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Adeno-Associated Virus (AAV) Vectors in Gene Therapy PDF

178 Pages·1996·5.082 MB·English
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Current Topics In Microbiology 218 and Immunology Editors R.W. Compans, Atlanta/Georgia M. Cooper, Birmingham/Alabama· H. Koprowski, Philadelphia/Pennsylvania· F. Melchers, Basel M. Oldstone, La Jolla/California· S. Olsnes, Oslo M. Potter, Bethesda/Maryland· H. Saedler, Cologne P.K. Vogt, La Jolla/California· H. Wagner, Munich Springer Berlin Heidelberg New York Barcelona Budapest Hong Kong London Milan Paris Santa Clara Singapore Tokyo Adeno-Associated Virus (AAV) Vectors in Gene Therapy Edited by K.I. Berns and C. Giraud With 38 Figures , Springer Professor KENNETH I. BERNS, M.D., Ph.D. CATHERINE GIRAUD, Ph.D. Cornell University Medical College Hearst Microbiology Research Center Department of Microbiology 1300 York Avenue, Box 62 New York, NY 10021 USA Cover illustration: The inverted terminal repeat of the adeno associated virus genome is shown in the folded conformation which maximizes base pairing, The inverted terminal repeat plays a significant role in the regulation of viral gene expression, DNA replication, and integration into and excision from the integration site in the human genome. The red letters indicate the binding site of the viral regulatory protein "rep 68/78." "trs" indicates the site nicked by the rep 68/78 protein. Cover design: Design & Production, Heidelberg ISSN 0070-217X ISBN-13: 978-3-642-80209-6 e-ISBN-13: 978-3-642-80207-2 001: 10.1007/978-3-642-80207-2 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer Verlag. Violations are liable for prosecution under the German Copyright Law. © Springer-Verlag Berlin Heidelberg 1996 Softcover reprint of the hardcover 1 st edition 1996 Library of Congress Catalog Card Number 15 -12910 The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting other relevant literature. Typesetting: Scientific Publishing Services (P) Ltd, Madras SPIN: 10528856 27/3020/SPS - 5432 1 0 - Printed on acid-free paper Preface Human gene therapy holds great promise for the cure of many genetic diseases. In order to achieve such a cure there are two requirements. First, the affected gene must be cloned, its se quence determined and its regulation adequately characterized. Second, a suitable vector for the delivery of a good copy of the affected gene must be available. For a vector to be of use several attributes are highly desirable: these include ability to carry the intact gene (although this may be either the genomic or the cDNA form) in a stable form, ability to introduce the gene into the desired cell type, ability to express the introduced gene in an appropriately regulated manner for an extended period of time, and a lack of toxicity for the recipient. Also of concern is the frequency of cell transformation and, in some cases, the ability to introduce the gene into nondividing stem cells. Sev eral animal viruses have been tested as potential vectors, but none has proven to have all the desired properties described above. For example, retroviruses are difficult to propagate in sufficient titers, do not integrate into nondividing cells, and are of concern because of their oncogenic properties in some hosts and because they integrate at many sites in the genome and, thus, are potentially insertional mutagens. Additionally, genes introduced by retroviral vectors are frequently expressed for relatively short periods of time. A second virus used as a vector in model systems has been adenovirus (Ad). The major deficit is that Ad does not integrate and functions as a transient vector, necessitating repeated administration with the possi bility of a toxic immune response. A third virus of interest as a possible vector is adeno-associated virus (MV), a small DNA virus which has many of the properties desired in a vector. This volume is devoted to descriptions of the manner in which MV has been used as a vector for gene therapy in cell culture and in model animal systems. The initial chapter is a general overview of the biology and molecular biology of M V with an emphasis on those properties directly pertinent to use as a vector. Also included are discussions of some of the questions that remain VI Preface to be answered before the possibility of clinical application. Subsequent chapters describe the preparation of AAV vectors, including attempts to develop packaging cell lines. The re maining chapters describe the construction and use in vitro of AAV virion vectors for the potential treatment of diseases of the hematopoietic system, cystic fibrosis, and AIDS. Two fundamental questions remain to be resolved. The first is practical: how to produce vectors in sufficient quantity for clinical use. The second is both theoretical and practical: should AAV vectors be designed to integrate at a specific site in the human genome. The reader should consider both of these is sues as the chapters on the use of AAV as a vector are read. July 1996 KENNETH I. BERNS List of Contents K.I. BERNS and C. GIRAUD Biology of Adeno-associated Virus J.A. CHIORINI, S.M. WIENER, L. YANG, R.H. SMITH, B. SAFER, N.P. KILCOIN, Y. LIU, E. URCELAY, and R.M. KOTIN The Roles of AAV Rep Proteins in Gene Expression and Targeted Integration ...................... 