| Preface |
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| Contributors |
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xxiii | |
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1 | (20) |
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1 | (2) |
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3 | (3) |
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2.1 Plasmid DNA Manufacture |
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5 | (1) |
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3 Plasmid DNA Gene Transfer Methods |
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6 | (11) |
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3.1 Plasmid DNA or "Naked DNA" as a Gene Delivery System |
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6 | (2) |
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3.1.1 Electroporation of Naked DNA |
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8 | (1) |
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3.1.2 Sonoporation of Naked DNA |
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9 | (1) |
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3.2 Plasmid DNA Formulations |
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9 | (1) |
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9 | (1) |
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3.2.1.1 In vitro transfection |
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10 | (1) |
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3.2.1.2 Systemic in vivo gene transfer |
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11 | (1) |
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3.2.1.3 Local administration of cationic lipid/pDNA transfection complexes |
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12 | (2) |
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14 | (1) |
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14 | (1) |
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15 | (2) |
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17 | (1) |
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17 | (4) |
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21 | (16) |
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21 | (1) |
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2 Adenoviral Capsid Structure |
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22 | (1) |
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23 | (1) |
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4 Production of Adenoviral Vectors |
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24 | (2) |
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5 Production of Targeted Adenoviral Vectors |
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26 | (2) |
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6 Gene Therapy Applications |
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28 | (2) |
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7 Immune Responses to Ad Vectors |
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30 | (2) |
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8 Safety and Regulatory Issues |
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32 | (1) |
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33 | (1) |
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33 | (4) |
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3 Retroviral Vectors and Integration Analysis |
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37 | (16) |
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37 | (1) |
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2 Design, Production and Mechanism of Transduction |
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38 | (3) |
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41 | (1) |
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4 Side Effects in Retroviral Gene Therapy |
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42 | (5) |
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4.1 Distribution of Retroviral Integration Sites in the Cellular Genome |
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42 | (3) |
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4.2 Side Effects in Clinical and Preclinical Gene Therapy Studies |
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45 | (2) |
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5 New Strategies for Vector Biosafety in Gene Therapy |
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47 | (2) |
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49 | (4) |
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53 | (16) |
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53 | (3) |
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2 Vector Design and Production |
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56 | (3) |
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56 | (2) |
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58 | (1) |
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3 Gene Transfer Concepts and Potential Applications |
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59 | (3) |
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3.1 Target Cells and Diseases |
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59 | (1) |
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59 | (1) |
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3.3 Cell Type Specific Targeting |
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60 | (1) |
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3.4 Integration-Defective Lentiviral Vectors |
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60 | (2) |
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62 | (1) |
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63 | (1) |
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6 Conclusions and Perspectives |
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64 | (1) |
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64 | (5) |
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5 Herpes Simplex Virus Vectors |
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69 | (18) |
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69 | (5) |
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2 HSV Biology in the Design of Replication Defective Vectors |
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74 | (3) |
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3 HSV Vector Design Technology |
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77 | (2) |
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4 Gene Transfer/Therapy Applications |
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79 | (1) |
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80 | (1) |
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6 Safety and Regulatory Issues |
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81 | (1) |
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81 | (1) |
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82 | (5) |
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6 Adeno-Associated Viral (AAV) Vectors |
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87 | (16) |
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87 | (1) |
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88 | (5) |
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93 | (3) |
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4 Vector Characteristics In Vivo |
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96 | (2) |
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5 Next Generation Vectors |
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98 | (1) |
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6 Conclusions and Outlook |
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99 | (1) |
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99 | (4) |
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7 Regulatory RNA in Gene Therapy |
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103 | (20) |
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103 | (3) |
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2 Delivery of Therapeutic RNAs |
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106 | (3) |
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109 | (2) |
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111 | (3) |
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5 Gene Therapy Using miRNA |
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114 | (1) |
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6 Aptamers, Decoys and Bi-Functional RNAs |
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115 | (1) |
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7 Modification of Cis-Acting Regulatory RNA Sequences |
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116 | (3) |
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119 | (1) |
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120 | (3) |
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8 DNA Integrating Vectors (Transposon, Integrase) |
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123 | (16) |
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123 | (5) |
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124 | (2) |
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126 | (2) |
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2 Vector Design and Production |
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128 | (2) |
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2.1 Design of Transposon Systems |
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128 | (1) |
