TARGETS IN GENE THERAPY Edited by Yongping You Targets in Gene Therapy Edited by Yongping You 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 indiwarm, 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 Targets in Gene Therapy, Edited by Yongping You p. cm. ISBN 978-953-307-540-2 free online editions of InTech Books and Journals can be found at www.intechopen.com Contents Preface IX Part 1 Target Strategy in Gene Therapy 1 Chapter 1 Choosing Targets for Gene Therapy 3 Karina J. Matissek, Ruben R. Bender, James R. Davis and Carol S. Lim Chapter 2 Gene Modulation by Peptide Nucleic Acids (PNAs) Targeting microRNAs (miRs) 29 Rosangela Marchelli, Roberto Corradini, Alex Manicardi, Stefano Sforza, Tullia Tedeschi, Enrica Fabbri, Monica Borgatti, Nicoletta Bianchi and Roberto Gambari Chapter 3 Effective Transgene Constructs to Enhance Gene Therapy with Trichostatin A 47 Hideki Hayashi, Yuhua Ma, Tomoko Kohno, Masayuki Igarashi, Kiyoshi Yasui, Koon Jiew Chua,Yoshinao Kubo, Motoki Ishibashi, Ryuji Urae, Shin Irie and Toshifumi Matsuyama Chapter 4 Suicide Gene Therapy by Herpes Simplex Virus-1 Thymidine Kinase (HSV-TK) 65 Dilip Dey and Gregory R.D. Evans Chapter 5 Translational Challenges for Hepatocyte-Directed Gene Transfer 77 Stephanie C. Gordts, Eline Van Craeyveld, Frank Jacobs and Bart De Geest Chapter 6 Physiologically-Regulated Expression Vectors for Gene Therapy 99 Olivia Hibbitt and Richard Wade-Martins Chapter 7 PLP-Dependent Enzymes: a Potent Therapeutic Approach for Cancer and Cardiovascular Diseases 119 Ashraf S. El-Sayed and Ahmed A. Shindia VI Contents Chapter 8 Improvement of FasL Gene Therapy In Vitro by Fusing the FasL to Del1 Protein Domains 147 Hisataka Kitano, Atsushi Mamiya and Chiaki Hidai Chapter 9 Feasibility of BMP-2 Gene Therapy Using an Ultra-Fine Needle 159 Kenji Osawa, Yasunori Okubo, Kazumasa Nakao, Noriaki Koyama and Kazuhisa Bessho Part 2 Gene Therapy of Cancer 167 Chapter 10 Current Strategies for Cancer Gene Therapy 169 Yufang Zuo, Xiaofang Ying, Hui Wang, Wen Ye, Xiangqi Meng, Hongyan Yu, Yi Zhou, Wuguo Deng and Wenlin Huang Chapter 11 Gene Therapy Strategy for Tumour Hypoxia 185 Hiroshi Harada Chapter 12 Gene Therapy of Glioblastoma: Anti – Gene Anti IGF-I Strategy 201 Jerzy Trojan Chapter 13 Mechanism of Hypoxia-Inducible Factor-1alpha Over- Expression and Molecular-Target Therapy for Hepatocellular Carcinoma 225 Dengfu Yao, Min Yao, Shanshan Li and Zhizhen Dong Chapter 14 Cancer Gene Therapy via NKG2D and FAS Pathways 243 Yanzhang Wei, Jinhua Li and Hari Shankar R. Kotturi Chapter 15 Emergence of IFN-lambda as a Potential Antitumor Agent 275 Ahmed Lasfar and Karine A. Cohen-Solal Chapter 16 Intramuscular IL-12 Electrogene Therapy for Treatment of Spontaneous Canine Tumors 299 Maja Cemazar, Gregor Sersa, Darja Pavlin and Natasa Tozon Part 3 Gene Therapy of Other Diseases 321 Chapter 17 Gene Therapy Targets and the Role of Pharmacogenomics in Heart Failure 323 Dimosthenis Lykouras, Christodoulos Flordellis and Dimitrios Dougenis Contents VII Chapter 18 Gene Therapy of the Heart through Targeting Non-Cardiac Cells 337 Guro Valen Chapter 19 Transplantation of Sendai Viral Angiopoietin-1-Modified Mesenchymal Stem Cells for Ischemic Heart Disease 357 Jianhua Huang, Huishan Wang and Hirofumi Hamada Chapter 20 Using Factor VII in Hemophilia Gene Therapy 369 Bahram Kazemi Chapter 21 The Different Effects of TGF-β1, VEGF and PDGF on the Remodeling of Anterior Cruciate Ligament Graft 389 Changlong Yu, Lin Lin and Xuelei Wei Chapter 22 Different ex Vivo and Direct in Vivo DNA Administration Strategies for Growth Hormone Gene Therapy in Dwarf Animals 396 Cibele Nunes Peroni, Nélio Alessandro de Jesus Oliveira, Claudia Regina Cecchi, Eliza Higuti and Paolo Bartolini Chapter 23 Protection from Lethal Cell Death in Cecal Ligation and Puncture-Induced Sepsis Mouse Model by In Vivo Delivery of FADD siRNA 409 Yuichi Hattori and Naoyuki Matsuda Chapter 24 Muscle-Targeted Gene Therapy of Charcot Marie-Tooth Disease is Dependent on Muscle Activity 423 Stephan Klossner, Marie-Noëlle Giraud, Sara Sancho Oliver, David Vaughan and Martin Flück Preface Up to now, major diseases often attempted to be treated by gene therapy include cancer, cardiovascular disease and monogenic diseases. Despite many decades of gene therapy research on these fatal diseases, most of the products fail to make it to market. One urgent problem is to identify the key targets for specific drugs. The aim of our book is to cover key aspects of existing problems in the emerging field of targets in gene therapy. With the contribution of leading experts and pioneers in various disciplines of gene therapy, this book brings together major approaches: 1. Target Strategy in Gene Therapy, 2. Gene Therapy of Cancer, 3. Gene Therapy of Other Diseases. The publication of this book was made possible by the efforts and collaboration of many individuals. We thank the contributors and section editors for generously sharing their expertise and scientific skills. We hope that this book will provide a realistic image of the huge potential, perspective and challenges facing the field of gene therapy in its quest to cure disease and prolong life. Yongping You Professor and Chief Physician Department of Neurosurgery The First Affiliated Hospital of Nanjing Medical University China [...]