VIRAL GENE THERAPY Edited by Ke Xu Viral Gene Therapy Edited by Ke Xu Published by InTech Janeza Trdine 9, 51000 Rijeka, Croatia Copyright © 2011 InTech All chapters are Open Access articles distributed under the Creative Commons Non Commercial Share Alike Attribution 3.0 license, which permits to copy, distribute, transmit, and adapt the work in any medium, so long as the original work is properly cited. After this work has been published by InTech, authors have the right to republish it, in whole or part, in any publication of which they are the author, and to make other personal use of the work. Any republication, referencing or personal use of the work must explicitly identify the original source. Statements and opinions expressed in the chapters are these of the individual contributors and not necessarily those of the editors or publisher. No responsibility is accepted for the accuracy of information contained in the published articles. The publisher assumes no responsibility for any damage or injury to persons or property arising out of the use of any materials, instructions, methods or ideas contained in the book. Publishing Process Manager Romina Krebel Technical Editor Teodora Smiljanic Cover Designer Jan Hyrat Image Copyright Steve Mann, 2010. Used under license from Shutterstock.com First published July, 2011 Printed in Croatia A free online edition of this book is available at www.intechopen.com Additional hard copies can be obtained from orders@intechweb.org Viral Gene Therapy, Edited by Ke Xu p. cm. ISBN 978-953-307-539-6 free online editions of InTech Books and Journals can be found at www.intechopen.com Contents Preface IX Part 1 Retroviral Vector 1 Chapter 1 Retroviral Vectors in Gene Therapy: Mechanism of Integration, Successes in Gene Therapy Trials, Emerging Problems and Potential Solutions 3 Ahmed Salem, Johanna A. Smith, Michael P. Lisanti and René Daniel Chapter 2 Production of Retroviral and Lentiviral Gene Therapy Vectors: Challenges in the Manufacturing of Lipid Enveloped Virus 15 Ana F. Rodrigues, Paula M. Alves and Ana S. Coroadinha Chapter 3 Surface Modification of Retroviral Vectors for Gene Therapy 41 Christoph Metzner and John A. Dangerfield Chapter 4 The Glucocorticoid Receptor in Retroviral Infection 73 Victor Solodushko and Brian Fouty Part 2 Adenoviral Vector 89 Chapter 5 Adenoviral Vectors: Potential and Challenges as a Gene Delivery System 91 Suresh K. Mittal, AnneMarie Swaim and Yadvinder S. Ahi Chapter 6 Adenovirus-Based Gene Therapy for Cancer 129 Changqing Su Chapter 7 Recombinant Adenovirus Infection of Human Dendritic Cells 149 William C. Adams and Karin Loré VI Contents Chapter 8 Harnessing the Potential of Adenovirus Vectored Vaccines 169 Peter Johannes Holst, Jan Pravsgaard Christensen and Allan Randrup Thomsen Part 3 Adeno-associated-viral Vector 193 Chapter 9 AAV Mediated β-Thalassemia Gene Therapy 195 Mengqun Tan, Xiaojuan Sun, Zhenqin Liu, Liujian Song, Jing Tian, Xiaolin Yin and Xinhua Zhang Chapter 10 Comparison of AAV Serotypes for Gene Delivery to Dopaminergic Neurons in the Substantia Nigra 205 J.A. Korecka, M. Schouten, R. Eggers, A. Ulusoy, K. Bossers and J. Verhaagen Chapter 11 Progress and Challenges in AAV-Mediated Gene Therapy for Duchenne Muscular Dystrophy 225 Takashi Okada and Shin’ichi Takeda Chapter 12 Viral Vectors as Tools to Investigate the Role of Dysregulated Proteins in Nervous System Pathologies: The Case of Acquired Motor Neuropathies 241 Carmen R. Sunico and Bernardo Moreno-López Part 4 Lentiviral Vector 261 Chapter 13 Designing Lentiviral Gene Vectors 263 Oleg E. Tolmachov, Tanya Tolmachova and Faisal A. Al-Allaf Chapter 14 Gene Regulatable Lentiviral Vector System 285 Yasutsugu Suzuki and Youichi Suzuki Chapter 15 Dendritic Cells and Lentiviral Vectors: Mapping the Way to Successful Immunotherapy 309 Cleo Goyvaerts, Grazyna Kochan, David Escors and Karine Breckpot Part 5 Other Types of Viral Vector 353 Chapter 16 Development and Application of HIV Vectors Pseudotyped with HIV Envelopes 355 Koichi Miyake and Takashi Shimada Chapter 17 Highly Efficient Retrograde Gene Transfer for Genetic Treatment of Neurological Diseases 371 Shigeki Kato, Masahito Kuramochi, Kenta Kobayashi, Ken-ichi Inoue, Masahiko Takada and Kazuto Kobayashi Contents VII Chapter 18 Herpes Simplex Virus Type 1 for Use in Cancer Gene Therapy: Looking Backward to Move Forward 381 Breanne Cuddington and Karen Mossman Chapter 19 Gene Therapy of Melanoma Using Inactivated Sendai Virus Envelope Vector (HVJ-E) with Intrinsic Anti-Tumor Activities 421 Yasufumi Kaneda, Eiji Kiyohara, Toshimitsu Itai and Toshihiro Nakajima Chapter 20 Pharmacokinetic Study of Viral Vectors for Gene Therapy: Progress and Challenges 435 Xianxing Xu, Jingwen Yang and Yuanguo Cheng Preface The general meaning of gene therapy is to correct defective genes that are responsible for disease development. The most common form of gene therapy involves the insertion, alteration or removal of genes within an individual's cells and biological tissues. Many of gene transfer vectors are modified viruses. The ability for the delivery of therapeutic