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

Table of Contents

0. Executive Summary

1. Basics of Drug Delivery to the Central Nervous System

• Introduction
• Historical evolution of drug delivery for CNS disorders
• Neuroanatomical and neurophysiological basis of drug delivery
• The cerebrospinal fluid
• The extracellular space in the brain
• Neurotransmitters
• Neuropharmacology relevant to drug delivery
• Introduction to neuropharmacology
• Pharmacokinetics
• Absorption and distribution of drugs
• Drug metabolism and elimination
• Pharmacodynamics
• Receptors
• Sites of drug action in the CNS
• Receptors coupled to guanine nucleotide binding proteins
• Acetylcholine receptor channels
• Dopamine receptors
• GABA receptor channels
• Glutamate receptor channels
• Non-competitive NMDA antagonists
• Serotonin receptors
• G-protein coupled receptors
• In vivo study of drug action in the CNS in human patients
• Electroencephalography
• Brain imaging
• Chronopharmacology as applied to the CNS

2. Blood Brain Barrier

• Introduction
• Features of the blood-brain barrier relevant to CNS drug delivery
• The neurovascular unit
• Functions of the BBB
• BBB as an anatomical as well as physiological barrier
• BBB as a biochemical barrier
• Genomics and proteomics of BBB
• Other neural barriers
• Blood-cerebrospinal fluid barrier
• Blood nerve barrier
• Blood-retinal barrier
• Blood-labyrinth barrier
• Passage of substances across the blood-brain barrier
• Transporters localized in the BBB
• Glucose transporter
• Amino acid transporters
• Ionic transporter
• Efflux transport systems
• BBB-specific enzymes
• Receptor-mediated transcytosis
• Lysophosphatidic acid-mediated increade in BBB permeability
• Folate transport system
• Molecular biology of the BBB
• Transport of peptides and proteins across the BBB
• Passage of leptin across the BBB
• Passage of cytokines across the BBB
• Passage of hormones across the BBB
• Passage of enzymes across the BBB
• Drugs that cross the BBB by binding to plasma proteins
• Current concepts of the permeability of the BBB
• Factors that increase the permeability of the BBB
• BBB disruption as adverse effect of vaccines for CNS disorders
• CNS disorders that affect the permeability of BBB
• Neurodegenerative disorders
• Mitochondrial encephalopathies
• Multiple sclerosis
• Central nervous system injuries
• Epilepsy
• Cerebrovascular disease
• Infections
• Autoimmune disorders
• Brain tumors
• Testing permeability of the BBB
• In vitro models of BBB
• In vivo study of BBB
• Brain imaging
• In silico prediction of BBB
• Relevance of the BBB penetration to pharmacological action
• BBB penetration and CNS drug screening
• CERENSESM
• Transthyretin monomer as a marker of blood-CSF barrier disruption
• Evaluation of BBB permeability by brain imaging
• Biomarkers of disruption of blood-brain barrier
• Future directions for research on the BBB
• Application of genomics and proteomics to the study of BBB
• Use of neural stem cells to construct the blood brain barrier
• Strategies to cross the BBB

