Methods and Applications of Direct Gene Transfer978-1-4684-6822-9/1.pdf · Methods and Applications of Direct Gene Transfer JonA. ... methods and applications of direct gene transfer

GENE THERAPEUTICS Methods and Applications of

Direct Gene Transfer

GENE THERAPEUTICS Methods and Applications of

Direct Gene Transfer

JonA. Wolff Editor

Foreword by James F. Crow

92 Illustrations with some color art

Birkhauser Boston • Basel • Berlin

JonA. Wolff University of Wisconsin Medical School Departments of Pediatrics, Medical Genetics, and Neurology Waisman Center, Room 607 1500 Highland Avenue Madison, WI 53705-2208 USA

Library of Congress Cataloging-in-Publication Data

Gene therapeutics: methods and applications of direct gene transfer I Jon A. Wolff, editor; foreword by James F. Crow.

p. cm. Includes bibliographical references and index. ISBN-13: 978-1-4684-6824-3 e-ISBN-13: 978-1-4684-6822-9 DOl: 10.1007/978-1-4684-6822-9 1. Gene therapy. I. Wolff, Jon A. (Jon Asher), 1956-[DNLM: 1. Gene Therapy-methods. 2. Transfection-methods. QW 51 G3256 1993]

RBI55.8.G46 1993 616.042-dc20 DNLMlDLC 93-42919 for Library of Congress

Printed on acid-free paper.

©1994 Birkhauser Boston

m® Birkhiiuser U(J?J

Softcover reprint of the hardcover 1 st edition 1994

Copyright is not claimed for works of U.S. Government employees.

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ISBN-13: 978-1-4684-6824-3

Camera-ready copy prepared by the editor and fonnatted using Aldus PageMake~

987654321

To my wife Katalin, for her understanding and inspiration.

Contents

Foreword James F. Crow .............................................................................................. xi

Preface Jon A. Wolff ............................................................................................... xiii

Contributors .................................................................................................... xv

I BACKGROUND

A History of Gene Transfer and Therapy Jon A. Wolff and Joshua Lederberg ............................................................... 3

Producing Mouse Genetic Models for Human Diseases J. David McDonald ..................................................................................... 26

Post-Transcriptional Considerations of Gene Expression: Translation, MRNA Stability, and Poly(A) Processing

Gary Brewer ................................................................................................ 40

Promoters, Enhancers, and Inducible Elements for Gene Therapy Robert G. Whalen ........................................................................................ 60

II METHODS AND MECHANISMS

Possible Mechanisms of DNA Uptake in Skeletal Muscle Martin E. Dowty and Jon A. Wolff .............................................................. 82

Receptor-Mediated Gene Delivery Employing Adenovirus-Polylysine­DNA Complexes

David T. Curiel ............................................................................................ 99

viii Contents

Gene Transfer in Mammalian Cells Using Liposomes as Carriers Arun Singhal and Leaf Huang ................................................................... 118

In Vivo Gene Therapy via Receptor-Mediated DNA Delivery Henry C. Chiou, George L Spitalny, June R. Merwin, and Mark A. Findeis .................................................................................. 143

Calcium Phosphate-Mediated DNA Transfection Patricia L. Chang ...................................................................................... 157

Cellular Internalization of Oligodeoxynucleotides LeonardM. Neckers .................................................................................. 180

Gene Transfer via Particle Bombardment: Applications of the Accell Gene Gun

Ning-Sun Yang, Carolyn De Luna, and Liang Cheng ............................... 193

Electrically-Induced DNA Transfer Into Cells. Electrotransfection In Vivo

Sergei I. Sukharev, Alexander V. Titomirov, and VadimA. Klenchin ......... 210

III APPLICATIONS

Pharmacokinetic Considerations in the Use of Genes as Pharmaceuticals

Fred D. Ledley ........................................................................................... 235

Virus-Mediated Genetic Treatment of Rodent Gliomas E. Antonio Chiocca, Julie K. Andersen, Yoshiaki Takamiya, Robert L. Martuza, and Xandra O. Breakefield ........................................ 245

Gene Therapy for Adenosine Deaminase Deficiency and Malignant Solid Tumors

Kenneth W. Culver and R. Michael Blaese ................................................ 263

Development of Herpes Simplex Virus Vectors for Gene Transfer to the Central Nervous System

Joseph C. Glorioso, Neal A. DeLuca, William F. Goins, and David J. Fink ...................................................................................... 281

Direct Gene Transfer and Catheter Based Gene Delivery Systems: Applications to Cardiovascular Diseases and Malignancy

