In 1993, the genetic mutation responsible for Huntington’s disease (HD) was identified. Considered a milestone in human genomics, this discovery has led to nearly two decades of remarkable progress that has greatly increased our knowledge of HD, and documented an unexpectedly large and diverse range of biochemical and genetic perturbations that seem to result directly from the expression of the mutant huntingtin gene.

Neurobiology of Huntington’s Disease: Applications to Drug Discovery presents a thorough review of the issues surrounding drug discovery and development for the treatment of this paradigmatic neurodegenerative disease. Drawing on the expertise of key researchers in the field, the book discusses the basic neurobiology of Huntington’s disease and how its monogenic nature confers enormous practical advantages for translational research, including the creation of robust experimental tools, models, and assays to facilitate discovery and validation of molecular targets and drug candidates for HD. Written to support future basic research as well as drug development efforts, this volume:

• Covers the latest research approaches in genetics, genomics, and proteomics, including high-throughput and high-content screening
• Highlights advances in the discovery and development of new drug therapies for neurodegenerative disorders
• Examines the practical realities of preclinical testing, clinical testing strategies, and, ultimately, clinical usage

While the development of effective drug treatments for Huntington’s disease continues to be tremendously challenging, a highly interactive and cooperative community of researchers and clinical investigators now brings us to the threshold of potential breakthroughs in the quest for therapeutic agents. The impressive array of drug discovery resources outlined in the text holds much promise for treating this devastating disease, providing hope to long-suffering Huntington’s disease patients and their families.

