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SUMMARY
Summary
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. 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 2007, projections are made to the years 2012 and
2017. 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 68 companies involved in drug delivery for CNS disorders are
presented along with their technologies, products and 63 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 50 tables and 8 figures.
TABLE OF CONTENTS
0. 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 45
- Autoimmune disorders 46
- Brain tumors 46
- Testing permeability of the BBB 46
- In vitro models of BBB 47
- In vivo study of BBB 47
- Brain imaging 48
- In silico prediction of BBB 48
- Relevance of the BBB penetration to pharmacological action 49
- BBB penetration and CNS drug screening 50
- CERENSESM 50
- Transthyretin monomer as a marker of blood-CSF barrier disruption 50
- Evaluation of BBB permeability by brain imaging 51
- Biomarkers of disruption of blood-brain barrier 51
- Future directions for research on the BBB 51
- Application of genomics and proteomics to the study of BBB 52
- Use of neural stem cells to construct the blood brain barrier 53
- Strategies to cross the BBB 53
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
- Transdermal drug delivery for neurological disorders 59
- Drug delivery to the brain via inner ear 59
- 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 61
- 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 64
- Osmotic opening of the BBB 64
- Focal disruption of BBB by ultrasound 65
- Chemical opening of the BBB 65
- Cerebral vasodilatation to open the BBB 65
- Use of nitric oxide donors to open the BBB 66
- Manipulation of the sphingosine 1-phosphate receptor system 66
- Pharmacological strategies to facilitate transport across the BBB 66
- 2B-Trans"! technology with specific carrier protein 67
- ABC afflux transporters and penetration of the BBB 67
- Carrier-mediated drug delivery across the BBB 68
- Glycosylation Independent Lysosomal Targeting 68
- Inhibition of P-glycoprotein to enhance drug delivery across the BBB 68
- Modification of the drug to enhance its lipid solubility 69
- Monoclonal antibody fusion proteins 70
- Neuroimmunophilins 70
- Peptide-mediated transport across the BBB 70
- Prodrug bioconversion strategies and their CNS selectivity 72
- Role of the transferrin-receptor system in CNS drug delivery 72
- Transport of small molecules across the BBB 73
- Transport across the BBB by short chain oligoglycerolipids 73
- Transvascular delivery across the BBB 73
- Trojan horse approach 73
- Use of receptor-mediated transocytosis to cross the BBB 74
- Cell-based drug delivery to the CNS 76
- Activated T lymphocytes 76
- Microglial cells 76
- Neural stem cells 76
- Drug delivery to the CNS by using novel formulations 77
- Crystalline formulations 77
- Liposomes 77
- Monoclonal antibodies 78
- Microspheres 79
- Microbeads 79
- Lipid-coated microbubbles 80
- Brain-targeted chemical delivery systems 80
- Nanotechnology-based drug delivery to CNS 81
- Nanoparticles for drug delivery to CNS 81
- Nanovesicles for transport across BBB 82
- Nanotechnology-based devices and implants for CNS 82
- Biochip implants for drug delivery to the CNS 83
- Controlled-release microchip 83
- Retinal implant chip 83
- Convection-enhanced delivery to the CNS 84
- Systemic administration of drugs for CNS effects 84
- Sustained and controlled release drug delivery to the CNS 84
- Fast dissolving oral selegiline 86
- Choice of the route of systemic delivery for effect on the CNS disorders
86
- Methods of delivery of biopharmaceuticals to the CNS 87
- Methods of delivery of peptides for CNS disorders 87
- Challenges for delivery of peptides across the BBB 88
- Transnasal administration of neuropeptides 88
- Direct delivery of neuropeptides into the brain 88
- Alteration of properties of the BBB for delivery of peptides 89
- Molecular manipulations of peptides to facilitate transport into CNS 89
- CNS delivery of peptides via conjugation to biological carriers 89
- Delivery of conopeptides to the brain 90
- Delivery of neurotrophic factors to the nervous system 90