Gregory E. Plautz, Elizabeth G. Nabel, and Gary J. Nabel... ................... 303

Contents ix

Gene Therapy for Arthritis Christopher H. Evans and Paul D. Robbins ............................................. 320

Gene Therapy: The Advent of Adenovirus Leslie D. Stratford-Perricaudet and Michel Perricaudet .......................... 344

In Vivo Gene Transfer Into the Heart Jeffrey M. Leiden and Eliav Barr .............................................................. 363

Receptor-Mediated Targeted Gene Delivery Using Asialoglycoprotein­Polylysine Conjugates

Stephen Furs and George Y. Wu ................................................................ 382

Retroviral-Mediated Gene Transfer and Duchenne Muscular Dystrophy Matthew G. Dunckley and George Dickson .............................................. 391

Keyword Index .............................................................................................. 411

Foreword

During the first half century of genetics, coinciding with the first half of this cen­tury, geneticists dreamt of the repair of genetic disease by altering or replacing defective genes. H. J. Muller wrote of the great advantages of mutations, "nanoneedles" in his apt term, for delicately probing physiological and chemical processes. In the same spirit, genes could be used to provide treatments of needle point delicacy. Yet, during this period no realistic possibility appeared; it remained but a dream.

The situation changed abruptly at the half century. Microbial genetics and its offshoot, cell culture genetics, provided the route. Pneumococcus transformation showed that exogenous DNA could become a permanent part of the genome; yet attempts to reproduce this in animals produced a few tantalizing hints of success, but mostly failures. Transduction, using a virus as mediator, offered a better op­portunity. The fITSt reproducible in vivo gene therapy in a whole animal came in 1981. This was in Drosophila, with a transposable element as carrier. Flies were "cured" of a mutant eye color by incorporation of the normal allele, and the effect was transmissible, foreshadowing not only somatic, but germ line gene therapy.

At the same time, retroviruses carrying human genes were found to be ex­tremely efficient in transferring their contents to the chromosomes of cultured cells. The viruses were simply doing what comes naturally and, as Dunckley and Dickson point out in this book, this activity seems not to be impaired by carrying all but the largest genes. By this time it was apparent that gene therapy would be developed; it was only a matter of time.

Gene therapy will be of greatest value, at least in the easily foreseeable future, for specific monogenic diseases. These, of course, are a small fraction of genetic disease, and a still smaller fraction of all disease. But it is an important fraction, because many of these diseases cause severe lifetime impairments, miserable for the person, distressing for the family, and expensive for society.

The technological advances that facilitate gene therapy will also lead to better treatments of other kinds. And they will lead to diagnosis at successively earlier ages, with corresponding ease of removing defective embryos. As with medicine in general, prevention is better than cure. Ironically, as it becomes increasingly effective, gene therapy may become of lesser importance. Ideally we would have

xii Foreword

one generation of treatment for those diseases already existing, followed by pre­vention of new ones.

How useful will gene therapy be for complex, polygenic disease? This will be much more difficult, although a high-resolution physical and linkage map will aid in the discovery of the more important individual components. There are grounds for optimism, as several articles in this volume attest.

For many monogenic diseases the time for gene therapy is here. Clinical trials are underway. Ethical doubts have been properly raised, but are of decreas­ing intensity as well thought-out protocols provide more predictable and safer re­lief for drastic disease. The humanitarian value of eliminating Duchenne muscular dystrophy, in my view, strongly outweighs any slippery-slope fears. I cheer the day that all existing Duchenne disease genes become extinct and we have ways of early detection of new mutations.

Practical applications of molecular biology have been slow in coming, sur­prisingly slow, but they are making up for this by an explosive growth now. The dream at the beginning of the century will become the reality at its end. How different this fin de siecle is from the last, though perhaps not in spirit.

James F. Crow

Preface

The best theories are usually those that explain much in simple tenns. There is a certain beauty to such ideas. Physicists in search of a "theory of everything," for example, like to admire the aesthetic qualities of their theoretical constructs.

The reasoning behind gene therapy is attractive for this very reason. It is simple: if a genetic disease is caused by a dysfunctioning gene, then the disease state can be corrected by giving the patient the nonnal, functioning gene.

Although gene therapy was initially fonnulated to treat single gene defects, it now holds promise for a wide range of disorders, including cancer, heart disease, and degenerative neurologic disorders. Potentially, it could be a "treatment of ev­erything," or at least of many things.

Initial attempts at gene therapy involved the genetic modification of cells in culture, which were then transplanted back into the body. This is known as an indirect, or ex vivo, approach. The focus of this book is the simpler, in vivo ap­proach that involves the direct introduction of genes into the body without cell transplantation.