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2.2 Design of Integrase Systems |
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128 | (1) |
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2.3 Production of Plasmid DNA |
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129 | (1) |
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3 Gene Transfer Protocols and Potential Applications |
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130 | (2) |
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3.1 Hepatocyte Transfection via Hydrodynamic Injection |
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130 | (1) |
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3.2 Lipophilic Complexes to Transfect Endothelial Cells and Glioblastoma |
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131 | (1) |
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3.3 Direct DNA Injection and Electroporation to Target Muscle, Retina, and Joints |
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131 | (1) |
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3.4 Integration into Cultured Cells for Ex vivo Gene Therapy |
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131 | (1) |
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132 | (1) |
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5 Safety and Regulatory Issues |
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133 | (2) |
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5.1 Integration Profiles and Associated Hazards |
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133 | (1) |
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5.2 Efforts to Enhance Integration Specificity |
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133 | (1) |
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5.3 Effects on Tumor Latency in Mouse Models of Cancer |
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134 | (1) |
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135 | (4) |
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9 Homologous Recombination and Targeted Gene Modification for Gene Therapy |
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139 | (24) |
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139 | (1) |
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2 Problems with Using Gene Targeting by Homologous Recombination |
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140 | (1) |
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3 Homologous Recombination in Embryonic Stem Cells |
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141 | (3) |
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4 Homologous Recombination using Adeno-Associated Virus |
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144 | (1) |
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5 Site-Specific Modification of the Genome using Double-Strand Breaks |
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144 | (1) |
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6 Double-Strand Break Repair |
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144 | (2) |
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7 Double-Strand Break Induced Homologous Recombination |
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146 | (1) |
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8 Re-design of Homing Endonucleases to Recognize New Target Sites |
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146 | (1) |
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9 Development of Zinc Finger Nucleases |
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147 | (1) |
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10 Using Zinc Finger Nucleases to Stimulate Gene Targeting |
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147 | (2) |
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11 Using Zinc Finger Nucleases to Site-Specifically Modify Genes by Mutagenic Non-Homologous End-Joining |
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149 | (2) |
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12 Strategies of Zinc Finger Nuclease Design |
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151 | (2) |
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13 Aspects of Zinc Finger Binding Sites and Structure of Zinc Finger Nucleases |
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153 | (1) |
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14 Zinc Finger Nuclease Toxicity: Measuring and Minimizing |
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154 | (2) |
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15 The Challenge of Delivery |
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156 | (1) |
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16 Future Directions and Promise of Homologous Recombination as a Gene Correction Approach to Gene Therapy |
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157 | (1) |
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157 | (6) |
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10 Gene Switches for Pre-Clinical Studies in Gene Therapy |
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163 | (18) |
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163 | (2) |
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2 Rapamycin-Dependent Regulatable System |
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165 | (3) |
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2.1 Molecular Mechanisms Involved in Transgene Regulation |
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165 | (1) |
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2.2 Pharmacology of Rapamycin |
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166 | (1) |
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2.3 Translation Development of the Rapamycin Dependent Regulation System |
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166 | (2) |
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3 Tetracycline-Dependent Regulatable Systems |
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168 | (7) |
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3.1 Molecular Mechanisms Involved in Transgene Regulation |
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168 | (3) |
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3.2 Pharmacology of Doxycycline (Dox) |
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171 | (1) |
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3.3 Translational Development of Tet-dependant Regulation Systems |
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171 | (4) |
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4 Other Regulatable Systems |
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175 | (2) |
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177 | (1) |
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177 | (4) |
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11 Gene Therapy for Central Nervous System Disorders |
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181 | (16) |
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181 | (1) |
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2 Gene Therapy for Parkinson's Disease |
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182 | (4) |
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3 Gene Therapy for Temporal Lobe Epilepsy |
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186 | (1) |
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4 Huntington's Disease Gene Therapy |
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187 | (2) |
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5 Amyotrophic Lateral Sclerosis (ALS) |
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189 | (1) |
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6 Gene Therapy for Canavan Disease |
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190 | (1) |
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7 Gene Therapy for Alzheimer's Disease |
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191 | (2) |
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8 Conclusions and Outlook |
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193 | (1) |
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194 | (3) |
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12 Gene Therapy of Hemoglobinopathies |
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197 | (16) |
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198 | (1) |
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198 | (1) |
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199 | (1) |
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200 | (8) |
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4.1 Oncoretroviral Vector-Mediated Globin Gene Transfer |
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202 | (1) |
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4.2 Lentiviral Vector-Mediated Globin Gene Transfer |
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203 | (1) |
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4.3 Adeno-Associaied Viral Vector-Mediated Globin Gene Transfer |
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204 | (4) |
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208 | (5) |
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13 Gene Therapy for Primary Immunodeficiencies |
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213 | (20) |
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214 | (1) |
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2 Adenosine Deaminase (ADA)-deficient SCID |