3. Methods of Drug Delivery to the CNS

• Introduction
• Routes of drug delivery to the brain
• Delivery of drugs to the brain via the nasal route
• Nasal delivery of insulin-like growth factor-I
• Nasal delivery of midazolam
• Nasal delivery of hypocretin
• Intranasal administration of IFN beta-1b
• Nasal delivery of thyrotropin-releasing hormone by nanoconstructs
• Nasal delivery of neuroprotective drugs for stroke
• Transdermal drug delivery for neurological disorders
• Drug delivery to the brain via inner ear
• Invasive neurosurgical approaches
• Intraarterial drug delivery to the brain
• Direct injection into the CNS substance or CNS lesions
• Intraventricular injection of drugs
• Intrathecal drug delivery
• Retrograde delivery to the brain via the epidural venous system
• Devices for drug delivery to the CNS
• Strategies for drug delivery to the CNS across the BBB
• Increasing the permeability (opening) of the BBB
• Osmotic opening of the BBB
• Focal disruption of BBB by ultrasound
• Chemical opening of the BBB
• Cerebral vasodilatation to open the BBB
• Use of nitric oxide donors to open the BBB
• Manipulation of the sphingosine 1-phosphate receptor system
• Pharmacological strategies to facilitate transport across the BBB
• 2B-Trans"! technology with specific carrier protein
• ABC afflux transporters and penetration of the BBB
• Carrier-mediated drug delivery across the BBB
• Glutathione transporters for drug delivery across the BBB
• Glycosylation Independent Lysosomal Targeting
• Inhibition of P-glycoprotein to enhance drug delivery across the BBB
• Modification of the drug to enhance its lipid solubility
• Monoclonal antibody fusion proteins
• Neuroimmunophilins
• Peptide-mediated transport across the BBB
• Prodrug bioconversion strategies and their CNS selectivity
• Role of the transferrin-receptor system in CNS drug delivery
• Transport of small molecules across the BBB
• Transport across the BBB by short chain oligoglycerolipids
• Transvascular delivery across the BBB
• Trojan horse approach
• Use of receptor-mediated transocytosis to cross the BBB
• Cell-based drug delivery to the CNS
• Activated T lymphocytes
• Microglial cells
• Neural stem cells
• Drug delivery to the CNS by using novel formulations
• Crystalline formulations
• Liposomes
• Monoclonal antibodies
• Microspheres
• Microbeads
• Brain-targeted chemical delivery systems
• Nanotechnology-based drug delivery to CNS
• Nanoparticles for drug delivery across the BBB
• Penetration of BBB by nanoparticles coated with polysorbate 80
• NanoDel™ technology for crossing the BBB
• Masking BBB-limiting characteristics by nanotechnology
• Peptide-nanoparticle conjugates for crossing the BBB
• Nanovesicles for transport across BBB
• Nanotechnology-based devices and implants for CNS
• Biochip implants for drug delivery to the CNS
• Controlled-release microchip
• Retinal implant chip
• Convection-enhanced delivery to the CNS
• Systemic administration of drugs for CNS effects
• Sustained and controlled release drug delivery to the CNS
• Fast dissolving oral selegiline
• Choice of the route of systemic delivery for effect on the CNS disorders
• Methods of delivery of biopharmaceuticals to the CNS
• Delivery of biopharmaceuticals across the BBB
• Methods of delivery of peptides for CNS disorders
• Challenges for delivery of peptides across the BBB
• Transnasal administration of neuropeptides
• Direct delivery of neuropeptides into the brain
• Alteration of properties of the BBB for delivery of peptides
• Molecular manipulations of peptides to facilitate transport into CNS
• CNS delivery of peptides via conjugation to biological carriers
• Delivery of conopeptides to the brain
• Delivery of neurotrophic factors to the nervous system
• Systemic administration of NTFs
• Delivery systems to facilitate crossing of the BBB by NTFs
• Use of microspheres for delivery of neurotrophic factors
• Intracerebroventricular injection
• Direct application of NTFs to the CNS
• Intrathecal administration
• Implants for delivery of neurotrophic factors
• Use of neurotrophic factor mimics
• Use of microorganisms for therapeutic entry into the brain
• Bacteriophages as CNS therapeutics
• Intracellular drug delivery in the brain
• Local factors in the brain affecting drug action
• Methods for testing drug delivery to the CNS
• Animal models for testing drug delivery
• Screening for drug-P-gp interaction at BBB

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

• Introduction
• Cell therapy of neurological disorders
• Methods for delivering cell therapies in CNS disorders
• Encapsulated cells
• Genetically modified stem cells for metachromatic leukodystrophy
• CNS neotissue implant
• CNS delivery of cells by catheters
• Subarachnoid delivery of stem cells
• Intravascular administration
• Gene therapy techniques for the nervous system
• Introduction
• Methods of gene transfer to the nervous system
• AAV vector mediated gene therapy for neurogenetic disorders
• Ideal vector for gene therapy of neurological disorders
• Promoters of gene transfer
• Routes of delivery of genes to the nervous system
• Direct injection into CNS
• Introduction of the genes into cerebral circulation
• Introduction of genes into cerebrospinal fluid
• Intravenous administration of vectors
• Delivery of gene therapy to the peripheral nervous system
• Cell-mediated gene therapy of neurological disorders
• Neuronal cells
• Neural stem cells and progenitor cells
• Astrocytes
• Cerebral endothelial cells
• Implantation of genetically modified encapsulated cells into the brain
• Genetically modified bone marrow cells
• Nanoparticles as non-viral vectors for CNS gene therapy
• Companies involved in cell/gene therapy of neurological disorders
• Antisense therapy of CNS disorders
• Delivery of antisense oligonucleotides to the CNS
• Delivery of oligonucleotides cross the BBB
• Cellular delivery systems for oligonucleotides
• High-flow microinfusion into the brain parenchyma
• Systemic administration of peptide nucleic acids
• Introduction of antisense compounds into the CSF Pathways
• Intrathecal administration of antisense compounds
• Intracerebroventricular administration of antisense oligonucleotides
• Nanoparticle-based delivery of antisense therapy to the CNS
• Methods of delivery of ribozymes
• Delivery aspects of RNAi therapy of CNS disorders
• Delivery of siRNA to the CNS
• Future drug delivery strategies applicable to the CNS

