An introduction to molecular medicine and gene therapy

Preface xiii Contributors xv Chapter 1 Molecular Medicine and Gene Therapy: An Introduction 1 Thomas F. Kresina and Andrea D. Branch Introduction 1 Genetic Manifestations of Molecular Medicine 2 Gene Therapy and Patterns of Gene Expression 7 Gene Therapy and Molecular Medicine 8 Gene Therapy: Current Basic Science Issues 15 Human Gene Therapy: Current Status and Basic Science Research Needs 17 Gene Therapies: Next Horizon 18 Key Concepts 20 Suggested Readings 22 Chapter 2 Nuclear Transplantation and New Frontiers in Genetic Molecular Medicine 25 D. Joseph Jerry and James Robl, with Ethics Note by Leonard M. Fleck Background 25 Introduction 25 Nuclear Transplantation: A Tool in Developmental Biology 26 Technical Developments in Nuclear Transplantation 29 Defining the Limits of Nuclear Reprogramming in Mammals 32 Toward an Understanding of the Mechanisms of Genetic Reprogramming 34 Application of Genetic Reprogramming 38 Human Embroyonic Stem Cell Research: An Ethics Note 39 Summary 41 Key Concepts 41 Suggested Readings 42 Chapter 3 Builing a Better Mouse: Genetically Altered Mice as Models for Gene Therapy 47 Eric Sandgren and William C. Kisseberth Background 47 Introduction 47 vii Producing Mouse Models of Human Disease 48 Mouse Models for Gene Therapy:What Makes a Good Model of Human Disease? 57 Models of Monogenic Disorders 58 Models of Polygenic and Multifactorial Disorders 62 Mouse Models of Molecular Therapeutics: Developing and Testing Gene Therapy Methodology 67 Generation of Chimeric Tissues 69 Human Cell Xenograft Models in Immunodeficient Mice 69 Mouse Models: The Next Generation 71 Key Concepts 72 Suggested Readings 74 Chapter 4 Vectors in Gene Therapy 77 Katherine Parker Ponder Introduction 77 Viral Vectors Used for Gene Therapy 78 Retroviral Vectors 78 Adenoviral Vectors 91 Adenovirus-Associated Virus 97 Herpes Simplex Virus 1 102 Other Viral Vectors 105 Nonviral Vectors 105 Oligonucleotides 108 Key Concepts 110 Suggested Readings 111 Chapter 5 Gene Targeting 113 Eric B. Kmiec Background and Challenges 113 Introduction of DNA into the Cell 114 Nonviral Transfer Vehicles 116 Gene Targeting 117 Recombinational and Repair Enzymes in Gene Targeting Efforts 119 Synthetic Oliogonucleotides as Tools for Targeting 120 Insertion of Fragments of DNA: Gene Disruption and Replacement 122 Gene Targeting Has Already Proven Useful 126 Gene Targeting: The Future 128 Key Concepts 129 Suggested Readings 129 Chapter 6 Gene Therapy for Hematological Disorders 133 Cynthia E. Dunbar and Tong Wu Introduction 133 Requirements for Gene Transfer into Hematopoietic Cells 134 Hematopoietic Stem and Progenitor Cells as Targets for Gene Therapy 137 viii CONTENTS Lymphocyte Gene Transfer 145 Current Problems and Future Directions 147 Summary 150 Key Concepts 150 Suggested Readings 151 Chapter 7 Gene Therapy for Liver Disease 153 Christy L. Schilling, Martin J. Schuster, and George Wu Background 153 Introduction 153 General Principles for Hepatic Gene Therapy 154 Clinical Applications of Liver-Directed Gene Therapy 161 Summary 178 Key Concepts 179 Suggested Readings 180 Chapter 8 Gene Therapy in Cardiovascular Disease 183 Victor J. Dzau, Afshin Ehsan, and Michael J. Mann Introduction 183 Genetic Manipulation of Cardiovascular Tissue 184 Gene Therapy of Restenosis 187 Gene Therapy for Angiogenesis 189 Gene Therapy of Vascular Grafts 192 Gene Therapy for the Heart 195 Summary 198 Key Concepts 198 Suggested Readings 199 Chapter 9 Components of Cell and Gene Therapy for Neurological Disorders 203 Laurie C. Doering Introduction 203 Sorting Out the Complexity of the Nervous System 205 What Goes Wrong in Neurological Disorders? 