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Drug Delivery in Central Nervous System Diseases - Technologies, Markets & Companies

  • ID: 4748176
  • Report
  • 389 Pages
  • Jain PharmaBiotech
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The 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. A special chapter is devoted to drug delivery for brain tumors. 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 2017, projections are made to the years 2023 and 2028. 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 the development of new products, these include the application of innovative methods of delivery to older drugs to improve their actions and extend their patent life.

Profiles of 76 companies involved in drug delivery for CNS disorders are presented along with their technologies, products and 101 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 contain over 420 publications that are cited in the report. The report is supplemented with 52 tables and 17 figures.

The report contains information on the following:

  • Basics of drug delivery to the CNS
  • Blood-brain barrier
  • Methods of drug delivery to the CNS
  • Delivery of cell, gene and antisense therapies to the CNS
  • Drug delivery in the treatment of CNS disorders
  • Drug delivery for brain tumors
  • Markets for drug delivery in CNS disorders
  • Companies
Note: Product cover images may vary from those shown
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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 lymphatic drainage system of the brain  
The extracellular space in the brain  
Neurotransmitters  
Extracellular vesicles as drug delivery vehicles  
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  
Role of drug delivery in personalized therapy of CNS disorders  

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  
Glucose transporters at the BBB
Role of shear stress on development of BBB  
Genomics of BBB
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
Adenosine carrier  
Amino acid transporters
Efflux transport systems  
Glucose transporter
Ionic transporter
BBB-specific enzymes
Receptor-mediated transcytosis
Lysophosphatidic acid-mediated increase in BBB permeability
Folate transport system  
Transferrin receptor
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  
Passage of omega-3 fatty acids across the BBB
Drugs that cross the BBB by binding to plasma proteins.
Current concepts of the permeability of the BBB  
BBB permeability in relation to disease  
BBB permeability in relation to drug delivery  
Factors that increase the permeability of the BBB
BBB disruption as an adverse effect of pharmaceuticals  
BBB disruption as adverse effect of vaccines for CNS disorders  
CNS disorders and BBB  
Autoimmune disorders  
Brain tumors
Primary brain tumors.
Cerebral metastases  
Central nervous system injuries
Cerebrovascular disease
Cerebral ischemia
Intracerebral hemorrhage  
Epilepsy  
Infections
Inflammation.
Mitochondrial encephalopathies
Multiple sclerosis  
Neurodegenerative disorders
BBB in Alzheimer disease
BBB in Parkinson disease
BBB in amyotrophic lateral sclerosis  
West Nile virus infection
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
BBB models for testing drug delivery
CERENSE SM
In vivo brain distribution of P-glycoprotein
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
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  
Drug deliverys to the brain via the nasal route  
Devices for nasal administration of drugs for CNS
Nasal mucosal patch to facilitate drug delivery across the BBB
Passage of viruses to the brain via the nasal route  
Potential and limitations of nasal drug delivery to the brain  
Drugs that can be delivered to the brain via the nasal route  
Erythropoietin.
Esketamine  
Hypocretin
IFN beta-1b  
Lysosomal enzymes  
Midazolam
Neurotrophic factors  
Thyrotropin-releasing hormone
Neuroprotective drugs for stroke
Transdermal drug delivery for neurological disorders  
Drug delivery to the brain via inner ear  
Drug delivery for disorders of the spinal cord.
Intrathecal drug delivery
Anatomical & physiological aspects of intrathecal drug delivery
Advantages of intrathecal drug delivery
Drugs that can be delivered by intrathecal route
Pharmacokinetics of intrathecal drug delivery
Retrograde delivery to the brain via the epidural venous system
Devices for drug delivery to the CNS  
Catheters for drug delivery to the CNS  
Reservoirs and pumps for drug delivery to the CNS
Invasive neurosurgical approaches
Intraarterial drug delivery to the brain
Direct injection into the CNS substance or CNS lesions  
Targeted delivery of biologicals to the spinal cord by microinjection  
Intraventricular injection of drugs
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  
Modulation of vascular permeability by laser irradiation
Neurostimulation for opening 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
ABC afflux transporters and penetration of the BBB
Adenosine agonist-mediated drug delivery across the BBB
Carrier-mediated drug delivery across the BBB
Fusion of receptor-binding peptide from apoE with therapeutic protein  
G-Technology®  
Glycosylation Independent Lysosomal Targeting
Inhibition of P-glycoprotein to enhance drug delivery across the BBB  
LipoBridge technology
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
Transport of small molecules across the BBB  
Transport across the BBB by short chain oligoglycerolipids
Transvascular delivery across the BBB
Trojan horse approach
Role of the transferrin-receptor system in CNS drug delivery  
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  
Nanovesicles for transport across BBB