5. Drug Delivery in the Treatment of CNS Disorders

• Parkinson' s disease
• Drug delivery systems for Parkinson' s disease
• Duodenal levodopa infusion
• Transdermal drug delivery for PD
• Transdermal dopamine agonists for Parkinson' s disease
• Transdermal administration of other drugs for Parkinson' s disease
• Intracerebral administration of GDNF
• Cell therapy for Parkinson' s disease
• Human dopaminergic neurons for PD
• Graft survival-enhancing drugs
• Xenografting porcine fetal neurons
• Encapsulated cells for PD
• Stem cells for PD
• Engineered stem cells for drug delivery to the brain in PD
• Human retinal pigment epithelium cells for PD
• Delivery of cells for PD
• Gene therapy for Parkinson disease
• Rationale
• Techniques of gene therapy for PD
• Prospects of gene therapy for Parkinson' s disease
• Companies developing gene therapy for PD
• RNAi therapy of Parkinson' s disease
• Alzheimer disease
• Drug delivery for Alzheimer disease
• Blood-brain partitioning of an AMPA receptor modulator
• Clearing amyloid through the BBB
• Delivery of the passive antibody directly to the brain
• Delivery of thyrotropin-releasing hormone analogs by molecular packaging
• Intranasal delivery of nerve growth factor to the brain
• Nanoparticle-based drug delivery for Alzheimer' s disease
• Perispinal etanercept
• Slow release implant of an AChE inhibitor
• Transdermal drug delivery in Alzheimer' s disease
• Trojan-horse approach to prevent build-up of Aβ aggregates
• Cell and gene therapy for Alzheimer disease
• NGF gene therapy
• Neprilysin gene therapy
• RNAi therapy of Alzheimer' s disease
• Huntington' s disease
• Treatment of Huntington' s disease
• Drug delivery in Huntington' s disease
• Gene therapy of Huntington' s disease
• Encapsulated genetically engineered cellular implants
• Viral vector mediated administration of neurotrophic factors
• RNAi therapeutics for the treatment of HD
• Amyotrophic lateral sclerosis
• Treatment of ALS
• Drug delivery in ALS
• Gene and antisense therapy of amyotrophic lateral sclerosis
• Neurotrophic factor gene therapies of ALS
• Antisense therapy of ALS
• RNAi therapy of amyotrophic lateral sclerosis
• Drug delivery for CNS involvement in Hunter syndrome
• Cerebrovascular disease
• Treatment of stroke
• Drug delivery in stroke
• Intraarterial administration of tissue plasminogen activator in stroke
• Drug delivery for prevention of restenosis of carotid arteries
• Modified NO donors
• In-stent restenosis
• Targeted local anti-restenotic drug delivery
• Catheter-based drug delivery for restenosis
• Stents for prevention of restenosis
• Drug-eluting stents
• Antisense approach to prevent restenosis
• Drug-eluting stents for the treatment of intracranial atherosclerosis
• Tissues transplants for stroke
• Transplant of encapsulated tissue secreting neurotrophic factors
• Cell therapy for stroke
• Stem cell transplant into the brain
• Immortalized cell grafts for stroke
• Intravenous infusion of marrow stromal cells
• Intravenous infusion of umbilical cord blood stem cells
• Future of cell therapy for stroke
• Gene therapy of cerebrovascular diseases
• Gene transfer to cerebral blood vessels
• NOS gene therapy for restenosis
• Gene therapy for cerebral ischemia
• Gene therapy of strokes with a genetic component
• Drug delivery to intracranial aneurysms
• Drug delivery for vasospasm following subarachnoid hemorrhage
• Intrathecal tissue plasminogen activator
• Gene therapy for vasospasm
• Drug delivery in multiple sclerosis
• Oral therapies for MS
• Antisense and RNAi approaches to MS
• Cell therapy for multiple sclerosis
• Hematopoietic stem cell transplantation for multiple sclerosis
• Embryonic stem cells and neural precursor cells for MS
• Gene therapy for multiple sclerosis
• Drug delivery in epilepsy
• Routes of administration of antiepileptic drugs
• Controlled-release preparations of carbamazepine
• Various methods of delivery of diazepam