25 J.P. TREMPE Packaging Systems for Adeno-associated Virus Vectors 35 o J.S. LEBKOWSKI, T.B. KARMA, and R. PHILIP The Challenges of Recombinant Adeno-associated Virus Manufacturing: Alternative Use of Adeno-associated Virus Plasmid/Liposome Complexes for Gene Therapy Applications ......... 51 S. CHATTERJEE and K.K. WONG JR. Adeno-associated Virus Vectors for Gene Therapy of the Hematopoietic System. . . . . . . . . . . . . . . . . . . 61 D.M. MCCARTY and R.J. SAMULSKI Adeno-associated Virus Vectors for Gene Transfer into Erythroid Cells 75 A. SRIVASTAVA, X.-S. WANG, S. PONNAZHAGAN, S.Z. ZHOU, and M.C. YODER Adeno-associated Virus 2-Mediated Transduction and Erythroid Lineage-Specific Expression in Human Hematopoietic Progenitor Cells . . . . . . . . . . 93 B.J. CARTER and T.R. FLOTTE Development of Adeno-associated Virus Vectors for Gene Therapy of Cystic Fibrosis .............. 119 K.K. WONG JR. and S. CHATTERJEE Adeno-associated Virus-Based Vectors As Antivirals .. 145 Subject Index .............................. 171 List of Contributors (Their addresses can be found at the beginning of their respective chapters.) BERNS, K.1. 1 PONNAZHAGAN, S. 93 CARTER, B.J. 119 SAFER, B. 25 CHATIERJEE, S. 61, 145 SAMULSKI, R.J. 75 CHIORINI, J .A. 25 SMITH, R.H. 25 FLOTIE, T.R. 119 SRIVASTAVA, A. 93 GIRAUD, C. 1 TREMPE, J.P. 35 KILCOIN, N.P. 25 URCELAY, E. 25 KOTIN, R.M. 25 WANG, X.-S. 93 LEBKOWSKI, J.S. 51 WIENER, S.M. 25 LIU, Y. 25 WONG, K.K., JR. 61, 145 MCCARlY, D.M. 75 YANG, L. 25 o KARMA, T.B. 51 YODER, M.C. 93 PHILIP, R. 51 ZHOU, S.Z. 93 Biology of Adeno-associated Virus K.I. BERNS and C. GIRAUD 1 Adeno-associated Virus Life Cycle . 2 Genetics .. 4 3 Latent Infection 6 4 Rescue and Replicative Infection. 12 5 Adeno-associated Virus Vectors for Gene Therapy 14 References ... 18 1 Adena-associated Virus Life Cycle Adeno-associated Virus (AAV) is classified as a member of the family Parvovi ridae (SIEGL et al. 1985; BERNS 1990a). Members are small, nonenveloped, ico sahedral viruses (diameter ca. 20-26 nm) with linear, single-stranded DNA genomes of 4.7-6 kb. Parvoviridae have been isolated from many species ranging from insects to humans. AAV is assigned to the genus Oependovirus, so named because the virus was discovered as a contaminant in purified adeno virus (Ad) stocks and in most instances does not productively infect cells in culture unless there is a coinfection by an unrelated helper virus, which is most commonly Ad, but also can be any type of herpesvirus (ATCHINSON et al. 1965; HOGGAN et al. 1966; BULLER et al. 1981). Various serotypes have been isolated from birds and many mammalian species, including humans. About 90% of U.S. adults are seropositive, but in no case has the virus been implicated as the etiological agent for a human disease or as the cause of disease in any other species. Because of the requirement for a helper coinfection for productive infection in cell culture, AAV was long considered to be a defective virus. De tailed studies described below have demonstrated that the virus is not defective, but rather preferentially establishes a latent infection in a healthy cell and is only induced to undergo productive vegetative multiplication when the host cell is stressed. Department of Microbiology, Hearst Microbiology Research Center, Cornell University Medical College, 1300 York Avenue, New York, NY 10021, USA 2 K.I. Berns and C. Giraud •AAV \ Integrot1on In chromosome 1 9 ~-I AAVDNA Rescue H H /RePllcellon • • •••• Fig. 1. Adeno-associated virus (AAV) life cycle. Under nonpermissive conditions AAV integrates into the q arm of human chromosome 19 where it remains silent until challenged by a helper virus, e.g., adenovirus. This leads to rescue of the integrated virus from the chromosome and induction of the lytic cycle. Under permissive conditions, i.e., in the presence of a helper virus, such as adenovirus, AA V replicates, resulting in host cell lysis

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