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Gene Therapy Therapeutic Mechanisms and Strategies edited by Nancy Smyth Templeton Baylor College o~f e ~ i c i n e Houston, Texas Danilo D. Lasic Liposome Consultations Newark, California MARCEL MARCEL DEKKINECR. , NEWY ORK BASEL DEKKER ISBN: 0-8247-7665-8 This book is printed on acid-free paper. Headquarters Marcel Dekker, Inc. 270 Madison Avenue, New York, NY 10016 tel: 21 2-696-9000; fax: 2 12-685-4540 Eastern Hemisphere Distribution Marcel Dekker AG Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-261-8482; fax: 41-61-261-8896 World Wide Web http:l/www.dekker.com The publisher offers discounts on this book when ordered in bulk quantities. For more information, wrtiote S pecial Sales/Professional Marketing at the headquarters address above. Copyright 0 2000 by Marcel Dekker, Inc. All Rights Reserved. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher. Current printing (last digit): 1 0 9 8 7 6 5 4 3 2 1 PRINTED IN THE UNITED STATES OF AMERICA To our friend and colleague ~ichaeSlt rauss This Page Intentionally Left Blank Foreword The promise of being able to manipulate human genetic material in order to treat diseases has long been a hope for patients with heretofore untreatable diseases, as well as a goal for scientists and an anticipated new tool in the physician’s medicine bag. However, lest we forget, Edward Jenner in 1798 pioneered the then unheralded use of cowpox as a vaccine to prevent smallpox. Today we know that specific immunity to a virus similar to smallpox was induced in the persons who were vaccinated, and that from a global perspective, the practice, if not the knowledge of altering the gene structure of humans has proceeded for 1200 years. In fact, the United States has a broad-based public policy that such vaccinations represent good public health practice, and the list of vaccines required for infants and children continues to grow. Thus, the modern hope stems from an older proven idea. However, vaccines have been less successful in preventing or treating diseases of noninfectious origin. In this volume * you will find an astonishing variety of potential strategies to treat and prevent genetic diseases, cancer, and metabolic, neurological, and other therapeutically resistant disorders. You yvill find that the original theories about using viruses as natural messengers of genes have been greatly augmented by novel collaborations among chemists, biochemists-engineers, physicists, and others to provide a wonderfully synergistic, dare one say, holistic-approach to specified genetic therapies. Chemical approaches to soap films lead to liposomes with plasmids. Highly technical engineering leads to a gun to drive genes directly through the cell wall. Molecular biologists who know how to reengineer any sequence to whatever is needed work with leading virologists who can pull from their freezers viral tools once used mostly as reagents to form the most intriguing of therapeutic agents. Going once more back to see the future, how did this happen? An apocryphal theory that I have on occasion put forward is that the United States had a “secret” 40-year bond, one that began in 1957 with the launch of the Russian-developed satellite Sputnik. Massive public investment in education, engineering, medical specialties, and other struggling disciplines led to a dizzying array of breakthroughs: large-scale successful vaccination programs, solid-state electronics, the Internet, the broadening of the National Institutes of Health, and progress in new chemistry, physics and biology, and biotechnology. Medical specialties proliferated, and chemical and biological advances led to immunosuppression making it possible for human organs to be transplanted. The first wave of biotechnology yielded new products that could stimulate growth of red and white cells, while products formerly produced from animals were now made synthetically in bacterial, animal, and human cells. With the Internet has come the democratization of knowledge so that patients are as knowledgeable about diseases as many physicians, and are beginning to ask the hard question of “why not for me?” Like any good 40-year bond that matures, it is time to pick the fruits of that investment and reinvest in the future, a future that must deliver on the excitement and promise of the past 40 years. Indeed, what you will glimpse in this volume is the beginning of the reinvestment, and a knowledgeable public will be able to encourage, as well as judge, how its reinvestment is progressing. Unlike any other field of pharmaceutical and biological product production, gene therapy has always been open to the scrutiny of the public, as detailed in the chapter on regulatory aspects of gene therapy. This public scrutiny has not always focused strictly on science, but it has the vi Foreword distinctly American flavor of allowing everyone to participate, particularly public policy makers, ethicists, and patients. In that sensei t places the public, whop aid for that initial 40-year bond, in the position in whithchey can, will?a nd should shape the public policyo f how to further the potential of gene therapy as a reality. To end this brief foreword, let us focus on the word “reality.” At this writing, no gene therapy product has been approved by the FDA as safe and effective for any disease. It is the hope that that will happen in the future. How near that future is, depends on all of us-the public, the FDA, the NIH, industry-to work, debate, and negotiate toward this goal in the new millennium. I am honored by the request of the publisher and editors to provide this brief introduction, and I am pleased that many of the chapters are written not just by outstanding scientists but also by groups conducting clinical trials regulated by the FDA. The authors are representative of the large arena of gene therapy participants, and as such they and others are moving the field forward in a professional, collegial, and rigorous manner. It is my hope that the authors consider the FDA to be a partner in these efforts. Philip D. Noguchi, M.D. Director Division of Cellular and Gene Therapies Center for Biologics valuation and Research Food and Drug ~dministration Rockville, Ma~land Preface These are exciting times for everyone involved in gene therapy as it evolves into a mature scientific field. Much progress has been made since its inception in the early 1970s. As you will read in this text, many hurdles remain that must be overcome in order for gene therapy to be used routinely as a therapeutic in the clinic. However, the current problems should not be taken as