神經基因體科學與神經治療策略：平台、目標、治療法的新方向性

Overview

CNS disorders affect a vast patient population and represent a huge area of unmet therapeutic need. In the United States alone, Alzheimers disease (AD), Parkinsons disease (PD), and amyotrophic lateral sclerosis (ALS) afflict more than 6.5 million people. Drug discovery efforts for the most prevalent CNS diseases have met with varying success; it is estimated that billions of dollars are spent every year on prescription drug sales, however, many current therapies merely treat the symptoms but do not provide cures.

The complexity of CNS diseases make this area a challenging but potentially very rewarding area for research. Neurogenomics and Neurotherapeutic Strategies: New Directions in Platforms, Targets, and Therapeutic Approaches evaluates drug development efforts in six major CNS diseases:

• Alzheimers disease
• Parkinsons disease
• Amyotrophic Lateral Sclerosis
• Schizophrenia
• Depression

Bipolar disorder

This report surveys the numerous R&D efforts under way at companies and institutions around the world, focusing on discovery projects, preclinical studies, and early-stage human trials. It also addresses investigational methods, proposed mechanisms of action, pathways, and targets that research teams are exploring in order to move one step closer to developing effective therapeutics. Novel tools and platforms, including animal models, molecular imaging, and biomarkers, will also be covered.

Table of Contents

Chapter 1. Introduction

• 1.1 Alzheimers Disease
• 1.2 Parkinsons Disease
• 1.3 Amyotrophic Lateral Sclerosis
• 1.4 Schizophrenia
• 1.5 Depression
• 1.6 Bipolar Disorder
• 1.7 Conclusion
• Part 1. Neurological Diseases

Chapter 2. Alzheimers Disease

• 2.1 Epidemiology of Alzheimers Disease
• 2.2 Types of Dementia
• -Parkinsons Disease
• -Diffuse Lewy Body Disease
• -Vascular Dementia
• -Multi-Infarct Dementia
• -Subcortical Vascular Dementia
• -Frontal Lobe Dementia and Picks Disease
• -Huntingtons Disease
• 2.3 Etiology and Pathophysiology: How the AD Brain Works
• 2.4 The Genetics of AD
• -Classification of AD Types Based on Genetic Inheritance
• -Genes Involved in Early- and Late-Onset AD
• --The Apolipoprotein E (APOE) Gene
• --The GSTO1 Gene and Age of Onset of AD
• 2.5 AD Therapeutics
• -Cholinesterase Inhibitors: The Gold Standard for Mild-to-Moderate AD
• -Treatment for Moderate to Severe AD: The Glutamate Pathway
• -Investigative Therapies for AD
• --Axonyxs Phenserine
• --Cortex Pharmaceuticals CX516
• --Ceregenes Nerve Growth Factor (NGF)
• --Neurochems Alzhemed
• --Targacepts NNRs
• --Memory Pharmaceuticals Compounds
• --Myriad Genetics Compounds
• --Eunoes COGNIShunt: A Medical Device
• --Prana Biotechnologys PTB-1 Compound
• --Praecis Pharmaceuticals Apan
• --ReGen Therapeutics Colostrinin
• --Acumen Pharmaceuticals ADDL Mechanism
• --Sanofi-Synthelabo
• --GlaxoSmithKline
• --Wyeth
• --Bristol-Myers Squibb
• --Forest Laboratories
• --Boehringer-Ingelheim Pharmaceuticals
• --Hoffmann-La Roche
• -Alternative Treatments for Alzheimers Disease
• --Coenzyme Q10 or Ubiquinone
• --Ginkgo biloba
• --Huperzine A
• --Phosphatidylserine
• --Vitamin E
• --Other Naturopathic Treatments
• 2.6 Early-Stage Tools and Approaches Used in Alzheimers R&D
• -A Urine Test to Detect AD
• -The Trojan Horse Strategy
• -Notch-Protein Signaling Cascade
• -Transthyretin Protein
• -Samaritan Pharmaceuticals Neuroprotective Compound SP-33
• -Biomarkers for AD
• --CCR1 As a Biomarker
• --The M266 Biomarker for Amyloid in the Blood
• --A Biomarker Panel for AD Detection
• -Vaccines for AD
• --Elans AN-1792 Vaccine (Suspended)
• --Oral Vaccine Developed
• -Repurposing Other Drugs for AD
• --Clioquinol: An Antibiotic
• --Lithium Shows Promise in AD Mouse Model
• --Lipitor and Other Statins
• -Cell Therapy
• -In Vitro Brain Slice Techniques
• -The Role of Fyn in Synaptic Impairment
• 2.6 R&D Platforms
• -Molecular Imaging
• --Positron Emission Tomography (PET)
• --Pittsburgh Compound B
• --FDDNP
• --Applications of PET in Drug Efficacy Testing
• -Selected Imaging Initiatives Focusing on AD
• --The NIAs Neuroscience and Neuropsychology of Aging Program
• --The Alzheimers Disease Neuroimaging Initiative
• --The UCLA Neuroimaging Lab
• --Li-Cor Biosciences Odyssey Infrared Imaging System for AD
• -Animal Models of AD
• --APP Models
• --PS1 Models
• --Transgenic Mice
• --Transgenic Flies
• -Companies and Organizations and Their AD Animal Models
• --Tranzyme Pharmas TranzExpression Technology
• --Neuromes Analysis of Elans Mouse Model of AD
• --Baylor College of Medicines VGLUT1 Knockout Mice
• --Harvard Medical Schools p25 and Cdk5 mouse model
• --Johns Hopkins Universitys Mouse Model of BACE1 Inhibition
• --University of California at Irvines Triple Transgenic Mice