... Strategy in Gene Therapy 1 Choosing Targets for Gene Therapy Karina J Matissek, Ruben R Bender, James R Davis and Carol S Lim University of Utah USA 1 Introduction Gene therapy is often attempted in fatal diseases with no known cure, or after standard therapies have failed Targeting gene defects includes addressing a single mutation, multiple mutations in several genes, or even addressing missing or... identified by individual labs using standard molecular and biochemical methods without a priori use of genomic information With the growing understanding of genes associated with many diseases the future for new gene therapeutics shows promise 10 Targets in Gene Therapy Fig 1 Finding Novel Gene Therapy Targets Integration of standard and modern technologies for disease-causing targets for gene therapy 3.1... determine which proteins are responsible for disease This information can be analyzed to identify hub proteins involved in disease progression Hub proteins are key proteins that signal to multiple other proteins in transduction cascades They are highly connected to other proteins with multiple interaction partners Hub proteins bind with several distinct binding sites to other proteins Studying the binding... therapy by replacing defective genes or imparting a new function In fact, 85% of clinical trials in gene therapy have been conducted for cancer, cardiovascular diseases and for inherited monogenic diseases In addition, 6.5% 4 Targets in Gene Therapy of clinical trials have been conducted for infectious diseases (mainly HIV) Cancer, cardiovascular diseases and HIV are ideal gene therapy targets because... being developed in our lab to direct proteins to other cellular compartments where their function is altered This chapter will summarize these and other known targets and also focus on choosing newer targets for gene therapy 2 Known targets for gene therapy The general aim of gene therapy is to introduce a well-defined DNA sequence into specific cells Almost any disease can be targeted with gene therapy. .. plasmidmediated short-hairpin RNA in combination with clinical drug vincristine resulted in inhibition of the growth of human hepatoma HepG2 in vivo (Sun et al 2009) This illustrates once again that the combination of gene therapy with standard chemotherapy is a promising approach for treatment of cancer 3.2.2.3 AKT AKT, a serine/threonine kinase, plays an essential role in oncogenesis The AKT family consists... zinc binding loops and metallothionein (Krishna et al 2003) The C2H2 zinc finger represents the most prevalent motif and contains a zinc ion coordinated by cysteines and histidines (Wolfe et al 2000) Although most C2H2 fingers apparently contribute to protein-DNA or protein-RNA interactions, examples for proteinprotein interactions also exist One example is Ikaros, a transcription factor participating... developments in gene therapy have focused on introducing genes encoding RNA or proteins which are capable of interfering with intracellular replication of HIV, socalled intracellular immunization So far, the approaches range from protein-based strategies such as fusion inhibitors or zinc finger nucleases to RNA-based approaches such as ribozymes, antisense or short hairpin RNA Currently, a promising target... prime targets for gene therapy due to their simple single gene mutations Their disease causing mechanisms are easier to elucidate which is advantageous for choosing a target for gene therapy In addition, the execution of therapy is more straightforward, since it is easier to transfer single genes into cells instead of several genes Other important factors are the location and the type of cell in which... classic gene therapy target with one single mutation which can be targeted by replacing the defect gene Unfortunately, all gene therapy approaches for CF have failed thus far Certain neurodegenerative diseases are affected by mutations in proteins involved in ER assembly Mutations in Parkin, which is an E3 ligase responsible for ubiquitinylation 18 Targets in Gene Therapy and regulation of proteasomal . known targets and also focus on choosing newer targets for gene therapy. 2. Known targets for gene therapy The general aim of gene therapy is to introduce a well-defined DNA sequence into specific. understanding of genes associated with many diseases the future for new gene therapeutics shows promise. Targets in Gene Therapy 10 Fig. 1. Finding Novel Gene Therapy Targets. Integration. TARGETS IN GENE THERAPY Edited by Yongping You Targets in Gene Therapy Edited by Yongping You Published by InTech Janeza Trdine 9, 51000 Rijeka,