• Methods of delivery of novel antiepileptic therapies
• Regulated activation of prodrugs
• Use of neuronal membrane transporter
• Delivery of the antiepileptic conopeptides to the brain
• Nasal administration of AEDs
• Intracerebral administration of phenytoin
• The role of drug delivery in status epilepticus
• Cell therapy of epilepsy
• Gene therapy for epilepsy
• Gene therapy for neuroprotection in epilepsy
• Concluding remarks on drug delivery in epilepsy
• Drug delivery for pain
• Intranasal delivery of analgesics
• Intranasal administration of morphine
• Intranasal fentanyl
• Intranasal buprenorphine
• Intranasal ketamine
• Delivery of analgesics by inhalation
• Spinal delivery of analgesics
• Epidural administration of encapsulated morphine
• Relief of pain by intrathecal ziconotide
• Intrathecal neostigmine
• Intrathecal prostaglandin antagonists
• Intrathecal non-NMDA antagonists
• Intrathecal siRNA for relief of neuropathic pain
• Intracerebroventricular drug delivery for pain
• Delivery of analgesics to the CNS across the BBB
• Drug delivery for migraine
• Management of migraine
• Novel drug delivery methods for migraine
• Nasal formulations for migraine
• Sublingual spray for migraine
• Needle-free drug delivery for migraine
• Relief of spasticity by intrathecal baclofen
• Drug delivery for brain tumors
• Methods for evaluation of anticancer drug penetration into brain tumor
• Innovative methods of drug delivery for glioblastoma multiforme
• Anticancer agents with increased penetration of BBB
• Local delivery of chemotherapeutic agents into the tumor
• Carmustine biodegradable polymer implants
• Fibrin glue implants containing anticancer drugs
• Biodegradable microspheres containing 5-FU
• Nanoparticles for delivery of drugs to brain tumors across BBB
• Convection-enhanced delivery
• Delivery of antibody-based anticancer therapy by ultrasound BBB disruption
• Targeted monoclonal antibodies conjugated with liposomes
• Immunoliposomes
• Lipid-coated microbubbles as a delivery vehicle for taxol
• Thermoliposomes containing cytotoxic drugs
• Introduction of the chemotherapeutic agent into the CSF pathways
• Intrathecal chemotherapy
• Intraventricular chemotherapy for meningeal cancer
• Increasing the permeability of blood-tumor barrier to anticancer drugs
• Disruption of BBB
• Nanoparticle-based targeted delivery of chemotherapy across the BBB
• Modulating efflux transporters to enhance chemotherapy penetration
• PDE5 inhibitors for enhancing tumor permeability to chemotherapy
• Intra-arterial chemotherapy
• Interstitial delivery of dexamethasone for reduction of peritumor edema
• Photodynamic therapy for chemosensitization
• Boron neutron capture therapy
• Gene therapy for glioblastoma multiforme
• Single-chain antibody-targeted adenoviral vectors
• Peptides targeted to glial tumor cells
• Antiangiogenic gene therapy
• RNAi gene therapy of brain cancer
• Drug delivery for traumatic brain injury
• Cell therapy of traumatic brain injury
• Gene therapy for traumatic brain injury
• Drug delivery for spinal cord injury
• Administration of neurotrotrophic factors for spinal cord injury
• Cell therapy for spinal cord injury
• Transplantation of glial cells for SCI
• Fetal neural grafts for SCI
• Embryonic stem cells for SCI
• Schwann cell transplants for SCI
• Olfactory glial cells for SCI
• Marrow stromal cells for SCI
• Intravenous injection of stem cells for spinal cord repair
• Combinatorial approach for regeneration in SCI
• Cell therapy of syringomyelia
• Gene therapy of spinal cord injury
• Drug delivery for retinal disorders
• Age-related macular degeneration
• TheraSight ocular brachytherapy system for wet AMD
• Combretastatin A4P for myopic macular degeneration
• Gene therapy for AMD
• Anti-VEGF approach to AMD
• Delivery of aptamers for treatment of AMD
• Stem cell therapy for retinitis pigmentosa
• Proliferative retinopathies
• Drug delivery in CNS infections
• Drug delivery in neuroAIDS

