神経疾患治療における飛躍的発展動向：アルツハイマー病、パーキンソン病、鬱病、双極性障害、統合失調症

Abstract

Current therapies for neurodegenerative and psychiatric diseases leave much to be desired. Alzheimer' s and Parkinson' s diseases are an increasing burden on the health care systems of the developed countries as the proportion of their elderly population rises. As for psychiatric disorders, their social and economic impact can be measured by the fact that antipsychotics and antidepressants account for nearly a quarter of total sales for the world' s top 10 best-selling drugs. Potential Breakthroughs in Neurotherapeutics: Alzheimer' s Disease, Parkinson' s Disease, Depression, Bipolar Disorder, and Schizophrenia, a new CHA Advances report, provides a comprehensive assessment of truly innovative, early-stage research that we feel will translate into significant advances in neurotherapy. Specifically, it:

• Surveys current basic academic research relevant to drug or target discovery
• Highlights topics that show promise of future commercial potential
• Examines conditions in the technology transfer milieu relevant to these emerging opportunities
• Assesses the commercial potential for these emerging opportunities
• Seeks the views of individuals in industry and academia with insight into the foregoing issues

The report begins with an analysis of the technology transfer process that bridges university research and the commercial world ― its triumphs, but also its difficulties operating in the current risk-aversive commercial environment. Although industrial R&D activity focused on CNS disorders is intense, progress toward significant innovation remains slow and largely dependent on new leads generated from academia. Potential Breakthroughs in Neurotherapeutics describes one research program in neurology that is turning out to be a ' poster child' for translational medicine.

For each of the 5 diseases, Potential Breakthroughs in Neurotherapeutics reviews consensus thinking about the pathophysiological mechanisms, targets, and the state-of-the-art in drug therapy. Then it launches into a review of significant research findings in each disease ― the compounds and their targets already in discovery or early development with potential therapeutic value. In evaluating the commercial potential of each target or compound, the report relies on a proprietary scoring system based on the following criteria:

• Stage of the project
• Number of directly related citations in PubMed
• Strength of the mechanistic story and theoretical support
• Efficacy probability based on studies in cells, tissues, or animal disease models
• Overall rating from 1 (worst) to 10 (best)

More than 125 compounds and more than 40 targets, sponsored by 82 companies, are subjected to this rigorous evaluative process. Moreover, early stage research within each disease area is given an overall rating, and particularly strong compounds, targets, or therapeutic approaches are singled out for discussion. The report supplements this rich analysis with interviews with 8 thought leaders in neurotherapeutics from industry and academia, plus profiles of 20 companies at the forefront of CNS research.

Table of Contents

CHAPTER 1.

INTRODUCTION: NEUROLOGICAL DISORDERS HAVE CLEAR UNMET NEEDS

• 1.1. Clarifying the Problems
• 1.2. Translating the Research

CHAPTER 2.

CURRENT STATUS AND TRENDS IN TECHNOLOGY TRANSFER

• 2.1. The Nature of Technology Transfer Today
• 2.2. Effects of Government Policy on Technology Transfer
  • Dry-eye Therapeutic Agent
  • Blood Glucose Monitoring
• 2.3. Problems Surrounding Technology Transfer
• 2.4. Translational Medicine Comes to Academia

CHAPTER 3.

BACKGROUND INFORMATION ON DISEASES TARGETED FOR THIS REPORT

• 3.1. Alzheimer' s Disease
  • Key Findings Translated into Therapeutic Advances
  • State of the Art in Drug Therapy
• 3.2. Parkinson' s Disease
  • Key Findings Translated into Therapeutic Advances
  • State of the Art in Drug Therapy
• 3.3. Unipolar Depression
  • Key Findings Translated into Therapeutic Advances
  • State of the Art in Commercial Applications
• 3.4. Bipolar Disorder
  • Key Findings Translated into Therapeutic Advances
  • State of the Art in Drug Therapy
• 3.5. Schizophrenia
  • Key Findings Translated into Therapeutic Advances
  • State of the Art in Drug Therapy

CHAPTER 4.

