Development of hybrid promoters and viral vectors for improved gene delivery to the central nervous system

DEVELOPMENT OF HYBRID PROMOTERS AND VIRAL VECTORS FOR IMPROVING GENE DELIVERY TO THE CENTRAL NERVOUS SYSTEM WANG CHAOYANG (B.Sc.; M.Sc.) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF ANATOMY NATIONAL UNIVERSITY OF SINGAPORE & INSTITUTE OF BIOENGINEERING AND NANOTECHNOLOGY 2005 ACKNOWLEDGMENTS My sincere thanks and appreciation go to my supervisor Dr Wang Shu, group leader, Institute of Bioengineering and Nanotechnology, and Associate Professor, Department of Biological Science, NUS, for his full support, untiring guidance, stimulating discussions, and constant encouragement I also want to give my sincere thanks and appreciation to my co-supervisors, Dr Ng Yee Kong and Dr Xiao Zhicheng, for their support and guidance Without their helps the thesis would not be done so smoothly My sincere gratitude go to Ms Guo Haiyan, Dr Wang Xu, Dr Liu Beihui, Mr Gao Shujun, Ms Ma YueXia, and other members in the group of delivery of drugs, proteins and genes, for their technical advice in laboratory techniques, invaluable contributions to some aspects of this work and more importantly, their friendship II PUBLICATIONS Journals Wang CY, Wang S Astrocytic expression of transgene in the rat brain mediated by baculovirus vectors containing an astrocyte-specific promoter Gene Ther In press Wang CY, Wang S (2005) AAV inverted terminal repeats improve neuronal transgene expression mediated by baculovirus vectors in the rat brain Hum Gene Ther 16: 1219-1216 Wang CY, Guo HY, Lim TM, Ng YK, Neo HP, Hwang PYK, Yee WC, Wang S (2005) Improved neuronal transgene expression from an AAV-2 vector with a hybrid CMV enhancer/PDGF-b promoter J Gene Med 7: 945-955 Wang X, Wang C, Zeng J, Xu X, Hwang PY, Yee WC, Ng YK, Wang S (2005) Gene transfer to dorsal root ganglia by intrathecal injection: effects on regeneration of peripheral nerves Mol Ther 12: 314-320 Li Y, Wang J, Lee CGL, Wang CY, Gao SJ, Tang GP, Ma YX, Yu H, Mao HQ, Leong KW, Wang S (2004) CNS gene transfer mediated by a novel controlled release system based on DNA complexesof degradable polycation PPE-EA: a comparison with polyethylenimine/DNA complexes Gene Ther 11: 109-114 III Xu G, Nie DY, Chen JT, Wang CY, Yu FG, Sun L, Luo XG, Ahmed S, David S, Xiao ZC (2004) Recombinant DNA vaccine encoding multiple domains related to inhibition of neurite outgrowth: a potential strategy for axonal regeneration J Neurochem 91: 1018–1023 Nie DY, Zhou ZH, Ang BT, Teng FYH, Xu G, Xiang T, Wang CY, Zeng L, Takeda Y, Xu TL, Ng YK, Faivre-Sarrailh C, Popko B, Ling EA, Schachner M, Watanabe K, J Pallen C, Tang BL, Xiao ZC (2003) Nogo-A at CNS paranodes is a ligand of Caspr: possible regulation of K+ channel localization EMBO J 22: 5666-5678 Patent Wang S, Wang CY “Method of using baculovirus vectors fro glioma therapy”, PCT application pending, 2005 Conference papers Wang CY, Wang S Retarget AAV Vectors to NGF Receptor Positive Cells The First International SBE Conference on Bioengineering and Nanotechnology September 2004, Singapore Wang CY, Chen XL, Ng YK, Wang S, Xiao ZC EGFL Domain of Tenasin-R is Antiadhesive to Activated Microglial Cells The First Asia Pacific Conference & Exhibition on Anti-Aging Medicine June 2002, Singapore IV CONTENTS PAGE Acknowledgements II Publications III Table of contents V Summary IX List of figures XI Abbreviations XIII Chapter Introduction 1.1 Current progress in gene therapy 1.2 Gene delivery to the CNS 1.3 Promoters used for gene delivery to the CNS 1.3.1 Promoters derived from viral genomes 1.3.2 Mammalian promoters 1.3.3 Hybrid promoters 10 1.3.4 Other DNA elements regulating the gene expression 11 1.4 Vectors used for gene delivery to the CNS 12 1.4.1 Non-viral vectors 13 1.4.2 Viral vectors 14 1.4.3 Hybrid viral vectors 17 1.5 Objectives of this study 19 V Chapter Hybrid Neuron-Specific Promoter 21 2.1 