6. Markets for Drug Delivery in CNS Disorders

• Introduction
• Methods of calculation of CNS drug delivery markets
• Markets for CNS drug delivery technologies
• Drug delivery share in selected CNS markets
• CNS share of drug delivery technologies
• Geographical distribution of CNS drug delivery markets
• Impact of improved drug delivery on CNS drug markets
• Neurodegenerative disorders
• Alzheimer' s disease
• Parkinson' s Disease
• Huntington' s disease
• Amyotrophic lateral sclerosis
• Epilepsy
• Migraine and other headaches
• Stroke
• Spinal cord injury
• Multiple sclerosis
• Brain tumors
• Limitations of the current drug delivery technologies for CNS
• Unmet needs in CNS drug delivery technologies
• Future strategies for expanding CNS drug delivery markets
• Education of neurologists
• Demonstration of the advantages of the newer methods of delivery
• Rescue of old products by novel drug delivery methods
• Facilitation of the approval process of new drugs

7. Companies

• Introduction
• Profiles
• Collaborations

8. References

Tables

• Table 1 1: Landmarks in the development of drug delivery to the CNS
• Table 2 1: Proteins expressed at the neurovascular unit
• Table 2 2: Transporters that control penetration of molecules across the BBB
• Table 2 3: Enzymes that control the penetration of molecules across the BBB
• Table 2 4: Factors that increase the permeability of the BBB
• Table 2 5: Diseases that affect the BBB
• Table 3 1: Various methods of drug delivery to the central nervous system
• Table 3 2: Drugs available for intrathecal administration
• Table 3 3: Strategies for drug delivery to the CNS across the BBB
• Table 3 4: Specific inhibitors of P-glycoprotein in clinical development
• Table 3 5: Molecules attached to Trojan horses injected intravenously for CNS effect
• Table 3 6: Examples of controlled and sustained release drug delivery for CNS disorders
• Table 3 7: Novel methods of delivery of drugs for CNS disorders
• Table 3 8: Indications for the clinical applications of NTFs in neurologic disorders
• Table 3 9: Methods for delivery of neurotrophic factors to the CNS
• Table 4 1: Methods for delivering cell therapies in CNS disorders
• Table 4 2: Classification of methods of gene therapy
• Table 4 3: Methods of gene transfer as applied to neurologic disorders
• Table 4 4: Companies developing cell/gene therapies for CNS disorders
• Table 4 5: Methods of antisense delivery as applied to the CNS
• Table 5 1: Strategies for the treatment of Parkinson' s disease
• Table 5 2: Drug delivery systems for Parkinson' s disease
• Table 5 3: Types of cell used for investigative treatment of Parkinson' s disease
• Table 5 4: Status of cell therapies in development for Parkinson' s disease
• Table 5 5: Gene therapy techniques applicable to Parkinson disease
• Table 5 6: Companies developing gene therapy for Parkinson' s disease
• Table 5 7: Classification of pharmacotherapy for Alzheimer disease
• Table 5 8: Novel drug delivery methods for Alzheimer disease therapies
• Table 5 9: Classification of neuroprotective agents for amyotrophic lateral sclerosis
• Table 5 10: Methods of delivery of therapies in development for ALS
• Table 5 11: Classification of treatments for stroke
• Table 5 12: Treatments of stroke involving innovative drug delivery methods
• Table 5 13: Drug delivery for prevention of carotid artery restenosis after angioplasty
• Table 5 14: Gene transfer in animal models of carotid artery restenosis
• Table 5 15: Neuroprotective gene transfer strategies in models of cerebral ischemia
• Table 5 16: Gene Therapy for reducing cerebral infarction in animal stroke models
• Table 5 17: Pharmacological agents for treatment of cerebral vasospasm
• Table 5 18: Gene therapy strategies for vasospasm
• Table 5 19: A classification of drug delivery methods used in management of pain
• Table 5 20: Spinal/intrathecal administration of drugs for pain
• Table 5 21: Investigational drugs for pain administered by intrathecal route
• Table 5 22: Current management of migraine
• Table 5 23: Novel drug delivery methods for migraine
• Table 5 24: Innovative methods of drug delivery for glioblastoma multiforme
• Table 5 25: Strategies for gene therapy of malignant brain tumors
• Table 6 1: Share of drug delivery technologies in selected CNS markets: 2008-2018
• Table 6 2: CNS market share of drug delivery technologies 2008-2018
• Table 6 3: Value of CNS drug delivery in the major world markets from 2008-2018
• Table 6 4: Limitations of the current drug delivery technologies for CNS
• Table 7 1: Collaborations of companies in CNS drug delivery

Figures

• Figure 1 1: Interaction of neurotransmitters with receptors
• Figure 2 1: The neurovascular unit
• Figure 2 2: Various forms of passage of substances across the blood brain barrier
• Figure 3 1: Routes of drug delivery to the brain
• Figure 3 2: Use of receptor-mediated transcytosis to cross the BBB
• Figure 5 1: Oral versus transdermal administration of a drug in Parkinson' s disease
• Figure 5 2: Effect of tyrosine hydroxylase gene delivery on dopamine levels
• Figure 5 3: A concept of targeted drug delivery to GBM across the BBB
• Figure 6 1: Unmet needs in the CNS drug delivery technologies