genes made them desirable for engineering virus vector systems. Recently, the viral vectors in laboratory and clinical use have been based on RNA and DNA viruses processing very different genomic structures and host ranges. Various viral vectors have been developed and optimized, such as retrovirus, adenovirus, lentivirus and adeno-associated virus. This book provides broad coverage of the field of viral gene therapy. In the first section of this book, ‘Retroviral Vector’, chapter one discusses the efficiency of retroviral DNA integration, the preferences of integration for certain regions, and advances on integration site selection and gene therapy. Chapter two reviews and discusses the current cell lines and bioreaction platforms used for production of retroviral and lentiviral vectors, focusing on the current bottlenecks and future directions with a particular emphasis in the metabolic constrains. Modification of the surface of these vectors is a key element for their successful research and clinical use. Chapter three discusses the methods to modify surfaces of retroviral vectors, and the applications for surface modification of retroviral vectors, such as targeting and immune modulation. Chapter four reviews the role of the nuclear glucocorticoid receptor in controlling retroviral infection and function, and highlights its potential importance in retroviral-based gene therapy applications. Adenoviral vectors serve as an excellent gene delivery system for a variety of cell types or organs for gene therapy and immunization applications. In the second section ‘Adenoviral Vector’, chapter five introduces the history of adenovirus research, the advantage and disadvantage of adenoviral vector, the adenoviral vector induced innate immune response, the evolution of adenoviral vector system, the application of adenoviral vector in gene therapy, and adenoviral vaccine. Chapter six reviews the background of virotherapy and the approaches of conditionally replicating adenoviruses (CRAds) on cancer treatment. The author also points out the exiting problems and obstacles in this field. In chapter seven, Adams et al. discuss how adenoviral vectors interact with human immune cells, particularly how adenoviral X Preface vectors interact with professional antigen presenting cells, namely dendritic cells. Chapter eight reviews the properties of the immune response induced by adenoviral vaccines and the mechanisms which control the quality of T cell response generated during such vaccination. Holst et al. compare the adenovirus vectors with other vaccination tools in the immunological arsenal, and discuss potential future clinical application of adenovirus vectored vaccines. The third section of this book is ‘Adeno-associated-virus Vector’. Chapter nine by Sun et al. introduces the adeno-associated virus (AAV) mediated β-thalassemia gene therapy. Human hematopoietic stem cells (HSCs) were obtained from β-thalassemia patients, transfected with the recombinant AAV containing β-globin gene. The transfected cells were then transplanted into Nude/SCID mice, and the long term expression of β-globin in vivo was examined. In the tenth chapter, Korecka et al. compare AAV serotypes for gene delivery to dopaminergic neurons in the substantia nigra (SN). They found that AAV5 and 7-syn-GFP resulted in the highest percentage of nigral dopaminergic neurons transduction, where AAV7 showed the highest efficiency in transducing the nigrostriatal projection pathway. Accordingly, they conclude that AAV7-syn-GFP is the most suitable SN gene delivery vehicle in mice. In the eleventh chapter, Okada et al. developed a new method of producing AAV vectors. They applied these AAV vectors in muscle transduction for the treatment of Duchenne muscular dystrophy (DMD). In chapter twelve, Sunico et al. introduce their study on the function of 2 dysregulated proteins in pathological events occurring at the peripheral (nerve) and central (motoneuron) levels after the severe crushing of a motor nerve in adult rats, using AAV and lentiviral vector. In the section on ‘Lentiviral Vector’, the generation of high-titre lentiviral vectors capable of efficiently expressing transgenes over long periods of time is governed by a number of vector design rules. Chapter thirteen highlights the guiding design principles and the technical of the successful lentiviral gene vector design. Chapter fourteen reviews current status of lentiviral vector development, especially the progress in the lentiviral vector systems allowing the controlling of gene expression. It also discusses the ability of future application of the gene regulatable lentiviral vectors to therapeutic approach for the treatment of HIV-1 infection and acquired immunodeficiency syndrome (AIDS). Chapter fifteen discusses the development of lentiviral vectors, their evaluation for ex vivo and in vivo gene delivery to dendritic cells, and the efforts made to improve the biosafety of the lentiviral vector system. In the last section on ‘Other Types of Viral Vector’, chapter sixteen introduces the development of HIV vector pseudotyped with HIV envelope, and applications of these vectors for AIDS or adult T-cell leukemia. Chapter seventeen introduces the development of novel vector system for highly efficient retrograde gene transfer by pseudotyping the HIV-1 vector with fusion glycoprotein B type (FuG-B). Herpes simplex virus type 1 (HSV-1) is a human pathogen associated with keratitis and cold sores. Chapter eighteen reviews the biology of HSV-1, and clinical trails and [...]