Drug Delivery in Central Nervous System Disorders - technologies, markets and companies |
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0. Executive Summary .. 12 1. Basics of Drug Delivery to the Central Nervous System ...... 14 Introduction. 14 Historical evolution of drug delivery for CNS disorders ............. 14 Neuroanatomical and neurophysiological basis of drug delivery... 15 The cerebrospinal fluid....15 The extracellular space in the brain ....16 Neurotransmitters ..........16 Neuropharmacology relevant to drug delivery ........ 18 Introduction to neuropharmacology ....18 Pharmacokinetics ...........18 Absorption and distribution of drugs ..18 Drug metabolism and elimination ..19 Pharmacodynamics.........19 Receptors.................19 Sites of drug action in the CNS ..........19 Receptors coupled to guanine nucleotide binding proteins ........20 Acetylcholine receptor channels ....20 Dopamine receptors ..20 GABA receptor channels...............21 Glutamate receptor channels ........21 Non-competitive NMDA antagonists ...21 Serotonin receptors ...22 G-protein coupled receptors .........22 In vivo study of drug action in the CNS in human patients.............22 Electroencephalography ...............22 Brain imaging ...........23 Chronopharmacology as applied to the CNS...............23 2. Blood Brain Barrier ... 26 Introduction. 26 Features of the blood-brain barrier relevant to CNS drug delivery 26 The neurovascular unit ...26 Functions of the BBB ......27 BBB as an anatomical as well as physiological barrier ..............27 BBB as a biochemical barrier ........28 Genomics and proteomics of BBB ..28 Other neural barriers ......29 Blood-cerebrospinal fluid barrier....29 Blood nerve barrier....29 Blood-retinal barrier ..29 Blood-labyrinth barrier.................29 Passage of substances across the blood-brain barrier .............. 30 Transporters localized in the BBB .......30 Glucose transporter ...31 Amino acid transporters ...............32 Ionic transporter .......32 Efflux transport systems ..............32 BBB-specific enzymes .....33 Receptor-mediated transcytosis .........34 Lysophosphatidic acid-mediated increade in BBB permeability .......34 Folate transport system ..35 Molecular biology of the BBB .............35 Transport of peptides and proteins across the BBB .....35 Passage of leptin across the BBB...35 Passage of cytokines across the BBB .36 Passage of hormones across the BBB.36 Passage of enzymes across the BBB ..37 Drugs that cross the BBB by binding to plasma proteins...........37 Current concepts of the permeability of the BBB ........37 Factors that increase the permeability of the BBB .. 38 BBB disruption as adverse effect of vaccines for CNS disorders ......38 CNS disorders that affect the permeability of BBB ......39 Neurodegenerative disorders ........40 Mitochondrial encephalopathies.....41 Multiple sclerosis.......41 - 4 - Central nervous system injuries ....41 Epilepsy .42 Cerebrovascular disease...............42 Infections.................42 Autoimmune disorders.................43 Brain tumors ............43 Testing permeability of the BBB........ 43 In vitro models of BBB ....44 In vivo study of BBB.......44 Brain imaging ...........45 In silico prediction of BBB45 Relevance of the BBB penetration to pharmacological action..........46 BBB penetration and CNS drug screening .............47 CERENSESM...............47 Transthyretin monomer as a marker of blood-CSF barrier disruption...47 Evaluation of BBB permeability by brain imaging........47 Biomarkers of disruption of blood-brain barrier ..........48 Future directions for research on the BBB............... 48 Application of genomics and proteomics to the study of BBB..........49 Use of neural stem cells to construct the blood brain barrier ..........49 Strategies to cross the BBB............... 50 3. Methods of Drug Delivery to the CNS............ 52 Introduction. 52 Routes of drug delivery to the brain.. 53 Delivery of drugs to the brain via the nasal route .......53 Nasal delivery of insulin-like growth factor-I .........54 Nasal delivery of midazolam .........54 Nasal delivery of hypocretin..........55 Intranasal administration of IFN beta-1b..............55 Nasal delivery of thyrotropin-releasing hormone by nanoconstructs.................55 Invasive neurosurgical approaches .....56 Intraarterial drug delivery to the brain .................56 Direct injection into the CNS substance or CNS lesions.............57 Intraventricular injection of drugs .57 Intrathecal drug delivery..............58 Devices for drug delivery to the CNS .59 Nanotechnology-based devices and implants for CNS...............60 Strategies for drug delivery to the CNS across the BBB ............ 