Nanoparticle-based reservatrol delivery to the brain  
Penetration of BBB by nanoparticles coated with polysorbate 80
Targeting nicotinic acetylcholine receptor
Transcytosis of transferrin-containing nanoparticles across the BBB  
V-SMART® drug delivery platform  
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  
Alteration of properties of the BBB for delivery of peptides
Challenges for delivery of peptides across the BBB  
CNS delivery of peptides via conjugation to biological carriers  
Delivery of conopeptides to the brain.
Direct delivery of neuropeptides into the brain  
Molecular manipulations of peptides to facilitate transport into CNS  
Transport to spinal cord motor neurons after peripheral injection  
Transnasal administration of neuropeptides  
Delivery of neurotrophic factors to the nervous system
Systemic administration of NTFs
Delivery systems to facilitate crossing of the BBB by NTFs
Direct application of NTFs to the CNS  
Intracerebroventricular injection
Intrathecal administration  
Implants for delivery of neurotrophic factors  
Use of neurotrophic factor mimics
Use of microspheres for delivery of neurotrophic factors  
Use of nanobiotechnology for delivery of neurotrophic factors
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  
Cerebrospinal fluid-stem cell interactions for therapy of CNS disorders  
Engineered stem cells for drug delivery to the brain  
Encapsulated cells
Intrathecal delivery of stem cells  
Intraparenchymal delivery of stem cells to the spinal cord
Intravascular administration
Neural stem cells as therapeutic delivery vehicles
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 nonviral vectors for CNS gene therapy  
Applications of gene therapy for neurological disorders
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 for Treatment of Neurological Disorders  
Introduction  
Targeted drug delivery for neurological disorders
Parkinson's disease
Drug delivery systems for Parkinson's disease
Methods of delivery of levodopa in PD
Duodenal levodopa infusion  
Inhaled levodopa  
Sublingual apomorphine  
Transdermal drug delivery for PD  
Transdermal dopamine agonists for PD  
Transdermal administration of other drugs for PD
Intracerebral administration of GDNF  
Cell therapy for PD
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 PD  
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.
Nanoparticle-based drug delivery for Alzheimer’s disease  
Perispinal etanercept  
Slow release implant of an AChE inhibitor
Intranasal insulin in Alzheimer disease
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 HD  
Gene therapy of HD
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
Delivery of stem cell therapy for ALS  
Gene and antisense therapy of ALS  
Neurotrophic factor gene therapies of ALS  
Antisense therapy of ALS
RNAi therapy of amyotrophic lateral sclerosis
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
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  
Methods for delivery of neurotrophic factors in stroke
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
An electronic device for self injection of interferon beta-1a  
Oral therapies for MS
Drug delivery for MS across the BBB  
Delivery of methylprednisolone across the BBB
Monoclonal antibodies for MS and the BBB
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  
Intravenous carbamazepine
Various routes of administration of benzodiazepines  
Methods of delivery of novel antiepileptic therapies  
Use of neuronal membrane transporter  
Delivery of the antiepileptic conopeptides to the brain
Nasal administration of AEDs  
Intracerebral administration of AEDs
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 morphine derivatives  
Intranasal fentanyl  
Intranasal buprenorphine
Intranasal ketamine  
Intranasal ketorolac  
Delivery of analgesics by inhalation  
Delivery of analgesics to peripheral nerves  
Spinal delivery of analgesics  
Epidural dexamethasone  
Epidural morphine
Relief of pain by intrathecal ziconotide
Intrathecal neostigmine
Intrathecal prostaglandin antagonists  
Intrathecal fadolmidine  
Intrathecal siRNA for relief of neuropathic pain
Concluding remarks on intrathecal delivery of analgesic agents  
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
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 in CNS infections  
Drug delivery in neuroAIDS
Drug delivery for miscellaneous neurological disorders
Drug delivery for CNS involvement in Hunter syndrome  
Trojan horse therapeutics to treat mucopolysaccharidosis types I & II
Antisense therapy for spinal muscular atrophy
Antisense gene splicing for SMA  
Intrathecal antisense delivery
Genetically modified stem cells for metachromatic leukodystrophy
Relief of spasticity by intrathecal baclofen
Drug delivery for retinal disorders
Age-related macular degeneration.
Squalamine  
Combretastatin A4P for myopic macular degeneration
Gene therapy for AMD
Anti-VEGF approach to AMD
Delivery of pegaptanib for treatment of AMD  
Stem cell therapy for retinitis pigmentosa
Proliferative retinopathies
Drug delivery for inner ear disorders
Delivery of stem cells for hearing loss
Auditory hair cell replacement by gene therapy
Future prospects of drug delivery to the inner ear  
Drug delivery in psychiatric disorders  
Delivery of antidepressants
Transdermal delivery of antidepressants  
Nasal delivery of antidepressants  
Delivery methods and formulations of antipsychotics  
Long-acting injectable antipsychotics
Transdermal haloperidol  
Transdermal risperidone for treatment of schizophrenia
Transdermal blonanserin for treatment of schizophrenia  
Transnasal oxytocin for schizophrenia  
Transdermal lithium for bipolar disorder

