108

Table 4 4: Potential indications for gene therapy of neurologic disorders 114

Table 4 5: Companies developing cell/gene therapies for CNS disorders 115

Table 4 6: Methods of antisense delivery as applied to the CNS 117

Table 5 1: Strategies for the treatment of Parkinson's disease 125

Table 5 2: Drug delivery systems for Parkinson's disease 127

Table 5 3: Types of cell used for investigative treatment of Parkinson's disease 131

Table 5 4: Status of cell therapies in development for Parkinson's disease 131

Table 5 5: Gene therapy techniques applicable to Parkinson disease 137

Table 5 6: Companies developing gene therapy for Parkinson's disease 141

Table 5 7: Classification of pharmacotherapy for Alzheimer disease 142

Table 5 8: Novel drug delivery methods for Alzheimer disease therapies 142

Table 5 9: Classification of neuroprotective agents for amyotrophic lateral sclerosis 150

Table 5 10: Methods of delivery of therapies in development for ALS 151

Table 5 11: Classification of treatments for stroke 154

Table 5 12: Treatments of stroke involving innovative drug delivery methods 155

Table 5 13: Drug delivery for prevention of carotid artery restenosis after angioplasty 157

Table 5 14: Gene transfer in animal models of carotid artery restenosis 164

Table 5 15: Neuroprotective gene transfer strategies in models of cerebral ischemia 165

Table 5 16: Gene Therapy for reducing cerebral infarction in animal stroke models 166

Table 5 17: Pharmacological agents for treatment of cerebral vasospasm 167

Table 5 18: Gene therapy strategies for vasospasm 168

Table 5 19: A classification of drug delivery methods used in management of pain 178

Table 5 20: Spinal administration of drugs for pain 183

Table 5 21: Investigational drugs for pain administered by intrathecal route 184

Table 5 22: Current management of migraine 189

Table 5 23: Novel drug delivery methods for migraine 190

Table 5 24: Innovative methods of drug delivery for glioblastoma multiforme 193

Table 5 25: Strategies for gene therapy of malignant brain tumors 203

Table 6 1: Share of drug delivery technologies in selected CNS markets: 2009-2019 216

Table 6 2: CNS market share of drug delivery technologies 2009-2019 216

Table 6 3: Value of CNS drug delivery in the major world markets from 2009-2019 217

Table 6 4: Limitations of the current drug delivery technologies for CNS 221

Table 7 1: Collaborations of companies in CNS drug delivery 300

FiguresFigure 1 1: Interaction of neurotransmitters with receptors 20

Figure 2 1: The neurovascular unit 29

Figure 2 2: Various forms of passage of substances across the blood brain barrier 33

Figure 3 1: Routes of drug delivery to the brain 56

Figure 3 2: Use of receptor-mediated transcytosis to cross the BBB 76

Figure 5 1: Oral versus transdermal administration of a drug in Parkinson's disease 129

Figure 5 2: Effect of tyrosine hydroxylase gene delivery on dopamine levels 138

Figure 5 3: A concept of targeted drug delivery to GBM across the BBB 199

Figure 6 1: Unmet needs in the CNS drug delivery technologies 221

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