Contents

• Series Preface
• Preface
• Editors
• Contributors
• 1. Huntington’s Disease: Clinical Features and Routes to Therapy
  Henry L. Paulson and Roger L. Albin.
  • OVERVIEW
  • CLINICAL FEATURES
  • NEUROPATHOLOGICAL FEATURES
  • THERAPY: PRESENT AND FUTURE
  • SUMMARY
  • REFERENCES
• 2. Huntington’s Disease Pathogenesis: Mechanisms and Pathways
  Albert R. La Spada, Patrick Weydt, and Victor V. Pineda.
  • INTRODUCTION
  • PROTEIN AGGREGATION AND DEGRADATION
  • PROTEOLYTIC CLEAVAGE
  • TRANSCRIPTIONAL DYSREGULATION
  • EVIDENCE FOR MITOCHONDRIAL ABNORMALITIES AND DEFECTIVE ENERGY METABOLISM IN HD
  • NEUROTROPHIC FACTORS
  • CYTOSKELETAL DEFECTS AND AXONAL TRANSPORT
  • A ROLE FOR THE LOSS OF HUNTINGTIN NORMAL FUNCTION IN HD?
  • NON-CELL AUTONOMOUS DEGENERATION IN HD
  • NEUROINFLAMMATION IN HD: HOW IMPORTANT ARE MICROGLIA?
  • CONCLUSIONS
  • REFERENCES
• 3. Protein Interactions and Target Discovery in Huntington’s Disease
  John P. Miller and Robert E. Hughes.
  • INTRODUCTION
  • PROTEIN INTERACTIONS IMPLICATE MECHANISMS AND TARGET PATHWAYS IN HD
  • TECHNOLOGIES FOR DETECTION OF PROTEIN INTERACTIONS AND PROTEIN COMPLEXES
  • LARGE-SCALE INTERACTION NETWORKS AND NEXT-GENERATION DATA MINING
  • TRANSCRIPTION PROTEIN INTERACTIONS WITH HUNTINGTIN
  • POTENTIAL PROSURVIVAL PROTEIN INTERACTIONS WITH NORMAL HUNTINGTIN
  • POTENTIAL DETRIMENTAL INTERACTION PARTNERS OF MUTANT HUNTINGTIN
  • TRANSCRIPTION PROTEIN INTERACTION SUMMARY
  • REFERENCES
• 4. Target Validation for Huntington’s Disease
  Seung P. Kwak, James K. T. Wang, and David S. Howland.
  • INTRODUCTION
  • THE CHALLENGE OF TARGET VALIDATION FOR HD
  • THE CHDI TARGET VALIDATION PROCESS
  • ADDRESSING BOTTLENECKS IN TARGET VALIDATION
  • REFERENCES
• 5. High-Throughput and High-Content Screening for Huntington’s Disease Therapeutics
  Hemant Varma, Donald C. Lo, and Brent R. Stockwell.
  • INTRODUCTION
  • HIGH-THROUGHPUT SCREENING
  • ASSAY DEVELOPMENT
  • HTS ASSAYS IN HD AND RELATED POLYGLUTAMINE DISORDERS
  • HIGH-CONTENT SCREENING APPROACHES TOWARD HD
  • HTS ACHIEVEMENTS
  • CHALLENGES IN PRIORITIZING HIT COMPOUNDS
  • SMALL MOLECULES AS CHEMICAL TOOLS FOR UNDERSTANDING HD MECHANISMS
  • FUTURE DIRECTIONS
  • REFERENCES
• 6. Value of Invertebrate Genetics and Biology to Develop Neuroprotective and Preventive Medicine in Huntington’s Disease
  Christian Neri.
  • INTRODUCTION
  • INVERTEBRATE BIOLOGY AS A PATH TOWARD PREVENTIVE MEDICINE
  • COMPLEXITY IN HUNTINGTON’S DISEASE: A NETWORK OF DISEASE MODIFIERS?
  • NETWORK BIOLOGY AND NEUROPROTECTIVE DRUG DISCOVERY
  • CONCLUSIONS
  • REFERENCES
• 7. Mouse Models for Validating Preclinical Candidates for Huntington’s Disease
  X. William Yang and Michelle Gray.
  • INTRODUCTION
  • MOUSE GENETIC MODELS OF HD FOR PRECLINICAL STUDIES
  • PRECLINICAL TRIALS WITH MOUSE MODELS OF HD
  • TRANSLATING PRECLINICAL STUDIES TO THE CLINIC
  • REFERENCES
• 8. Pharmaceutical Development for Huntington’s Disease
  Richard J. Morse, Janet M. Leeds, Douglas Macdonald, Larry Park, Leticia Toledo-Sherman, and Robert Pacifici.
  • INTRODUCTION
  • MUTANT HTT AFFECTS SOME CELLS MORE THAN OTHERS, BUT WE DO NOT KNOW WHICH AFFECTED CELLS CAUSE HD PATHOGENESIS
  • THE DRUG DISCOVERY PROCESS
  • CASTING A WIDE NET FOR POSSIBLE HD THERAPIES
  • REFERENCES
• 9. RNA- and DNA- Based Therapies for Huntington’s Disease
  Sass Meghan and Aronin Neil.
  • INTRODUCTION
  • HD THERAPEUTICS BASED ON ANTISENSE TECHNOLOGIES
  • GETTING ANTISENSE OLIGONUCLEOTIDES INTO CELLS
  • GETTING ANTISENSE OLIGONUCLEOTIDES INTO THE BRAIN
  • HD THERAPEUTICS BASED ON RNA INTERFERENCE
  • ANTISENSE VERSUS RNAi
  • OPINIONS AND SPECULATIONS
  • REFERENCES
• 10. Recombinant Intrabodies as Molecular Tools and Potential Therapeutics for Huntington’s Disease
  Khoshnan Ali, Amber L. Southwell, Charles W. Bugg, Jan C. Ko, and Paul H. Patterson.
  • INTRODUCTION
  • STRATEGIES FOR INTRABODY CONSTRUCTION
  • DEVELOPMENT OF EPITOPE-SPECIFIC INTRABODIES AGAINST HUNTINGTIN
  • INTRABODIES AS RESEARCH TOOLS TO DISSECT MECHANISMS OF HTT DISEASE PATHOGENESIS
  • NOVEL TARGETS FOR INTRABODY THERAPY IN HD
  • DELIVERY OF INTRABODIES TO THE HD BRAIN
  • FUTURE DIRECTIONS FOR INTRABODIES IN HD THERAPY
  • REFERENCES
• 11. Biomarkers to Enable the Development of Neuroprotective Therapies for Huntington’s Disease
  Steven M. Hersch and H. Diana Rosas.
  • INTRODUCTION
  • BIOMARKERS AND CLINICAL STAGES OF HD
  • BIOMARKER DEVELOPMENT AND CHARACTERIZATION
  • OXIDATIVE STRESS AND INFLAMMATION
  • TRANSCRIPTIONAL MARKERS
  • SMALL MOLECULES
  • HUNTINGTIN
  • REFERENCES
• 12. Huntington’s Disease: Clinical Experimental Therapeutics
  Dorsey E. Ray and Shoulson Ira.
  • INTRODUCTION
  • CANDIDATES FOR EXPERIMENTAL THERAPEUTICS
  • DETECTION OF THERAPEUTIC EFFECTS
  • CLINICALLY MEANINGFUL OUTCOMES
  • SPECIAL CHALLENGES AND OPPORTUNITIES IN HD CLINICAL TRIALS
  • REFERENCES

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