Made by Cellculture 23 May 2003 www.dnathink.org www.biolover.com www.bioin.org StemCellBiologyandGeneTherapy EditedbyPeterJ.Quesenberry,GaryS.Stein,BernardG.Forget,ShermanM.Weissman Copyright1998Wiley-Liss,Inc. ISBNs:0-471-14656-0(Paper);0-471-22395-6(Electronic) STEM CELL BIOLOGY AND GENE THERAPY STEMCELLBIOLOGY ANDGENETHERAPY Edited by PETER J. QUESENBERRY GARY S. STEIN University of Massachusetts Worcester, Massachusetts BERNARD G. FORGET SHERMAN M. WEISSMAN Yale University School of Medicine New Haven, Connecticut A JOHN WILEY & SONS, INC., PUBLICATION New York l Chichester l Weinheim l Brisbane l Singapore l Toronto Designationsusedbycompaniestodistinguishtheirproductsareoften claimedastrademarks.InallinstanceswhereJohnWiley&Sons,Inc.,is awareofaclaim,theproductnamesappearininitialcapitalorALL CAPITALLETTERS.Readers,however,shouldcontacttheappropriate companiesformorecompleteinformationregardingtrademarksand registration. Copyright1998Wiley-Liss,Inc.Allrightsreserved. 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CONTENTS Preface vii Contributors ix Stem Cell Systems: Basic Principles and Methodologies 1 Susan K. Nilsson and Peter J. Quesenberry Cytokine/Growth Factor Responsiveness of Early Hemopoietic 15 Progenitor Cells Antony W. Burgess Molecular Mechanisms Controlling the Cell Cycle and 41 Proliferation-Differentiation Interrelationships Gary S. Stein, Andre J. Van Wijnen, Dennet R. Hushka, Baruch Frenkel, Jane B. Lian, and Janet L. Stein Stem Cell Transcription 81 Sherman M. Weissman and Archibald S. Perkins Hematopoietic Stem Cells: Proliferation, Purification and 133 Clinical Applications Ruth Pettengell and Malcolm A. S. Moore Delivery Systems for Gene Therapy: The Adenovirus 161 Thomas Shenk Gene Transfer to Muscle and Spinal Cord Using Herpes 179 Simplex Virus-Based Vectors Johnny Huard, William F. Goins, Giridhar R. Akkaraju, David Krisky, Tom Oligino, Peggy Marconi, Charles S. Day, andJoseph C. Glorioso V vi CONTENTS 8 Herpes Virus Vectors 201 Xandra 0. Breakefield, Peter Pechan, Karen Johnston, and David Jacoby 9 Delivery Systems for Gene Therapy: Adeno-Associated Virus 235 Gabriele Kroner- Lux, Christopher E. Walsh, and Richard Jude Sam&ski 10 Delivery Systems for Gene Therapy: Adeno-Associated 257 Virus 2 A run Srivastava 11 Ribozyme Gene Therapy Targeting Stem Cells for 289 Human Immunodeficiency Virus Infection Anthony D. Ho, Ping Law, Xinqiang Li, and Flossie Wong-Staal 12 Elements of DNA Vaccine Design 309 Michael J. Caufield and Margaret A. Liu 13 Development of Gene Therapy for Gaucher Disease 331 J.A. Barranger, E. 0. Rice, J. Dun&an, M. Eljanne, N. Takivama, M. Nimgaonkar, J. Mierski, M. Beeler, A. Kemp, J. Lancia,dS. Lucot, S. Schierer-Fochler, J. Mannion-Henderson, T. Mohney, W. Swaney, A. Bahnson, V. Bansal, and E. Ball 14 Clinical Applications of Gene Therapy: Correction of Genetic 363 Disease Affecting Hematopoietic Cells Jeffrevd A. Medin, Johan Richter, and Stefan Karlsson 15 Gene Therapy for Hemophilia 385 Katherine A. High 16 Clinical Applications of Gene Therapy: Anemias 411 George F. Atweh and Bernard G. Forget 17 Clinical Applications of Gene Therapy in Cancer: Modification 429 of Sensitivity to Therapeutic Agents Thomas Licht, Michael M. Gottesman, and Ira Pastan 18 Clinical Applications of Gene Therapy: Brian Tumors 455 Kenneth W. Culver and John C. Van Gilder 19 Clinical Applications of Gene Therapy: Cardiovascular Disease 471 Jonathan C. Fox 20 Applications of Gene Therapy to Neurological Diseases 503 and Injuries Derek L. Choi-Lundberg and Martha C. Bohn Index 555 PREFACE During the past several years there have been significant conceptual and experimental advances in stem cell biology and gene therapy. Consequently, this is a topic of importance to a broad spectrum of investigators and physicians pursuing biological regulatory mechanisms and treatment of human disease. At one time, stem cell investigations were principally confined to identification and characterization of primitive cells which commit to the hematopoietic lineage. In a restricted sense, such studies provided a viable basis for defining regulatory parameters of hematopoietic cell differentiation. But significantly, from a broader biological perspective, a paradigm was established for studying progenitor cells which are competent to develop and sustain the phenotypic properties in a series of cells and tissues. Insight into fundamental properties of stem cells is being translated to therapeutic applications. Here again, the hematopoietic stem cell has paved the way for emerging applications of stem cell biology to treatment of disease. In response to the requirement for a volume which covers stem cell biology and gene therapy from both biological and clinical standpoints, we have orga- nized this book into four sections. The first section presents fundamental regulatory mechanisms which are operative in stem cells. Consideration is given to the strengths and limitations of protocols for stem cell isolation. The validity of markers for the primitive status of stem cell populations is critically evaluated. Regulatory mechanisms which support competency for prolifera- tion and cell cycle progression as well as down regulation of growth that accompanies differentiation are reviewed. Cytokines and growth factors which are key modulators of growth control and microenvironmental (stromal) in- vii . . . VIII PREFACE