6. Drug delivery for brain tumors
Introduction  
Methods for evaluation of anticancer drug penetration into brain tumor  
Innovative methods of drug delivery for glioblastoma
Delivery of anticancer drugs across the blood-brain barrier  
Anticancer agents with increased penetration of BBB  
BBB disruption
Nanoparticle-based targeted delivery of chemotherapy across the BBB
Tyrosine kinase inhibitor increases topotecan penetration into CNS  
Bypassing the BBB by alternative methods of drug delivery  
Intranasal perillyl alcohol  
Intraarterial chemotherapy
Enhancing tumor permeability to chemotherapy
PDE5 inhibitors for increasing BTB permeability
Local delivery of therapeutic agents into the brain  
Biodegradable microspheres containing 5-FU
Carmustine biodegradable polymer implants
Fibrin glue implants containing anticancer drugs.
Interstitial delivery of dexamethasone for reduction of peritumor edema  
Magnetically controlled microspheres  
Convection-enhanced delivery
CED for receptor-directed cytotoxin therapy  
CED of topotecan
CED of a modified diphtheria toxin conjugated to transferrin
CED of nanoliposomal CPT-11  
CED for delivery
I-chTNT-1/B MAb  
Anticancer drug formulations for targeted delivery to brain tumors  
Intravenous delivery of anticancer agents bearing transferrin  
Liposomes for drug delivery to brain tumors  
MAbs targeted to brain tumors  
Targeted delivery of drug-peptide conjugates to glioblastoma
Multiple targeted drugs for brain tumors
Nanoparticles for targeted drug delivery in glioblastoma
Targeted antiangiogenic/apoptotic/cytotoxic therapies  
Targeted drug delivery to gliomas using cholera toxin subunit B  
Introduction of the chemotherapeutic agent into the CSF pathways
Intraventricular chemotherapy for meningeal cancer  
Intrathecal chemotherapy
Photodynamic therapy for chemosensitization of brain tumors
Nanoparticles for photodynamic therapy of brain tumors.
Innovative delivery of radiotherapy to brain tumors
GliaSite Radiation Therapy System
Boron neutron capture therapy for brain tumors  
Cell therapy for malignant brain tumors  
Chimeric antigen receptor T cells
Mesenchymal stem cells to deliver treatment for gliomas  
Intra-cavity stem cell therapy for medulloblastoma  
Gene therapy for glioblastoma
Antiangiogenic gene therapy
Anticancer drug delivery by genetically engineered MSCs  
Intracerebroventricular delivery of gene therapy for gliomas by NSCs  
Intravenous gene delivery with nanoparticles into brain tumors
Ligand-directed delivery of dsRNA molecules targeted to EGFR  
MSC-based gene delivery  
Neural stem cells for drug/gene delivery to brain tumors  
Peptides targeted to glial tumor cells  
RNAi gene therapy of brain cancer
Single-chain antibody-targeted adenoviral vectors
Targeting normal brain cells with an AAV vector encoding interferon-
Poliovirus-based vaccine for glioblastoma
Treatment of medulloblastoma by suppressing genes in Shh pathway  
Virus-mediated oncolytic therapy of brain cancer
HIV-mediated Oncolysis
Autophagy by conditionally replicating adenoviruses  
Reovirus-mediated Oncolysis  
Measles virus-mediated oncolysis  
Oncolytic virus targeted to brain tumor stem cells
Oncolysis with vesicular stomatitis virus  
Future of viral-mediated oncolysis
Vaccination for glioblastoma