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215 | (3) |
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3 X-linked Severe Combined Immunodeficiency (SCID XI) |
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218 | (2) |
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4 Gene Therapy for Other SCIDs |
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220 | (4) |
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4.1 V(D)J Recombination Defects |
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220 | (2) |
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4.2 Purine Nucleoside Phosphorylase (PNP) Deficiency |
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222 | (1) |
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4.3 Janus Kinase 3 (Jak3) Deficiency |
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222 | (1) |
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223 | (1) |
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4.5 Zeta Associated 70 kDa Phosphoprotein (ZAP-70) Deficiency |
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223 | (1) |
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5 Wiskott-Aldrich-Syndrome (WAS) |
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224 | (1) |
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6 Chronic Granulomatous Disease |
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225 | (2) |
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7 Conclusions and Outlook |
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227 | (1) |
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228 | (5) |
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14 Gene Therapy for Hemophilia |
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233 | (18) |
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233 | (2) |
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2 Limitations of Hemophilia Treatment With Coagulation Factor Concentrates or Recombinant Coagulation Factors |
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235 | (1) |
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3 Gene Transfer for Correction of Hemophilia |
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236 | (2) |
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3.1 Ex Vivo Gene Transfer of F. VIII and F. IX |
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236 | (1) |
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3.2 In Vivo Gene Transfer of F. VIII and F. IX |
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237 | (1) |
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4 AAV is a Preferred Gene Therapy Vector for In Vivo Gene Transfer to Correct of Hemophilia |
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238 | (1) |
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5 Immunological Considerations for Efficient F. IX Gene Transfer |
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239 | (3) |
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6 Advancements from Small and Large Animal Models of Hemophilia |
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242 | (2) |
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6.1 Murine Hemophilia Models |
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242 | (1) |
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6.2 Canine Hemophilia Models |
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242 | (2) |
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7 Gene Therapy Trials for Hemophilia Past, Present, and Future |
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244 | (1) |
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245 | (1) |
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246 | (5) |
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15 Gene Therapy for Obesity and Diabetes |
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251 | (10) |
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251 | (1) |
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2 Understanding Obesity: Why We Get Fat |
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252 | (1) |
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2.1 Genetic Factors: Human Obesity Gene Map |
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252 | (1) |
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2.2 Environmental Factors: The Big Two and Other Causal Contributors |
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253 | (1) |
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3 General Strategies in Gene Therapy for Obesity |
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253 | (2) |
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255 | (1) |
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5 Gene Targets for Obesity |
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255 | (5) |
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255 | (1) |
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256 | (1) |
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5.3 AMP-Activated Protein Kinase (AMPK) |
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256 | (1) |
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257 | (1) |
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257 | (1) |
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5.6 Obesity Gene Menu a la Carte |
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258 | (1) |
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259 | (1) |
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260 | (1) |
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16 Gene Therapy for Duchenne Muscular Dystrophy |
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261 | (18) |
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261 | (1) |
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1.1 Background of Duchenne Muscular Dystrophy |
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261 | (1) |
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2 Gene-replacement Strategies using Virus Vectors |
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262 | (4) |
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262 | (2) |
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2.2 Modification of the Dystrophin Gene and Promoter |
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264 | (2) |
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2.3 Use of Surrogate Genes |
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266 | (1) |
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3 AAV-Mediated Transduction of Animal Models |
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266 | (4) |
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266 | (1) |
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3.2 Animal Models for the Gene Transduction Study |
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267 | (1) |
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3.3 Immunological Issues of rAAV |
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268 | (1) |
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3.4 Intravascular Vector Administration by Limb Perfusion |
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269 | (1) |
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3.5 Global Muscle Therapies |
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269 | (1) |
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4 Safety and Potential Impact of Clinical Trials |
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270 | (1) |
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5 Development of Alternative Strategies |
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271 | (2) |
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5.1 Design of Read-through Drugs |
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271 | (1) |
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5.2 Modification of mRNA Splicing |
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272 | (1) |
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272 | (1) |
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273 | (1) |
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6.1 Pharmacological Intervention |
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273 | (1) |
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273 | (1) |
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7 Conclusions and Outlook |
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273 | (1) |
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274 | (5) |
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279 | (16) |
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Kirsten A.K. Weigel-Van Aken |
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280 | (1) |
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2 Targeting the Tumor Cell |
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280 | (6) |
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280 | (1) |
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2.2 Non-Oncolytic Viral Vectors |
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281 | (1) |
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281 | (1) |
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282 | (1) |
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282 | (1) |
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283 | (1) |
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283 | (1) |
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284 | (1) |
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285 | (1) |
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2.3.5 Vesicular stomatitis virus |