... pharmacokinetic evaluations of viral vectors, and challenges and prospects We hope that the reviews and research described here will provide a wide-ranging forum in the viral gene therapy field It is clear from these chapters that much more progress is required for the improvement of viral gene therapy It is believed that the next few decades will see the application of viral gene therapy in the treatment... Medical University General Hospital Tianjin, China XI Part 1 Retroviral Vector 1 Retroviral Vectors in Gene Therapy: Mechanism of Integration, Successes in Gene Therapy Trials, Emerging Problems and Potential Solutions Ahmed Salem, Johanna A Smith, Michael P Lisanti and René Daniel 1Division of Infectious Diseases - Center for Human Virology, and Jefferson Center for Stem Cell Biology and Regenerative Medicine,... "Relationship between retroviral DNA integration and gene expression." J Virol 74(18): 8382-9 Woods, N B., V Bottero, et al (2006) "Gene therapy: therapeutic gene causing lymphoma." Nature 440(7088): 1123 Wu, X., Y Li, et al (2003) "Transcription start regions in the human genome are favored targets for MLV integration." Science 300(5626): 1749-51 2 Production of Retroviral and Lentiviral Gene Therapy Vectors:... increasing viral titers and transgene expression 2.1 Retroviral vectors For both retroviral and lentiviral vector production, different packaging systems, named generations, have been developed Each new generation aimed at minimizing and reduce the risk of RCPs formation face to the previous one (Fig 3) In the case of vectors based on MLV or other simple retrovirus, the non-cytotoxicity of the viral genes... expression of the delivered gene (Coroadinha et al 2010; Schweizer and Merten 2010) According to the most recent updates, retroviral and lentiviral vectors represent 23% of all the vector types and 33% of the viral vectors used in Gene Therapy clinical trials Moreover, retroviral vectors are currently the blockbuster vectors for the treatment of monogenic and infectious diseases and gene marking clinical... viral replication in infected cells (Fig 2B) Production of Retroviral and Lentiviral Gene Therapy Vectors: Challenges in the Manufacturing of Lipid Enveloped Virus 17 Fig 2 Retroviral genomes Schematic representation of (A) MLV and (B) HIV-1 wild-type genomes representing simple and complex retrovirus, respectively 2 Cell line platforms for the production The establishment of retroviral and lentiviral... the physical separation of the viral genome into different transcriptional units to minimize the risk of generating replication-competent particles (RCPs) (Fig 3) Some of Fig 3 Transcriptional units used for retroviral and lentiviral vector generation (A) Three construct system used for (simple) retroviral vector and (B) four construct system used for third generation lentiviral vector production Only... membrane Consequently, the viral particle is uncoated, liberating the viral core into the cell cytoplasm The viral DNA is reverse transcribed to DNA Then, the viral DNA is transported to the nucleus where it is integrated into the host cell’s genome From there, viral DNA is transcribed to RNA, some of which is translated to proteins The viral RNA is packed in a viral particle along with viral proteins Then,... Philadelphia 2Department of Stem Cell Biology and Regenerative Medicine, Thomas Jefferson University, Philadelphia, U.S.A 1 Introduction Retroviral vectors have gained an increasing value in gene therapy because they stably deliver therapeutic genes to the host cell genome These therapeutic genes are supposed to rectify consequences of inherited and acquired mutated genes in the host cell genome, or alter host... influences the fate of lymphopoiesis in SCID-X1 gene therapy. " J Clin Invest 117(8): 2225-32 Derse, D., B Crise, et al (2007) "Human T-cell leukemia virus type 1 integration target sites in the human genome: comparison with those of other retroviruses." J Virol 81(12): 6731-41 Escors, D and K Breckpot "Lentiviral vectors in gene therapy: their current status and future potential." Arch Immunol Ther Exp (Warsz) . University General Hospital Tianjin, China Part 1 Retroviral Vector 1 Retroviral Vectors in Gene Therapy: Mechanism of Integration, Successes in Gene Therapy Trials, Emerging Problems and Potential. controlling retroviral infection and function, and highlights its potential importance in retroviral-based gene therapy applications. Adenoviral vectors serve as an excellent gene delivery system. Preface IX Part 1 Retroviral Vector 1 Chapter 1 Retroviral Vectors in Gene Therapy: Mechanism of Integration, Successes in Gene Therapy Trials, Emerging Problems and Potential Solutions 3