deterrents or barriers to future work or as reasons to abandon gene therapy for the treatment of disease. These hurdles shoulbde embraced as challenges that can be overcome with greater knowledge and research efforts. The authors of this text have provided thoughtful insights into the challenges that must be met in specific applicationosf gene therapy. Medicine has passed through several revolutions in its history. In early times, the healing power of some plants was discovered. Later, primitive surgery and immobilizatioonf broken bones had been achieved. In the last centuries developments included anesthesia,, vaccination, blood transfusion, surgery, and antibiotics. Most recently, major improvements have included novel imaging methods, microsurgery, lasers, organ transplantation, drug libraries based on combinatorial chemistry and high-throughput screening, and the emerging field of gene therapy discussed in this monograph. The origin of many diseases is defective genes. For example, cells can overexpress certain proteoirn ps roduce nonfunc- tional proteins leading to uncontrolled cell division. The goal of gene therapy is to produce normal gene products or, alternatively, to turn off, silence, or down-regulate genes encoding undesirable gene productsT. he first approach requires the delivery of an appropriate cDNA encoding a gene product into the nuclei of the target cells, while protein synthesis can be prevented by antisense oligonucleotides and/or ribozymes that destroy the abiliotfy target mFWAs to be translated. Successful gene therapy requires the knowledgeo f the molecular origin of the disease and the ability to synthesize wild- type gene products at appropriate levels in the target cells. Following the ground-breaking 1950~th~e first concepts of gene transfection and its use in therapy emerged in the 1960s. The obstacles were immense and, although the concept was proven, the first promising results surfaced only in the 1990s. In nature, only viruses and sperm cells are able to transfect their genetic material into appropriate cells in the human body. While the former mechanism is accompanbiye ds evere unwanted side effects, the latter operates in highly specialized conditions. Obviously, man must design new gene delivery systems. Three basic strategies have appeared, including mechanical methods (direct injection, gene gun, electroporation), chemical methods (the complexation of plasmids with cations, polymers, or liposomes), and biological approaches (redesigned, semiartificial viruses). Increased understanding of the genetic origins of many diseases has provided therapeutically interesting results with biological end-points as discussed in the present volume. Furthermore, developments in recombinant DNA technology have produced large-scale preparation of high-expression plasmids and gene delivery vehicles. The field of gene therapy is extremely multidisciplinary, consisting of researchers in life sciences, molecular biologists, biochemists, physiologists, and many other investigators who track the oroigf idni seases and determine the functionaliotyf various proteins. Scientists involved in recombinant DNA technology are constructing and manufacturing plasmids, and virologists are modifying viruses. Chemists are synthesizing new polymers and lipids, and physicists are studying the structure of various DNA- vii viii Preface carrier constructs. Pharmacologists, toxicologists, and physicians analyze the results of gene therapeutics in preclinical models and clinical trials. Because the field of gene therapy is so broad, researchers have found it difficult to be familiar with all the different multidisciplinary aspects. Although several books exist, they cover the field mainly from rather specialized perspectives. The need for a more inclusive treatment, as well as the rapid advances resulting in importannt ew developments, was the reason for assembling this book. We have organized the volume in several parts so that all aspects would be covered comprehensively by leading experts. An additional goal wast o assemble a concisea nd up-to-date book that couldb e used by students as a textbook. Therefore, we asked the contributors to broaden introductions in order to provide sufficient fundamental information to allow easy learning and unders~anding. The authors have provided knowledge covering broad topics in their areas of expertise and have gone well beyond discussion of their focused research efforts. The primary goal of this book is to provide students, scientists, and other interested readers with a broad knowledge of all aspects and tools available in the field of gene therapy. We welcome your comments and criticisms for use in the preparation of future editions. We hope to provide frequent updates that will include additional volumes to cover other topics in depth. This volume is designed to encompass the most widely used vehicles for the deliveryo f nucleic acids, including viraal nd nonviral systems,a nd discussions of the major disease targets for gene therapy. All chapters and illustrations are composed so that readers from diverse disciplines can understand the topics presented. We wish to thank all the individualsw ho were not able to contribute to this edition but provided much useful advice, including Drs. Flossie Wong-Staal, Didier Trono, Theodore Friedmann, Imi KovesdiF, red Ledley, and others. Nancy Smyth Templeton Danilo D. Lasic Contents Foreword v Philip D. Noguchi, M.D. Preface vii Contributors xi Part I. Viral Delivery and Therapeutic Strategies 1. Retroviral Vectors for Gene Therapy 1 Paula M. Cannon and W. French Anderson 2. Adenovirus Vectors for Gene Therapy 1'7 Neil R. Hackett and Ronald G. Crystal 3, Adeno-Associated Virus and Adeno-Associated Virus Vectors for Gene Delivery 41 Barrie J. Carter 4. Ex Vivo Gene Therapy Using Myoblasts and Regulatable Retroviral Vectors 61 Clare R. Ozawa, Matthew L. Springer, and Helen M. Blau 5. Design and Use of Herpes Simplex Viral Vectors for Gene Therapy 81 Darren Wove, William F. Coins, David J. Fink, and Joseph C. Glorioso, I11 6. Alphavirus-Based Vectors for Vaccine and Gene Therapy Applications 109 Thomas W. Dubensky, Jr., John M. Polo, and Douglas J. Jolly Part 11. Nonviral Delivery and Therapeutic Strategies '7. Gene Delivery with Polyethylenimine 131 S. M. Zou, Jean-Paul Behr, D. Goula, and Barbara Demeneix 8. Receptor-Mediated Gene Transfer 141 Kurosh Ameri and Ernst Wagner 9. Modification of Melanoma Cells via Ballistic Gene Delivery for Vaccination 165 Ulrich R. Hengge and Dirk Schadendorf 10. Polymer-Encapsulated Cells for Gene Therapy 181 Dwaine F. Emerich and Elizabeth Razee ix