Chapter 3. Parkinsons Disease

• 3.1 Epidemiology of PD
• 3.2 Etiology and Pathology of PD
• 3.3 Symptoms of PD
• -Tremor
• -Rigidity
• -Bradykinesia
• -Postural Instability
• 3.4 The Genetics of PD
• -Genetic Risk Factors
• -Mitochondrial Impairment
• -Genes for Early-Onset PD
• -Genes for Late-Onset PD
• 3.5 Other Theories of Etiology
• -Oxidative Neuronal Damage
• -Smoking and Coffee
• -Free-Radical Theory
• -Endogenous and Exogenous Toxins
• 3.6 Parkinsonism: Conditions That Mimic PD
• -Postencephalitic Parkinsonism
• -Drug-Induced Parkinsonism
• -Striatonigral Degeneration
• -Arteriosclerotic Parkinsonism
• -Toxin-Induced Parkinsonism
• -Parkinsonism-Dementia Complex of Guam
• -Parkinsonism Accompanying Other Conditions
• 3.7 Parkinsons Disease Therapeutics
• -Levodopa-Carbidopa: The Gold-Standard Treatment
• -Other Leading Therapeutic Classes
• --Dopamine Agonists
• --Selegiline
• --Anticholinergic Drugs
• --Amantadine
• --COMT Inhibitors
• -Improvements on Current Therapies
• --Tolcapone Combination Therapy
• --Parcopa Orally Disintegrating Tablets
• -Investigational Treatments for Parkinsons Disease
• --Newron Pharmaceuticals Safinamide
• --Aderis Pharmaceuticals SPM-962 (Rotigotine)
• --Avigens AV-201 Gene Therapy Approach
• --Ceregenes GDNF Gene Delivery Approach
• --Acadia Pharmaceuticals ACP-103
• --Boston Life Sciences Altropane Imaging Agent
• --Cephalons CEP-1347
• --Neurologixs NLX-P101 Gene Therapy
• --Schering-Ploughs Adenosine-2a Antagonist
• --Teva Neuroscience/Eisais Agilect (Rasagiline mesylate)
• --Titan Pharmaceuticals Speramine
• --Guilford Pharmaceuticals Neuroimmunophilin Ligands
• --GlaxoSmithKlines ReQuip
• 3.8 Surgical Procedures to Treat Parkinsons Disease
• -Lesioning Techniques
• -Deep-Brain Stimulation
• -Activa Tremor Control System
• 3.9 Investigative Pathways and Techniques
• -The Dopamine Degeneration Theory of PD
• --MPTP As an Investigative Tool
• --Dopamine Transporter Malfunction
• --Novel Dopamine Receptors
• --Dopamine Implants
• --PET Scanning of Dopamine Receptors
• --Controlled-Release Formulas and Implantable Pumps
• -Cellular Implant Therapies
• --Nerve Cell Implantation
• --LEAPS: Encapsulated Cell Delivery of GDNF
• --Stem-Cell Approaches
• -The Inflammation Model of PD
• -Sonic Hedgehog and Gli-1 Proteins
• 3.10 Animal Models Platforms in PD
• -Transgenic Mice and Other Nonprimate Models: Applications and Limitations
• -Nonhuman Primate Models
• -Toxin Models
• --MPTP
• --6-OHDA
• --Rotenone
• -Gene-Knockout and Transgenic Animals