fluences are discussed within the contexts of physiological control and as an arsenal of factors to selectively influence the extent to which stem cells engage in renewal, proliferation and differentiation. The second section is devoted to a consideration of stem cells from a therapeutic perspective. Preparations of stem cells are addressed in relation to retention of biological activities, ability to sustain lineage potentials follow- ing ex-vivo expansion and capabilities for both engraftment and differentiation following return to the in vivo environment. These are important considera- tions for the therapeutic potential of stem cells as vehicles for gene therapy. Additionally, insight into regulatory components of tissue remodelling can be appreciated. Section three addresses delivery systems for gene therapy. It is here that the rate limiting steps for many applications of DNA-mediated treatment of human disease reside. An overview of the most promising vectors is presented. Consideration is given to levels of activity, sustained expression and options for conditional activity. Immunization by gene transfer and antisense strategies are considered. The final section focuses on clinical applications for gene therapy. There is a systematic assessment of approaches to eliminate defective genes or replace or supplement activities of defective genes by manipulating cells at the molecu- lar level. Our intention was not to be inclusive. Rather, we have provided examples to illustrate how gene therapy offers viable alternatives to conven- tional treatments and options for therapy where currently success has been minimal. Examples include but are not restricted to metabolic disorders, coag- ulation disorders, anemias, pulmonary diseases, cancer, cardiovascular disease, and neurological disorders. Because gene therapy is a rapidly advancing field, it would not be realistic to comprehensively cover the basic biological and clinical parameters. Rather, we have selected components of regulatory mechanisms that are central to clinical applications. The therapeutic applications were chosen as representa- tive of the potential which gene therapy provides for treatment of human disease. The challenges now faced are numerous. These are being met by refinements in vector systems as well as gene modifications and improvements in stem cell engraftment strategies. THE EDITORS CONTRIBUTORS Giridhar R. Akkaraju, Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 George F. Atweh, Professor of Medicine, Division of Hematology, Mount Sinai School of Medicine, One Gustav Levy Place, New York, NY 10029 A. Bahnson, University of Pittsburgh Medical Center, Pittsburgh, PA 15261 E. Ball, University of Pittsburgh Medical Center, Pittsburgh, PA 15261 V. Bansal, University of Pittsburgh Medical Center, Pittsburgh, PA 15261 .I. A. Barranger, University of Pittsburgh Medical Center, Pittsburgh, PA 15261 M. Beeler, University of Pittsburgh Medical Center, Pittsburgh, PA 15261 Martha C. Bohn, Children’s Memorial Institute for Education and Research, Department of Pediatrics, Northwestern University Medical School, Chi- cago, IL 60614 Xandra 0. Breakfield, Massachusetts General Hospital East, Molecular Neu- rogenetics Unit, 13th Street, Building 149, Charlestown, MA 02129 Antony W. Burgess, Ludwig Institute for Cancer Research? Melbourne 3050, Australia Michael J. Caufield, Department of Virus and Cell Biology, Merck Research Labs, West Point, PA 19454 ix X CONTRIBUTORS Derek Choi-Lundberg, Department of Neurobiology and Anatomy, Box 603, 601 Elmwood Ave, University of Rochester School of Medicine and Den- tistry, Rochester, NY 14642 Kenneth W. Culver, Director, Gene Therapy Research and Clinical Affairs, Codon Pharmaceuticals, Gaithesburg, MD 20877 Charles S. Day, Department of Orthopedic Surgery, Musculoskeletal Re- search Center, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 J. Dunigan, University of Pittsburgh Medical Center, Pittsburgh, PA 15261 M. Eljanne, University of Pittsburgh Medical Center, Pittsburgh, PA 15261 Bernard G. Forget, Professor of Medicine, Hematology Section, Yale Univer- sity School of Medicine, 333 Cedar Street, New Haven, CT 06510 Jonathan C. Fox, University of Pennsylvania, Department of Medicine, Room 809c, Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104-6100 Baruch Frenkel, Department of Orthopedics & Institute for Genetic Medi- cine, University of Southern California School of Medicine, 2250 Alcazar St., Los Angeles, CA 90033 Joseph C. Glorioso, Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 William F. Goins, Department of Molecular Genetics and Biochemistry, Uni- versity of Pittsburgh School of Medicine, Pittsburgh, PA 15261 Michael M. Gottesman, Laboratory of Cell Biology, National Cancer Insti- tute, NIH, Building 37, Room lB22, 37 Convent Drive, Bethesda, MD 20892-4255 Katherine A. High, The Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Room 310 Abramson Research Center, Philadel- phia, PA 19104 Anthony D. Ho, Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0671 Johnny Huard, Department of Orthopedic Surgery, Musculoskeletal Re- search Center, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 Dennet R. Hushka, 1708 William & Mary Common, Hillsboro, NJ 08876 David Jacoby, Massachusetts General Hospital East, Molecular Neuroge- netics Unit, 13th Street, Building 149, Charlestown, MA 02129