- Systemic administration of NTFs 92
- Delivery systems to facilitate crossing of the BBB by NTFs 93
- Use of microspheres for delivery of neurotrophic factors 93
- Intracerebroventricular injection 94
- Direct application of NTFs to the CNS 94
- Intrathecal administration 95
- Implants for delivery of neurotrophic factors 95
- Use of neurotrophic factor mimics 95
- Use of microorganisms for therapeutic entry into the brain 97
- Bacteriophages as CNS therapeutics 97
- Intracellular drug delivery in the brain 97
- Local factors in the brain affecting drug action 98
- Methods for testing drug delivery to the CNS 98
- Animal models for testing drug delivery 98
- Screening for drug-P-gp interaction at BBB 98
4. Delivery of Cell, Gene and Antisense Therapies to the CNS 99
- Introduction 99
- Cell therapy of neurological disorders 99
- Methods for delivering cell therapies in CNS disorders 99
- Encapsulated cells 100
- Genetically modified stem cells for metachromatic leukodystrophy 101
- CNS neotissue implant 101
- CNS delivery of cells by catheters 101
- Intravascular administration 102
- Gene therapy techniques for the nervous system 102
- Introduction 102
- Methods of gene transfer to the nervous system 104
- AAV vector mediated gene therapy for neurogenetic disorders 104
- Ideal vector for gene therapy of neurological disorders 104
- Promoters of gene transfer 105
- Routes of delivery of genes to the CNS 105
- Cell-mediated gene therapy of neurological disorders 106
- Neuronal cells 106
- Implantation of genetically modified encapsulated cells into the brain 107
- Genetically modified bone marrow cells 108
- Nanoparticles as non-viral vectors for CNS gene therapy 108
- Companies involved in cell/gene therapy of neurological disorders 109
- Antisense therapy of CNS disorders 109
- Delivery of antisense oligonucleotides to the CNS 110
- Delivery of oligonucleotides cross the BBB 111
- Cellular delivery systems for oligonucleotides 112
- High-flow microinfusion into the brain parenchyma 112
- Systemic administration of peptide nucleic acids 112
- Introduction of antisense compounds into the CSF Pathways 113
- Intrathecal administration of antisense compounds 113
- Intracerebroventricular administration of antisense oligonucleotides 114
- Nanoparticle-based delivery of antisense therapy to the CNS 114
- Methods of delivery of ribozymes 115
- Delivery aspects of RNAi therapy of CNS disorders 115
- Delivery of siRNA to the CNS 115
- Future drug delivery strategies applicable to the CNS 116
5. Drug Delivery in the Treatment of CNS Disorders 117
- Parkinson's disease 117
- Drug delivery systems for Parkinson's disease 118
- Duodenal levodopa infusion 120
- Transdermal drug delivery for PD 120
- Transdermal dopamine agonists for Parkinson's disease 120
- Transdermal administration of other drugs for Parkinson's disease 122
- Intracerebral administration of GDNF 122
- Cell therapy for Parkinson's disease 122
- Human dopaminergic neurons for PD 124
- Graft survival-enhancing drugs 124
- Xenografting porcine fetal neurons 124
- Encapsulated cells for PD 125
- Stem cells for PD 125
- Engineered stem cells for drug delivery to the brain in PD 127
- Human retinal pigment epithelium cells for PD 127
- Delivery of cells for PD 128
- Gene therapy for Parkinson disease 128
- Rationale 128
- Techniques of gene therapy for PD 129
- Prospects of gene therapy for Parkinson's disease 132
- Companies developing gene therapy for PD 133
- RNAi therapy of Parkinson's disease 133
- Alzheimer disease 134
- Drug delivery for Alzheimer disease 134
- Blood-brain partitioning of an AMPA receptor modulator 135
- Clearing amyloid through the BBB 135
- Delivery of the passive antibody directly to the brain 136
- Delivery of thyrotropin-releasing hormone analogs by molecular packaging
136
- Intranasal delivery of nerve growth factor to the brain 136
- Nanoparticle-based drug delivery for Alzheimer's disease 137
- Perispinal etanercept 137
- Slow release implant of an AChE inhibitor 137
- Transdermal drug delivery in Alzheimer's disease 138
- Trojan-horse approach to prevent build-up of Ab
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