Chapter 4. Amyotrophic Lateral Sclerosis

• 4.1 Epidemiology of ALS
• 4.2 Etiology, Pathophysiology, and Genetic Components of ALS
• -SOD1: The First ALS Gene
• -ALS2
• -ALS4
• -Linkage to Chromosome 16
• -Other ALS Gene Mutations
• -Neurofilament Gene Mutations in Sporadic ALS
• 4.3 ALS Therapeutics
• -Riluzole: The Gold-Standard Treatment for ALS
• -Other Treatments for ALS
• --Colchicine
• --Fluorouracil (Pfizers Adrucil)
• -Investigational Treatments for ALS
• --CytRxs RNAi Gene-Silencing Technology
• --Ceregene and Chirons IGF-1 Gene Therapy Programs
• --Ceftriaxone, Promethazine, and Ebselen
• -Compounds Under Investigation at the ALS Therapy Development Foundation
• --Lantus
• --Insulin ICV
• --Long-Acting IGF-1
• --Trehalose
• --Nelfinavir
• --Guanidine hydrochloride
• --TNF-alpha
• --Polyamines
• --Counting Neurons
• 4.4 Early-Stage Approaches in ALS R&D
• -The Oxidative Stress Model
• -The SOD1 Toxin Model
• -Regenerating Axons via Nogo Inhibition
• -SOD1 Mutations: Neuronal Aggregates and Abnormal Protein Folding
• 4.5 Tools and Platforms for Discovery
• -Biomarkers
• -Stem Cells
• --The Challenge to the Use of Stem Cells in ALS
• --Olfactory Bulb Stem Cells
• --Olfactory Neural Stem Cells in the Mouse Model for ALS
• --Spinal Cord Stem Cells
• -The Role of Astrocytes in Neuronal Degeneration
• -Peripherin and the Role of Toxic Splice Variants in ALS
• -Gene Therapy
• -Trophic Factors
• --IGF-1
• --Autoimmunity and IgG
• --VEGF
• -Animal Models
• --The SOD1 Transgenic Mouse Model of ALS
• --The Wobbler Mouse
• --Candida albicans
• --Reintroduction of Stem-Cell-Generated Motor Neurons into an ALS Rat
• --Model
• --The SOD1 C. elegans Model
• --Zebrafish Model

Part 2. Psychiatric Disorders

Chapter 5. Schizophrenia

• 5.1 Epidemiology of Schizophrenia
• 5.2 Types of Schizophrenia and Related Illnesses
• -Paranoid Schizophrenia
• -Disorganized (Hebephrenic) Schizophrenia
• -Catatonic Schizophrenia
• -Residual Schizophrenia.
• -Schizoaffective Disorder
• -Undifferentiated Schizophrenia.
• -Differential Diagnosis: Bipolar Disorder (Manic Depression)
• 5.3 Pathophysiology of Schizophrenia
• 5.4 Manifestations and Symptoms
• -Manifestations
• -Symptomatology
• --Distorted Perceptions of Reality
• --Hallucinations and Illusions
• --Delusions
• --Disordered Thinking
• --Emotional Expression
• 5.5 Genetic Basis of Schizophrenia
• -Genetic Predisposition
• -Familial Linkage
• -Genes Discovered
• -Key Genes Involved
• --Dysbindin-1
• --Neuregulin-1 (NRG1)
• --ERBB3
• --G30, G72, and DAO
• --RGS4
• --COMT
• --PRODH
• Conclusion
• 5.6 Schizophrenia Therapeutics
• -Currently Marketed Antipsychotic Drugs
• -Companies with Therapeutics Under Investigation
• --GlaxoSmithKline
• --Wyeth
• --Targacept
• --American Biogenetic Sciences
• --NPS Pharmaceuticals
• --Cortex Pharmaceuticals
• --deCODE genetics
• --Acadia Pharmaceuticals
• --Potomac Pharma and the Stanley Medical Research Institute
• 5.7 Mechanisms of Action and Pathways Under Investigation
• -Glutamate and Dopamine Neurotransmitter Systems
• -Glutamate Receptor: GRM
• -Linkage Mapping Studies
• -Research at the Mental Health Research Institute
• --Brain Scans
• --The Muscarinic Receptors
• --Serotonin Receptors
• --Benzodiazepine Binding Sites
• --Role of Apolipoproteins
• --Protein S100b
• --High-Throughput Screening to Identify Genes Involved in
• --Schizophrenia Pathology
• --Brain Serotonin
• --Abnormal Eye Movements
• --Unraveling Endophenotypes
• --New Dynamic Imaging Techniques for Studying Schizophrenia
• --Brain Imaging
• --The Endocannabinoid System
• --PKC Overactivation
• --Glycine Transporters
• --Prenatal Evidence of Schizophrenia As a Developmental Disorder
• --Early Biochemical Changes
• 5.8 Animal Models
• -Prepulse Inhibition in Mice and Rats
• -Administration of Hallucinogens in Animal Models
• -Blocking NMDA Receptors in Animal Models
• -Mice Lacking the Brain Protein Calcineurin