The direct approach resembles conventional phannaceutical delivery meth­ods and promises to be much less expensive than the indirect, ex vivo approaches. There is a certain elegance to its simplicity.

Of course, patients care only for alleviation of their disease. They are con­cerned with risk versus benefit ratios, not with the aesthetics of the theoretical underpinnings of their treatment. Only the results of clinical trials will enable us to judge the clinical value of direct gene therapeutics. However, the tremendous progress reported in this book suggests that this approach has a very promising future.

The book is divided into three sections. The first provides a scientific back­ground for the concepts involved in gene therapy that include a history of previous experiments, and the production of mouse genetic models. The basic tenets of expression are explored in one chapter that addresses transcription and another chapter that addresses the post-transcriptional elements of expression. The second section covers the spectacular new methodologies and how these systems work. The methods include naked DNA, oligonucleotides, calcium phosphate precipita­tion, polylysine-complexes, adenovirus-polylysine DNA complexes, liposomes, electroporation, and particle bombardment. The third section covers applications

xiv Preface

for specific organs and diseases. They encompass gene delivery to the eNS skel­etal muscle, heart, liver, lung, thyroid and joints. Applications for cardiovascular disease, brain tumors, immunization, arthritis, cystic fibrosis, and Duchenne mus­cular dystrophy are discussed. Pharmacokinetic considerations are also covered in the chapter by Fred Ledley.

JonA. Wolff

Contributors

Julie K. Andersen, Division of Neurogerontology, Ethel Percy Andrus Gereontology Center, 3715 McClintockAvenue, University of Southern Cali­fornia, Los Angeles, California 90080-0191, USA

Eliav Barr, Department of Medicine, University of Chicago, 5841 South Mary­land Avenue, Chicago, Illinois 60637, USA

R. Michael Blaese, Cellulaur Immunology Section, Metabolism Branch, National Cancer Institute, National Institutes of Health, Building 10, Room 6B05, Bethesda, Maryland 20892, USA

Xandra O. Breakefield, Neuroscience Center, Massachusetts General Hospital, East, Building 149, 13th Street, Charlestown, Massachusetts 02129, USA

Gary Brewer, Department of Microbiology & Immunology, Bowman Gray School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157-1064, USA

Patricia L. Chang, Department of Pediatrics, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5

Liang Cheng, Institute of Pathology, Case Western Reserve School of Medicine, University Hospitals of Cleveland, 2085 Adelbert Road, Cleveland, Ohio 44106, USA

E. Antonio Chiocca, Neuroscience Center, Massachusetts General Hospital- East, Building 149, 13th Street, Charlestown, Massachusetts 02129, USA

Henry C. Chiou, TargeTech, Inc., 290 Pratt Street, Meriden, Connecticut 06450, USA

James F. Crow, Professor Emeritus of Genetics, Genetics Department, University of Wisconsin, Madison, Wisconsin 53706, USA

xvi Contributors

Kenneth W. Culver, Human Gene Therapy Research Institute, Iowa Methodist Medical Center, 1415 Woodland Avenue, Suite 218, Des Moines, Iowa 50309, USA

David Curiel, University of Alabama at Birmingham, 1824 6th Avenue South, Lurleen B. Wallace Thmor Institute, Room 620, Birmingham, Alabama 35294-3300, USA

Neal A. DeLuca, Department of Molecular Genetics & Biochemistry, University of Pittsburgh, W1l52 Biomedical Science Tower, Pittsburgh, Pennsylvania 15261, USA

Carolyn DeLuna, Agracetus, Inc., 8520 University Green, Middelton, Wisconsin 53562, USA

George Dickson, Department of Experimental Pathology, Guy's Hospital, Lon­don Bridge, London SEI 9RT, United Kingdom

Martin E. Dowty, The Procter and Gamble Company, Miami Valley Laborato­ries, P.O. Box 398707, Cincinnati, Ohio 45239-8707, USA

Matthew G. Dunckley, Department of Experimental Pathology, Guy's Hospital, London Bridge, London SEI 9RT, United Kingdom

Christopher H. Evans, The Ferguson Laboratory, Department of Orthopedic Sur­gery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA

Mark A. Findeis, TargeTech, Inc., 290 Pratt Street, Meriden, Connecticut 06450, USA

David J. Fink, Department of Neurology & VA Medical Center, University of Michigan Medical School, Ann Arbor, Michigan 48109-0618, USA

