Neurogenomics and Neurotherapeutic Strategies: New Directions in Platforms, Targets, and Therapeutic Approaches

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