Chapter 6. Major Depression

• 6.1 Epidemiology
• 6.2 Types of Depression
• -Dysthymia
• -Bipolar Depression
• -Seasonal Affective Disorder
• 6.3 Symptoms
• 6.4 Causes of Major Depression
• -The Monoamine Theory
• 6.5 Therapeutic Classes for Depression
• -Marketed Therapeutic Treatments
• --Tricyclic Antidepressants
• --Monoamine Oxidase Inhibitors
• --Selective Serotonin Reuptake Inhibitors
• --Serotonin and Norepinephrine Reuptake Inhibitors
• --Bupropion
• -Therapeutics Under Investigation
• --Neurocrine Biosciences: Corticotropin-Releasing Factor
• --Pherin Pharmaceuticals
• --Targacept
• --Wyeth
• --GlaxoSmithKline
• --Pfizer
• --Sanofi-Synthelabo
• --AstraZeneca
• --Aventis Pharmaceuticals
• --Eli Lilly
• --Forest Laboratories
• --Lexicon Genetics
• --Somerset Pharmaceuticals
• -Alternative Treatments
• --Psychotherapy
• --Cognitive-Behavioral Therapy
• --Interpersonal Therapy
• --Electroconvulsive Therapy
• 6.6 New Genes Discovered
• -TPH2 Isoform
• -A New Gene Discovery: CHRM2
• -NIMH Research Efforts
• -University of Pittsburgh Research Efforts: Locating Chromosomal
• -Regions
• -CREB1 Gene
• -Susceptibility Gene
• 6.7 Mechanisms of Action and Pathways Under Investigation
• -Fibroblast Growth Factors
• -Blocking Neuron Formation
• 6.8 Tools and Platforms Used to Study Depression
• -Imaging Technologies
• --Brain Imaging
• --PET Technology
• Animal Models
• -Catecholamine Deficiency
• -Learned Helplessness
• -Behavioral Despair

Chapter 7. Bipolar Disorder

• 7.1 Epidemiology
• 7.2 Symptoms
• -Hypomania
• -Psychosis
• 7.3 Types of Bipolar Disorder
• 7.4 Causes of Bipolar Disorder
• 7.5 Bipolar Disorder Treatments
• -Currently Marketed Treatments
• --Mood Stabilizers
• --Antiseizure Medications
• --Antidepressants
• --Atypical Antipsychotics
• --Psychotropics
• -Psychosocial Interventions
• -Alternative Treatments
• --Electroconvulsive Therapy
• --Herbal Remedies
• 7.6 Genetic Elements and Investigational Methods and Approaches
• -DARPP-32, PENK, and TAC1
• -G-Protein Receptor Kinase 3
• -Other GRK3 Gene Evidence
• -GSK-3 Inhibition
• -Brain-Imaging Studies
• -Benzodiazepine Binding Sites
• -Protein S100b
• -LifeShirt System for Monitoring Cardiopulmonary Parameters
• -Fine Mapping in Candidate Chromosomal Regions
• -Scanning Genes for Variation

Part 3. Companies and Pipelines

Chapter 8. Therapeutics in Development

• Introduction
• 8.1 Company Profiles: Company Focus; Targets and Technology; In the Pipeline
• -Ceregene
• -NPS Pharmaceuticals
• -Targacept
• -Cortex Pharmaceuticals
• -Neurocrine Biosciences
• -Neurochem
• -Lexicon Genetics
• -Avigen
• -Neurologix
• -CytRx
• -Cephalon
• -Newron Pharmaceuticals
• -deCODE genetics
• -Acadia Pharmaceuticals
• -Prana Biotechnology