Introduction 22 2.2 Materials and methods 27 2.2.1 Plasmids for AAV-2 vectors 27 2.2.2 Production and titration of AAV-2 vectors 27 2.2.3 Generation of recombinant baculovirus vectors 29 2.2.4 In vitro transduction with viral vectors and PEI/DNA complexes 31 2.2.5 In vivo transduction with viral vectors and PEI/DNA complexes 33 2.2.6 Immunohistochemistry analysis 35 2.2.7 Southern blot analysis 36 2.2.8 Statistics 36 2.3 Results 37 2.3.1 In vitro and in vivo gene delivery with AAV-2 vectors carrying the hybrid CMV E/PDGF promoter 37 2.3.1.1 Gene expression in cultured cells 37 2.3.1.2 Gene expression in the striatum 39 2.3.1.3 Gene expression in the substantia nigra 45 2.3.2 In vitro and in vivo gene delivery with baculovirus vectors carrying the hybrid CMV E/PDGF promoter 48 2.3.2.1 Gene expression in cultured cells 48 2.3.2.2 Gene expression in the rat brain 52 2.4 Discussion 57 VI Chapter Hybrid Astrocyte-Specific Promoter 67 3.1 Introduction 68 3.2 Materials and methods 70 3.2.1 Construction of plasmids containing the hybrid promoter 70 3.2.2 Construction of recombinant baculovirus vectors 71 3.2.3 Plasmid transfection and virus infection 73 3.2.4 Immunohistochemistry analysis 73 3.2.5 Luciferase assay 74 3.2.6 Statistics 74 3.3 Results 75 3.3.1 Improved transgene expression in cultured cells using the hybrid CMV E/GFAP promoter 75 3.3.2 Astrocyte-specific transgene expression in the brain 80 3.3.3 Improved transgene expression in the brain 84 3.4 Discussion 87 Chapter Hybrid Baculovirus-AAV Vector 91 4.1 Introduction 92 4.2 Materials and methods 94 4.2.1 Construction of hybrid baculovirus-AAV vectors 94 4.2.2 In vitro virus infection 96 4.2.3 Luciferase assay 97 4.2.4 Nested PCR 97 VII 4.3 Results 4.3.1 In vitro transgene expression from hybrid viral vectors 98 98 4.3.2 Site-specific integration mediated by hybrid baculovirus-AAV vectors in human-originated cells 102 4.4 Discussion 104 Chapter Conclusion 109 Chapter References 112 VIII SUMMARY Gene therapy is a promising approach for the treatment of neurological disorders in the central nervous system (CNS) Because of the complex structure and high vulnerability of the CNS, it is critical that the expression of a therapeutic gene is restricted within the target regions or cells, and the level and duration of the expression can be regulated as desired With currently available promoters and gene delivery vectors, it remains a great challenge to temporally and spatially control the transgene expression in the CNS The purpose of this study was to develop novel promoters that can drive high level and neuron- or glia-specific transgene expression in the CNS, and to test or modify viral vectors suitable to harbor these promoters The ultimate objective of the study is to use these promoters and vectors for gene therapy of neurological disorders, particularly Parkinson’s disease (PD) and gliomas In the first part of this study, a hybrid promoter constructed by fusing the enhancer of human cytomegalovirus immediate-early gene (CMV E) to the promoter of human platelet-derived growth factor B-chain (PDGF), namely CMV E/PDGF promoter, was tested in the context of Adeno-associated viruses type (AAV-2) and baculovirus vectors to drive in vitro and in vivo transgene expression A high level, neuron-specific and long-term transgene expression was achieved in rat striatum and substantia nigra with the AAV-2 vectors, while a high level and neuron-specific, but only transient expression was observed with the baculovirus vectors In addition, the baculovirusmediated neuron-specific expression was improved with the introduction of IX inverted terminal repeats (ITRs) of AAV by flanking the expression cassette in baculovirus vectors Secondly, a hybrid astrocyte-specific promoter with high transcriptional activity, namely CMV E/GFAP promoter, was constructed by adding the CMV enhancer to the upstream of human glial fibrillary acidic protein (GFAP) promoter In vitro and in vivo gene transfer showed that a high level and astrocyte-specific, but transient gene expression could be achieved with baculovirus vectors carrying the CMV E/GFAP promoter ITRs could improve the baculovirus-mediated astrocyte-specific transgene expression as well Thirdly, a hybrid baculovirus-AAV viral vector was constructed by incorporating the two key elements of AAV, the ITRs and the Rep gene, into the backbone of baculovirus Promoters constructed in first two parts of this study were incorporated into this hybrid viral vector Gene transfer experiments confirmed its capacity of mediating a stable transgene expression in human-originated cells by site-specific integration of the transgene into the host chromosome 19 In conclusion, the novel hybrid promoters constructed in this study displayed high and cell type-specific transcriptional activities, and suitable for neuron- or astrocyte-specific gene delivery to the CNS By using AAV-2 vectors, baculovirus vectors with ITRs or hybrid baculovirus-AAV vectors, these promoters could be potentially applied for gene therapy for neurodegenerative diseases and possibly for malignant glioma tumors in the CNS X Chapter Conclusion The ultimate purpose of this study was to develop suitable delivery systems with novel promoters and viral vectors for gene therapy of disorders of the central nervous system (CNS), particularly Parkinson’s disease and malignant glioma tumors Promoters and viral vectors are the focuses of this study to achieve high level, cell type specific and long term transgene expression in the CNS By adding the enhancer of cytomegalovirus immediate-early gene (CMV E) upstream of mammalian promoters, hybrid CMV E/PDGF and CMV E/GFAP promoters were constructed Improved transcriptional activities and retained cell type specificity were observed in vitro and in vivo by using AAV-2 and baculovirus vectors Furthermore, ITRs of AAV were demonstrated to improve the baculovirus-mediated transgene expression To overcome the inherited disadvantages of AAV-2 vectors and baculovirus vectors, a hybrid baculovirus-AAV vector was constructed by placing the essential elements of AAV, ITRs and Rep gene, which are responsible for site-specific integration of AAV, into the backbone of baculovirus vector These hybrid vectors carrying the CMV E/PDGF promoter or CMV E/GFAP promoter could mediate more sustained transgene expression in humanoriginated cell lines Site-specific integration of the transgene delivered by the vectors into the AAVS1 locus on chromosome 19 was observed The present study applied the strategy of placing the CMV enhancer upstream of PDGF or GFAP promoter to create hybrid promoters, and 110 Chapter Conclusion achieved improved expression from these hybrid promoters in the CNS However, the applicability of this strategy depends largely on the interaction between the transcription factors attracted by the CMV enhancer and those by the cell type-specific promoter, which might not always have a positive effect on the transgene expression as achieved in this study In vivo gene delivery with the hybrid baculovirus-AAV vectors has yet to be performed, but hopefully a high level, cell type-specific and long-term transgene expression could be achieved Although only 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made by using different types of promoters and vectors for gene delivery to the CNS 1.1 Current progress in gene therapy Gene therapy, which usually refers to somatic gene therapy,... by the selection of promoters The gene delivery vector that carries and transfers the gene into the nuclei of target cell is another key Chapter Introduction issue of gene therapy The tropism of. .. 2003) 1.4.2 Viral vectors Viral vectors are the most efficient vectors to transduce mammalian cells, and therefore are employed in most gene delivery experiments A variety of viral vectors, including