61 Increasing the permeability (opening) of the BBB.......61 Osmotic opening of the BBB .........61 Focal disruption of BBB by ultrasound 62 Chemical opening of the BBB........62 Cerebral vasodilatation to open the BBB...............62 Use of nitric oxide donors to open the BBB ...........62 Manipulation of the sphingosine 1-phosphate receptor system ..63 Pharmacological strategies to facilitate transport across the BBB....63 Modification of the drug to enhance its lipid solubility...............63 Transvascular delivery across the BBB .................64 Use of transport or carrier systems64 Role of the transferrin-receptor system in CNS drug delivery ....64 Use of receptor-mediated transocytosis to cross the BBB .........65 2B-Trans™ technology with specific carrier protein66 ABC afflux transporters and penetration of the BBB .................66 Inhibition of efflux transporters that impede drug delivery........67 Trojan horse approach .................68 Transport of small molecules across the BBB ........69 Peptide-mediated transport across the BBB ..........69 Transport across the BBB by short chain oligoglycerolipids .......70 Monoclonal antibody fusion proteins ..71 Prodrug bioconversion strategies and their CNS selectivity .......71 Neuroimmunophilins..72 Cell-based drug delivery to the CNS ...72 Activated T lymphocytes ..............72 Microglial cells ..........72 Drug delivery to the CNS by using novel formulations.72 Crystalline formulations ...............72 Liposomes................73 Monoclonal antibodies74 Microspheres ............74 Microbeads...............75 - 5 - Lipid-coated microbubbles............75 Brain-targeted chemical delivery systems .................76 Nanotechnology-based drug delivery to CNS .......... 76 Nanoparticles for drug delivery to CNS76 Nanotechnology-based devices and implants for CNS .78 Biochip implants for drug delivery to the CNS......... 78 Controlled-release microchip .............78 Retinal implant chip........78 Convection-enhanced delivery to the CNS............... 79 Systemic administration of drugs for CNS effects ... 80 Sustained and controlled release drug delivery to the CNS ............80 Fast dissolving oral selegiline ........81 Choice of the route of systemic delivery for effect on the CNS disorders................82 Methods of delivery of biopharmaceuticals to the CNS.............. 82 Methods of delivery of peptides for CNS disorders ......82 Challenges for delivery of peptides across the BBB 83 Transnasal administration of neuropeptides ..........83 Direct delivery of neuropeptides into the brain ......83 Alteration of properties of the BBB for delivery of peptides .......84 Molecular manipulations of peptides to facilitate transport into CNS.................84 CNS delivery of peptides via conjugation to biological carriers...85 Delivery of conopeptides to the brain.85 Delivery of neurotrophic factors to the nervous system.................85 Systemic administration of NTFs ...87 Delivery systems to facilitate crossing of the BBB by NTFs........88 Use of microspheres for delivery of neurotrophic factors ..........88 Intracerebroventricular injection ...89 Direct application of NTFs to the CNS.89 Intrathecal administration ............90 Implants for delivery of neurotrophic factors.........90 Use of neurotrophic factor mimics .90 Use of microorganisms for therapeutic entry into the brain...... 92 Bacteriophages as CNS therapeutics...92 Intracellular drug delivery in the brain . 92 Local factors in the brain affecting drug action ....... 93 Methods for testing drug delivery to the CNS.......... 93 Animal models for testing drug delivery ..93 Screening for drug-P-gp interaction at BBB ...............93 4. Delivery of Cell, Gene and Antisense Therapies to the CNS. 94 Introduction. 94 Cell therapy of neurological disorders... 94 Methods for delivering cell therapies in CNS disorders.94 Encapsulated cells .....95 Genetically modified stem cells for metachromatic leukodystrophy 96 CNS neotissue implant .................96 CNS delivery of cells by catheters..96 Intravascular administration .........97 Gene therapy techniques for the nervous system ... 97 Introduction 97 Methods of gene transfer to the nervous system ........99 AAV vector mediated gene therapy for neurogenetic disorders.......99 Ideal vector for gene therapy of neurological disorders .................99 Promoters of gene transfer.............. 100 Routes of delivery of genes to the CNS . 100 Cell-mediated gene therapy of neurological disorders ................. 101 Neuronal cells ......... 101 Implantation of genetically modified encapsulated cells into the brain ............ 102 Genetically modified bone marrow cells.............. 103 Nanoparticles as non-viral vectors for CNS gene therapy............. 