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An Introduction to Molecular Medicine and Gene Therapy

An Introduction to Molecular Medicine and Gene Therapy

Thomas F. Kresina (Editor)

ISBN: 978-0-471-22387-0

Jan 2002

416 pages


Gene therapy, or the use of genetic manipulation for disease treatment, is derived from advances in genetics, molecular biology, clinical medicine, and human genomics. Molecular medicine, the application of molecular biological techniques to disease treatment and diagnosis, is derived from the development of human organ transplantation, pharmacotherapy, and elucidation of the human genome. An Introduction to Molecular Medicine and Gene Therapy provides a basis for interpreting new clinical and basic research findings in the areas of cloning, gene transfer, and targeting; the applications of genetic medicine to clinical conditions; ethics and governmental regulations; and the burgeoning fields of genomics, biotechnology, and bioinformatics. By dividing the material into three sections - an introduction to basic science, a review of clinical applications, and a discussion of the evolving issues related to gene therapy and molecular medicine-this comprehensive manual describes the basic approaches to the broad range of actual and potential genetic-based therapies.

In addition, An Introduction to Molecular Medicine and Gene Therapy:

  • Covers new frontiers in gene therapy, animal models, vectors, gene targeting, and ethical/legal considerations
  • Provides organ-based reviews of current studies in gene therapy for monogenetic, multifactoral or polygenic disorders, and infectious diseases
  • Includes bold-faced terms, key concepts, summaries, and lists of helpful references by subject in each chapter
  • Contains appendices on commercial implications and a review of the history of gene therapy

This textbook offers a clear, concise writing style, drawing upon the expertise of the authors, all renowned researchers in their respective specialties of molecular medicine. Researchers in genetics and molecular medicine will all find An Introduction to Molecular Medicine and Gene Therapy to be an essential guide to the rapidly evolving field of gene therapy and its applications in molecular medicine.

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

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

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

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

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