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285 | (1) |
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3 Targeting the Immune System |
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286 | (3) |
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287 | (1) |
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287 | (1) |
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287 | (1) |
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288 | (1) |
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288 | (1) |
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3.2 Mesenchymal Stem Cells (MSC) as Delivery Vehicles |
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288 | (1) |
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3.3 Adoptive T Cell Transfer |
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288 | (1) |
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4 Targeting the Tumor Microenvironment |
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289 | (1) |
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5 Challenges and Risks of Cancer Gene Therapy |
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289 | (1) |
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290 | (1) |
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290 | (1) |
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6.2 Immune Cells as Carriers for Viruses |
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290 | (1) |
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291 | (1) |
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291 | (4) |
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18 Gene Therapy for Autoimmune Disorders |
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295 | (16) |
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295 | (1) |
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296 | (5) |
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296 | (1) |
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296 | (1) |
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2.3 Target Tissues and Routes of Delivery |
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297 | (1) |
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2.3.1 Local RA Gene Therapy |
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297 | (1) |
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2.3.2 Systemic RA Gene Therapy |
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297 | (1) |
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298 | (1) |
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2.5 Overview of Preclinical Gene Therapy Studies |
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299 | (2) |
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2.6 Overview of Clinical Gene Therapy Studies |
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301 | (1) |
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3 Type I Diabetes Mellitus |
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301 | (6) |
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301 | (1) |
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302 | (1) |
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3.3 Target Tissues and Routes of Delivery |
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303 | (1) |
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303 | (2) |
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3.5 Overview of Preclinical Gene Therapy Studies |
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305 | (1) |
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3.6 Overview of Clinical Gene Therapy Studies |
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306 | (1) |
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4 Conclusions and Outlook |
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307 | (1) |
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308 | (3) |
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19 Gene Therapy for Inherited Metabolic Storage Diseases |
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311 | (16) |
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311 | (1) |
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2 Lysosomal Storage Diseases |
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312 | (2) |
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3 Glycogen Storage Diseases |
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314 | (1) |
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315 | (4) |
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5 Cross-Correction Strategies |
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319 | (2) |
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6 Direct Correction of Target Tissues |
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321 | (3) |
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7 Conclusions and Outlook |
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324 | (1) |
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324 | (3) |
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327 | (18) |
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327 | (3) |
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2 Rod and Cone Photoreceptors |
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330 | (3) |
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333 | (2) |
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335 | (2) |
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5 Retinal Pigment Epithelium |
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337 | (2) |
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6 LCA2 Gene Therapy, a Perspective on Translational Research |
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339 | (3) |
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342 | (3) |
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21 A Brief Guide to Gene Therapy Treatments for Pulmonary Diseases |
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345 | (16) |
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345 | (1) |
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346 | (2) |
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346 | (2) |
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2.2 Alpha-1 Antitrypsin (A1AT) |
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348 | (1) |
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3 Development of Viral Vectors for Lung Disease |
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348 | (2) |
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349 | (1) |
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3.2 Adeno-Associated Viral Vectors |
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349 | (1) |
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349 | (1) |
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350 | (2) |
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4.1 Alternative AAV Viral Vector Serotypes |
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350 | (1) |
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4.1.1 Addition of Expression Enhancing Elements |
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351 | (1) |
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351 | (1) |
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4.3 Physiological Hurdles in the Lung Environment |
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352 | (1) |
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352 | (1) |
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352 | (1) |
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5.2 Compacted DNA Nanoparticles |
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353 | (1) |
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6 Gene Therapy Development for Alpha-1 Anti-trypsin |
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353 | (1) |
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7 Lung Cancer Gene Therapy Development |
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354 | (1) |
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8 Cystic Fibrosis Animal Models |
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355 | (1) |
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9 Cell-Based Therapy for Cystic Fibrosis |
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356 | (1) |
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10 Conclusion and Outlooks |
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357 | (1) |
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358 | (3) |
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22 Cardiovascular Disease |
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361 | (18) |
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361 | (1) |
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362 | (5) |
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2.1 Congenital Heart Disease |
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362 | (3) |
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2.2 Coronary Artery Disease and Ischemia/ Reperfusion Injury |
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365 | (1) |
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365 | (1) |
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366 | (1) |
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2.5 Cardiac Contractility |
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367 | (1) |
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|
|
367 | (1) |
|
|
|
368 | (6) |
|
5 Conclusions and Outlook |
|
|
374 | (1) |
|
|
|
374 | (1) |
|
|
|
374 | (5) |
| Index |
|
379 | |