103 Companies involved in cell/gene therapy of neurological disorders ... 104 Antisense therapy of CNS disorders 104 Delivery of antisense oligonucleotides to the CNS..... 105 Delivery of oligonucleotides cross the BBB............... 106 Cellular delivery systems for oligonucleotides .......... 107 High-flow microinfusion into the brain parenchyma .. 107 Systemic administration of peptide nucleic acids ...... 107 Introduction of antisense compounds into the CSF Pathways ....... 108 Intrathecal administration of antisense compounds .. 108 Intracerebroventricular administration of antisense oligonucleotides . 109 Nanoparticle-based delivery of antisense therapy to the CNS....... 109 - 6 - Methods of delivery of ribozymes ..... 110 Delivery aspects of RNAi therapy of CNS disorders ................. 110 Delivery of siRNA to the CNS ........... 110 Future drug delivery strategies applicable to the CNS............. 111 5. Drug Delivery in the Treatment of CNS Disorders ............. 112 Parkinson's disease....... 112 Drug delivery systems for Parkinson's disease ......... 113 Duodenal levodopa infusion ........ 115 Transdermal drug delivery for PD 115 Transdermal dopamine agonists for Parkinson's disease......... 115 Transdermal administration of other drugs for Parkinson's disease ................ 116 Intracerebral administration of GDNF................. 117 Cell therapy for Parkinson's disease.. 117 Human dopaminergic neurons for PD ................. 119 Graft survival-enhancing drugs ... 119 Xenografting porcine fetal neurons .. 119 Encapsulated cells for PD ........... 120 Stem cells for PD..... 120 Engineered stem cells for drug delivery to the brain in PD ...... 122 Human retinal pigment epithelium cells for PD .... 122 Delivery of cells for PD ............... 123 Gene therapy for Parkinson disease.. 123 Rationale................ 123 Techniques of gene therapy for PD .. 124 Prospects of gene therapy for Parkinson's disease ................. 127 Companies developing gene therapy for PD ........ 128 RNAi therapy of Parkinson's disease . 129 Alzheimer disease ......... 129 Drug delivery for Alzheimer disease.. 129 Slow release implant of an AChE inhibitor................ 130 Blood-brain partitioning of an AMPA receptor modulator.............. 130 Clearing amyloid through the BBB .... 131 Trojan-horse approach to prevent build-up of A b aggregates ....... 131Delivery of the passive antibody directly to the brain 131 Delivery of thyrotropin-releasing hormone analogs by molecular packaging......... 132 Transdermal drug delivery in Alzheimer's disease..... 132 Intranasal delivery of nerve growth factor to the brain................ 133 Cell and gene therapy for Alzheimer disease............ 133 NGF gene therapy ... 133 Neprilysin gene therapy ............. 134 RNAi therapy of Alzheimer's disease . 134 Huntington's disease..... 135 Treatment of Huntington's disease ... 135 Drug delivery in Huntington's disease ... 135 Gene therapy of Huntington’s disease... 135 Encapsulated genetically engineered cellular implants............ 135 Viral vector mediated administration of neurotrophic factors... 136 RNAi therapeutics for the treatment of HD.......... 136 Amyotrophic lateral sclerosis.......... 136 Treatment of ALS ......... 136 Drug delivery in ALS..... 137 Gene and antisense therapy of amyotrophic lateral sclerosis........ 138 Neurotrophic factor gene therapies of ALS.......... 138 Antisense therapy of ALS ........... 139 RNAi therapy of amyotrophic lateral sclerosis...... 139 Drug delivery for CNS involvement in Hunter syndrome ......... 140 Cerebrovascular disease ................. 140 Treatment of stroke...... 141 Drug delivery in stroke . 141 Intraarterial administration of tissue plasminogen activator in stroke............. 142 Drug delivery for prevention of restenosis of carotid arteries ....... 143 Modified NO donors . 143 In-stent restenosis .. 144 Targeted local anti-restenotic drug delivery ........ 144 Catheter-based drug delivery for restenosis........ 145 Stents for prevention of restenosis .. 145 Drug-eluting stents . 146 Antisense approach to prevent restenosis........... 146 Drug-eluting stents for the treatment of intracranial atherosclerosis . 147 Tissues transplants for stroke .......... 147 - 7 - Transplant of encapsulated tissue secreting neurotrophic factors. 147 Cell therapy for stroke .. 147 Stem cell transplant into the brain... 148 Immortalized cell grafts for stroke... 148 Intravenous infusion of marrow stromal cells ...... 149 Intravenous infusion of umbilical cord blood stem cells .......... 149 Future of cell therapy for stroke .. 149 Gene therapy of cerebrovascular diseases ............... 150 Gene transfer to cerebral blood vessels............. |
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