207 Neurotophic Factors and Gene Therapy 210 Neural Transplants and Stem Cells 218 Clinical Neurodegenerative Conditions 222 Clinical Trials Testing Genetically Modified Cells and Neurotrophic Factors for Neurodegeneration 228 Future Considerations and Issues 229 Key Concepts 230 Suggested Readings 232 Chapter 10 Gene Therapy in the Treatment of Cancer 235 Simon J. Hall, Thomas F. Kresina, Richard Trauger, and Barbara A. Conley Background 235 Introduction 235 CONTENTS ix Genetic Basis of Carcinogenesis 236 Gene Therapy Approaches to the Treatment of Cancer 242 DNA Cancer Vaccines 255 Summary 260 Key Concepts 260 Suggested Readings 261 Chapter 11 Gene Therapy for HIV Infection 263 Bruce Bunnell Background 263 Introduction 263 Genetic Organization of HIV 264 Life Cycle and Pathogenesis of HIV-1 Infection 267 Genetic Approaches to Inhibit HIV Replication 269 Transdominant Negative Proteins 269 Nucleic-Acid-Based Gene Therapy Approaches 274 Genetic Approaches to Enhance Immunity in AIDS Stimulation of an HIV-Specific Immune Response 279 Practical Aspects of Gene Therapy for HIV 280 Anti-HIV Gene Therapy Clinical Trials 282 Conclusions 287 Key Concepts 287 Suggested Readings 288 Chapter 12 Gene Therapy Approaches for Rheumatoid Arthritis 291 Renate E. Gay, Steffen Gay, and Thomas Pap Introduction 291 General Considerations about Gene Therapy in RA 291 Delivery of Gene to Synovial Cells 294 Animal Models to Test Gene Therapy Approaches 295 Current Targets for Gene Therapy in RA 296 Clinical Status and Future Perspective 299 Key Concepts 299 Suggested Readings 300 Chapter 13 Federal Oversight of Gene Therapy Research 303 Thomas F. Kresina Background 303 Introduction 304 Office of Biotechnology Activities 305 Recombinant DNA Advisory Committee 306 Current Review and Approval Process 308 Moving Too Fast in a Field of Promise 311 Institutional Review of Recombinant DNA Research 312 International Efforts at Regulatory Oversight 315 Summary 315 x CONTENTS Key Concepts 316 Suggested Readings 317 Chapter 14 Ethical Issues in Molecular Medicine and Gene Therapy 319 Leonard M. Fleck Background 319 Introduction 319 Molecular Medicine and Gene Therapy: Ethical Issues in the Clinical Context 320 Gene Therapy: Ethical Issues at the Policy Level 333 Key Concepts 343 Suggested Readings 345 Chapter 15 Epilogue: Personal Genetic Medicine—The Future Is Now 347 Thomas F. Kresina Introduction 347 DNA Databases 347 Individual Genetic Preventive Medicine 348 Individual Genetic Medicine and Pharmacotherapy 349 Suggested Readings 350 Appendix: Commercial Implications: Large-Scale DNA Production and Quality Control; Technology Advancement and Elucidating the Human Genome 353 Charles Lollo and Andrea D. Branch Background 353 Introduction 353 Proprietary Technology 354 Considerations in Choosing a Target Disease for Gene Therapy 356 DNA Production and Quality Control 357 Large-Scale Production: An Overview 358 Large-Scale Production: The Purification Process 359 Large-Scale Production: Quality Control 362 Technology Advancement 364 Summary 371 Key Concepts 371 Suggested Readings 372 Index 375