Stephen Furs, Department of Medicine, University of Connecticut School of Medicine, Farmington, Connecticut 06030, USA

Joseph C. Glorioso, Department of Molecular Genetics & Biochemistry, Univer­sity of Pittsburgh, E1246 Biomedical Science Tower, Pittsburgh, Pennsylva­nia 15261, USA

William F. Goins, Department of Molecular Genetics & Biochemistry, University of Pittsburgh, E1251, Biomedical Science Tower, Pittsburgh, Pennsylvania 15261, USA

Contributors xvii

Leaf Huang, Department of Pharmacology, University of Pittsburgh School of Medicine, West 1351 Biomedical Science Tower, Pittsburgh, Pennsylvania 15261-2071, USA

Vadim A. Klencbin, University of Wisconsin, Laboratory of Molecular Biology, 1525 Linden Drive, Madison, Wisconsin 53706, USA

Joshua Lederberg, Rockefeller University, 1230 York Avenue, Suite 400, New York, New York 10021-6341, USA

Fred D. Ledley, Gene Medicine, Inc., 8080 North Stadium Drive, Houston, Texas 77054, and Departments of Cell Biology and Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA

Jeffrey M. Leiden, Department of Medicine and Pathology, Section of Cardiol­ogy, University of Chicago, MC 6080, 5841 South Maryland Avenue, Chi­cago, Illinois 60637, USA

Robert L. Martuza, Department of Neurosurgery, Georgetown University Medi­cal Center, 3800 Reservoir Road N.W., Washington, DC 20007, USA

J. David McDonald, The Wichita State University, Department of Biological Sci­ences, 1845 Fairmount, Box 26, Wichita, Kansas 67260-0026, USA

June R. Merwin, TargeTech, Inc., 290 Pratt Street, Meriden, Connecticut 06450, USA

Elizabeth G. Nabel, Associate Professor of Internal Medicine, Interim Director, Cardiovascular Research Center, The University of Michigan, 1150 W. Medi­cal Center Drive, 3560 MSRB II, Ann Arbor, Michigan, 48109-0688, USA

Gary J. Nabel, Associate Investigator, Howard Hughes Medical Institute and Pro­fessor, Internal Medicine and Biological Chemistry, The University of Michi­gan, 1150 W. Medical Center Drive, 4510 MSRB I, Ann Arbor, Michigan 48109-0650, USA

Leonard M. Neckers, Clinical Pharmacology Branch, Building 10, Room 12N22b, National Institutes of Health, National Cancer Institute, Bethesda, Maryland 20892, USA

Michel Perricaudet, Laboratoire de Genetique des Virus Oncogenes (CNRSUA 1301), Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France

xviii Contributors

Gregory E. Plautz, Assistant Professor, Pediatrics, The University of Michigan, 1150 W. Medical Center Drive, A510C MSRB I, Ann Arbor, Michigan 48109-0684, USA

Paul D. Robbins, Departments of Molecular Genetics and Biochemistry, Univer­sity of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA

Arun Singhal, Department of Pharmacology, University of Pittsburgh School of Medicine, Biomedical Science Tower, West 1316, Pittsburgh, Pennsylvania 15261-2071, USA

George L. Spitalny, TargeTech, Inc., 290 Pratt Street, Meriden, Connecticut 06450, USA

Leslie D. Stratrord-Perricaudet, Laboratoire de Genetique des Virus Oncogenes (CNRSUA 1301), Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France

Sergei I. Sukbarev, University of Wisconsin, Laboratory of Molecular Biology, 1525 Linden Drive, Madison, Wisconsin 53706, USA

Yoshiaki Takamiya, Department of Neurosurgery, Georgetown University Medi­cal Center, 3800 Reservoir Road N.W., Washington, DC 20007, USA

Alexander V. Titomirov, Informax, Inc., P.O. Box 2926, Gaithersburg, Maryland 20886, USA

Robert G. Whalen, Institut Pasteur, Departement de Biologie Moleculaire, Unite de Biochimie, 25 rue du Dr. Roux, 75724 Paris cedex 15, France

Jon A. Wolff, University of Wisconsin Medical School, Departments of Pediat­rics, Medical Genetics and Neurology, Waisman Center, Room 607, 1500 Highland Avenue, Madison, Wisconsin 53705-2208, USA

George Y. Wu, Division of Gastroenterology-Hepatology, University of Connecti­cut School of Medicine, 263 Farmington Avenue, Farmington, Connecticut 06030, USA

Ning-Sun Yang, Agracetus, Inc., 8520 University Green, Middleton, Wisconsin 53562, USA