CURRENT BASIC RESEARCH FINDINGS WITH HIGH POTENTIAL FOR COMMERCIAL APPLICATIONS

• 4.1. Alzheimer' s Disease
  • Compounds and Targets Currently in Discovery or Development
  • Disease-Modification Approaches
  • Acetylcholine Receptor Modulation
  • Other Approaches
  • Miscellaneous Mechanisms
  • Recent Advances Potentially Leading to New Therapies
  • p25/Cdk5
  • GSK-3
  • Fyn
  • ERK Pathway
  • Wnt Pathway
  • LR11
  • Amyloid and Ion Channels
  • Aß Degrading Enzymes
  • Oxidative Stress
  • Microtubule-Associated Proteins
  • Prostaglandin E2 E Prostanoid Subtype 2 (PGE2 EP2) Receptors
  • Cholesterol Metabolism and the LDL Receptor
  • Cannabinoid Receptors
• 4.2. Parkinson' s Disease
  • Compounds and Targets Currently in Discovery or Development
  • Recepter Agonists and Antagonists
  • Gene Therapy
  • Other Approaches
  • Recent Advances Potentially Leading to New Therapies
  • Leucine-Rich Repeat Kinase 2 (Lrrk2)
  • Parkin
  • PINK1
  • PPARγ
  • p53
  • Heme Oxygenase-1
  • Nicotinic Acetylcholine Receptors (nAChRs)
  • NADPH Oxidase
• 4.3. Unipolar Depression
  • Compounds and Targets in Discovery or Development
  • Neurotransmitter Modulation
  • Recent Advances Potentially Leading to New Therapies
  • Microtubule Stabilization
  • Cannabinoid CB1 Receptor
  • The Fibroblast Growth Factor (FGF) System
  • p11 (S100A10)
  • PAR-4
  • PSD-95
  • Galanin
• 4.4 Bipolar Disorder
  • Compounds and Targets in Discovery or Development
  • Recent Advances Potentially Leading to New Therapies
  • PSD-95
  • PACAP
  • FAT Gene
  • Protein Kinase C (PKC)
  • BAG-1
  • GSK-3
  • Inositol Metabolism
  • Arachidonic Acid Cascade
• 4.5. Schizophrenia
  • Compounds and Targets in Discovery or Development
  • Serotonin Receptor Antagonists
  • Multiple Factors in Causation
  • Recent Advances Potentially Leading to New Therapies
  • COMT and PRODH
  • Protein Kinase C (PKC)
  • Neuregulin 1
  • DISC1
  • Dysbindin-1
  • PSD-95

CHAPTER 5.

COMMERCIAL POTENTIAL OF SELECTED RESEARCH FINDINGS

• 5.1. Alzheimer' s Disease
  • p25/cdk5
  • Glycogen synthase kinase-3 (GSK-3)
  • Fyn
  • ERK Pathway
  • Wnt Pathway
  • LR11 (SorLA)
  • Amyloid Ion Channels
  • Aß Degrading Enzymes
  • Inflammation and Microglia
  • Oxidative Stress
  • Microtubule-Associated Proteins
  • Prostaglandin E2 E Prostanoid Subtype 2 Receptors (PGE2EP2)
  • Cholesterol Metabolism and the LDL Receptor
  • Cannabinoid Receptors
  • Summary
• 5.2. Parkinson' s Disease
  • Lrrk2
  • Parkin
  • PINK1
  • PPARγ
  • p53
  • Heme Oxygenase-1 (HO-1)
  • Nicotinic Acetylcholine Receptors (nAChRs)
  • NADPH Oxidase
  • Summary
• 5.3. Unipolar Depression
  • Microtubule Stabilization
  • Cannabinoid CB1 Receptor
  • The Fibroblast Growth Factor (FGF) System
  • p11 (S100A10)
  • PAR-4
  • PSD-95
  • Galanin
  • Summary
• 5.4. Bipolar Disorder
  • PSD-95
  • PACAP
  • FAT Gene
  • Protein Kinase C (PKC)
  • BAG-1
  • GSK-3
  • Inositol Metabolism
  • Arachidonic Acid Cascade
  • Summary
• 5.5. Schizophrenia
  • COMT and PRODH
  • Protein Kinase C (PKC)
  • Neuregulin
  • DISC1
  • Dysbindin-1
  • PSD-95
  • Summary

CHAPTER 6.

EXPERT COMMENTARIES

• 6.1. Mark A. Smith, PhD, Professor of Pathology, Case Western Reserve University
• 6.2. Maryka Quik, PhD, Professor, The Parkinson' s Institute
• 6.3. Ross L. Stein, PhD, Director, Laboratory for Drug Discovery in Neurodegeneration, Harvard Center for Neurodegeneration and Repair
• 6.4. Susan L. Stoddard, PhD, Licensing Manager, Mayo Clinic
• 6.5. Michael Palfreyman, PhD, DSc, Vice President, Program Management and Drug Development, En Vivo Pharmaceuticals
• 6.6. C. Anthony Altar, Ph.D., President and CSO, Psychiatric Genomics
• 6.7. Robert G. Urban, PhD, President and CEO, Acretia
• 6.8. Pamela Sklar, MD, PhD, Associate Professor of Psychiatry, Harvard Medical School

CHAPTER 7.

COMPANY PROFILES

• 7.1. Acadia Pharmaceuticals
• 7.2. Axonyx
• 7.3. Biomind
• 7.4. Cortex
• 7.5. Cytos Biotechnology
• 7.6. Elan
• 7.7. En Vivo
• 7.8. ExonHit
• 7.9. GlaxoSmithKline
• 7.10. Lay Line Genomics
• 7.11. Memory Pharmaceuticals
• 7.12. Merck & Co.
• 7.13. Neuro3D
• 7.14. Neurochem
• 7.15. Nymox
• 7.16. Panacea Pharmaceuticals
• 7.17. Psychiatric Genomics
• 7.18. Roche
• 7.19. sanofi-aventis
• 7.20. TorreyPines Therapeutics

References

Index