Neurogenomics and Neurotherapeutic Strategies

Chapter 1. Introduction

1.1 Alzheimer’s Disease
1.2 Parkinson’s 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. Alzheimer's Disease

2.1 Epidemiology of Alzheimer’s Disease
2.2 Types of Dementia
-Parkinson’s Disease
-Diffuse Lewy Body Disease
-Vascular Dementia
-Multi-Infarct Dementia
-Subcortical Vascular Dementia
-Frontal Lobe Dementia and Pick’s Disease
-Huntington’s 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
--Axonyx’s Phenserine
--Cortex Pharmaceuticals’ CX516
--CeregeneR 17;s Nerve Growth Factor (NGF)
--Neurochem’s Alzhemed
--Targacept’s NNRs
--Memory Pharmaceuticals’ Compounds
--Myriad Genetics’ Compounds
--Eunoe’s COGNIShunt: A Medical Device
--Prana Biotechnology’s PTB-1 Compound
--Praecis Pharmaceuticals’ Apan
--ReGen Therapeutics’ Colostrinin
--Acumen Pharmaceuticals’ ADDL Mechanism
--Sanofi-Synthélabo
--GlaxoSmithKline
--Wyeth
--Bristol-Myers Squibb
--Forest Laboratories
--Boehringer-Ingelheim Pharmaceuticals
--Hoffmann-La Roche
-Alternative Treatments for Alzheimer’s Disease
--Coenzyme Q10 or Ubiquinone
--Ginkgo biloba
--Huperzine A
--Phosphatidylserine
--Vitamin E
--Other Naturopathic Treatments
2.6 Early-Stage Tools and Approaches Used in Alzheimer’s 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
--Elan’s 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 NIA’s Neuroscience and Neuropsychology of Aging Program
--The Alzheimer’s 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 Pharma’s TranzExpression Technology
--Neurome’s Analysis of Elan’s Mouse Model of AD
--Baylor College of Medicine’s VGLUT1 Knockout Mice
--Harvard Medical School’s p25 and Cdk5 mouse model
--Johns Hopkins University’s Mouse Model of BACE1 Inhibition
--University of California at Irvine’s Triple Transgenic Mice

Chapter 3. Parkinson's 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 Parkinson’s 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 Parkinson’s Disease
--Newron Pharmaceuticals’ Safi namide
--Aderis Pharmaceuticals’ SPM-962 (Rotigotine)
--Avigen’s AV-201 Gene Therapy Approach
--Ceregene’s GDNF Gene Delivery Approach
--Acadia Pharmaceuticals’ ACP-103
--Boston Life Sciences’ Altropane Imaging Agent
--Cephalon’s CEP-1347
--Neurologix’s NLX-P101 Gene Therapy
--Schering-Plough’s Adenosine-2a Antagonist
--Teva Neuroscience/Eisai’s Agilect (Rasagiline mesylate)
--Titan Pharmaceuticals’ Speramine
--Guilford Pharmaceuticals’ Neuroimmunophilin Ligands
--GlaxoSmithKline’s ReQuip
3.8 Surgical Procedures to Treat Parkinson’s 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 (Pfizer’s Adrucil)
-Investigational Treatments for ALS
--CytRx’s RNAi Gene-Silencing Technology
--Ceregene and Chiron’s 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 N eurons
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-Generat ed 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< br> -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 Syst em
--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-Synthélabo
--AstraZeneca
--Aventis Pharmaceuticals
--Eli Lilly
--Forest Laboratories
--Lexicon Genetics
--Somerset Pharmaceuticals
-Alternative Treatments
--Psychothe rapy
--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 Meth ods 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

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

Chapter 9. Business Outlook

9.1 Expert Commentaries
-Raymond T. Bartus (Ceregene)
-Uli Hacksell (Acadi Pharmaceuticals)
-Michael Sorell (Neurologix)
-Wendell Wierenga (Neurocrine Biosciences)
9.2 Overvivew of Unmet R& amp;D Needs
-Animal Model Considerations
-The Search for more effective Treatments
9.3 Clinical Trial Considerations
-Issues in Endpoint Selection
9.4 Advances in Molecular Diagnostics
-AD, PD, ALS
9.5 Competitive Considerations