7. 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 disease
Parkinson disease
Huntington disease
Amyotrophic lateral sclerosis  
Epilepsy  
Migraine and other headaches
Stroke  
Central nervous system trauma
Multiple sclerosis  
Brain tumors
Limitations of the current drug delivery technologies for CNS
Unmet needs in CNS drug delivery technologies  
Regulatory considerations for drugs that cross the BBB  
Public-private collaboration for transfer of research to the clinic  
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

8. Companies  
Introduction  
Profiles of companies.
Collaborations  

9. 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 with associated disturbances of 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: Investigational drugs administered by intrathecal route  
Table 3-4: Strategies for drug delivery to the CNS across the BBB
Table 3-5: Specific inhibitors of P-glycoprotein in clinical development
Table 3-6: Molecules attached to Trojan horses injected intravenously for CNS effect
Table 3-7: Examples of controlled and sustained release drug delivery for CNS disorders
Table 3-8: Novel methods of delivery of drugs for CNS disorders
Table 3-9: Indications for the clinical applications of NTFs in neurologic disorders  
Table 3-10: 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: Potential indications for gene therapy of neurologic disorders  
Table 4-5: Companies developing cell/gene therapies for CNS disorders
Table 4-6: 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 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 6-1: Innovative methods of drug delivery for glioblastoma
Table 6-2: Strategies for gene therapy of malignant brain tumors  
Table 7-1: Share of drug delivery technologies in selected CNS markets: 2018-2028
Table 7-2: CNS market share of drug delivery technologies 2018-2028  
Table 7-3: Value of CNS drug delivery in the major world markets from 2018-2028
Table 7-4: Limitations of the current drug delivery technologies for CNS.
Table 8-1: 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 2-3: Disruptive vs non-disruptive changes in BBB as response to disease  
Figure 2-4: Role of BBB models for drug delivery in preclinical CNS drug development
Figure 3-1: Routes of drug delivery to the brain  
Figure 3-2: Extracellular mechanism for drug transportation to the brain following intranasal administration.  
Figure 3-3: Penetration of CSF into spinal cord  
Figure 3-4: Disposition of opioids after intrathecal administration  
Figure 3-5: Use of receptor-mediated transcytosis to cross the BBB
Figure 3-6: Nanotechnology-based strategies for delivery of BDNF to the CNS  
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: Trojan horse approach for delivery of AGT-181 to the brain  
Figure 6-1: A concept of targeted drug delivery to glioblastoma across the BBB  
Figure 6-2: Mechanism of antitumor effects of poliovirus-based vaccine for glioblastoma  
Figure 7-1: Unmet needs in the CNS drug delivery technologies  

Note: Product cover images may vary from those shown
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